Effect of Protocolized Weaning With Early Extubation to Noninvasive Ventilation vs Invasive Weaning on Time to Liberation From Mechanical Ventilation Among Patients With Respiratory Failure: The Breathe Randomized Clinical Trial

Abstract

Importance: In adults in whom weaning from invasive mechanical ventilation is difficult, noninvasive ventilation may facilitate early liberation, but there is uncertainty about its effectiveness in a general intensive care patient population.

Objective: To investigate among patients with difficulty weaning the effects of protocolized weaning with early extubation to noninvasive ventilation on time to liberation from ventilation compared with protocolized invasive weaning.

Design, setting, and participants: Randomized, allocation-concealed, open-label, multicenter clinical trial enrolling patients between March 2013 and October 2016 from 41 intensive care units in the UK National Health Service. Follow-up continued until April 2017. Adults who received invasive mechanical ventilation for more than 48 hours and in whom a spontaneous breathing trial failed were enrolled.

Interventions: Patients were randomized to receive either protocolized weaning via early extubation to noninvasive ventilation (n = 182) or protocolized standard weaning (continued invasive ventilation until successful spontaneous breathing trial, followed by extubation) (n = 182).

Main outcomes and measures: Primary outcome was time from randomization to successful liberation from all forms of mechanical ventilation among survivors, measured in days, with the minimal clinically important difference defined as 1 day. Secondary outcomes were duration of invasive and total ventilation (days), reintubation or tracheostomy rates, and survival.

Results: Among 364 randomized patients (mean age, 63.1 [SD, 14.8] years; 50.5% male), 319 were evaluable for the primary effectiveness outcome (41 died before liberation, 2 withdrew, and 2 were discharged with ongoing ventilation). The median time to liberation was 4.3 days in the noninvasive group vs 4.5 days in the invasive group (adjusted hazard ratio, 1.1; 95% CI, 0.89-1.40). Competing risk analysis accounting for deaths had a similar result (adjusted hazard ratio, 1.1; 95% CI, 0.86-1.34). The noninvasive group received less invasive ventilation (median, 1 day vs 4 days; incidence rate ratio, 0.6; 95% CI, 0.47-0.87) and fewer total ventilator days (median, 3 days vs 4 days; incidence rate ratio, 0.8; 95% CI, 0.62-1.0). There was no significant difference in reintubation, tracheostomy rates, or survival. Adverse events occurred in 45 patients (24.7%) in the noninvasive group compared with 47 (25.8%) in the invasive group.

Conclusions and relevance: Among patients requiring mechanical ventilation in whom a spontaneous breathing trial had failed, early extubation to noninvasive ventilation did not shorten time to liberation from any ventilation.

Trial registration: ISRCTN Identifier: ISRCTN15635197.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr McAuley reports receipt of personal fees from GlaxoSmithKline, SOBI, Peptinnovate, Boehringer Ingelheim, and Bayer; his institution has received funds from grants from the UK National Institute for Health Research (NIHR), Wellcome Trust, and others and from GlaxoSmithKline for Dr McAuley undertaking bronchoscopy as part of a clinical trial. In addition, Dr McAuley is 1 of 4 named inventors on patent US8962032 covering the use of sialic acid–bearing nanoparticles as anti-inflammatory agents issued to his institution, the Queen’s University of Belfast. Dr Varley reports receipt of nonfinancial support from La Jolla Pharmaceuticals and personal fees from EMAS Pharma. Dr Hart reports receipt of unrestricted research grants from Guy’s & St Thomas’ Charity and lecture fees from Fisher-Paykel, Philips, and Resmed. Dr Hart has a Myotrace patent pending and is on the Pulmonary Research Advisory Board for Philips; Philips-Respironics and Philips Research are contributing to the development of the Myotrace technology. Dr Hart’s Lane Fox Clinical Respiratory Physiology Research Group has received unrestricted grants (managed by Guy’s & St Thomas’ Foundation Trust) from Philips-Respironics, Philips, Resmed, Fisher-Paykel, and B&D Electromedical. No other disclosures were reported.

Figures

Figure 1.. Participant Flow Through a Randomized Clinical Trial of Protocolized Early Extubation to Noninvasive Weaning vs Protocolized Invasive Weaning Among Patients With Respiratory Failure

aThirty-four patients in the invasive ventilation group died during their inpatient stay. Three were withdrawn from the study during their inpatient stay (1 refused participation after being retrospectively approached for consent; 2 withdrew for personal reasons). bThirty-three patients in the noninvasive ventilation group died during their inpatient stay. Three were withdrawn from the study during their inpatient stay for personal reasons. cOne hundred sixty participants achieved liberation from ventilation. Twenty-two participants were censored (19 died, 2 were withdrawn from follow-up, and 1 was discharged without achieving liberation from ventilation and lost to follow-up). dOne hundred fifty-nine participants achieved liberation from ventilation. Twenty-three participants were censored (22 died and 1 was discharged without achieving liberation from ventilation and lost to follow-up).

Figure 2.. Time to Liberation From Mechanical Ventilation by Treatment Group

Hash marks indicate each censoring time. Median time to liberation from ventilation was 4.5 days (95% CI, 3.46-7.25 days) in the invasive group and 4.3 days (95% CI, 2.63-5.58 days) in the noninvasive group.

Figure 3.. Cumulative Incidence of Liberation From Ventilation or Death by Treatment Group