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Effect of Noninvasive Respiratory Strategies on Intubation or Mortality Among Patients With Acute Hypoxemic Respiratory Failure and COVID-19The RECOVERY-RS Randomized Clinical Trial

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Key Points

Question  What is the effect of initial noninvasive respiratory strategies using continuous positive airway pressure (CPAP) or high-flow nasal oxygen (HFNO), compared with an initial strategy of conventional oxygen therapy, on the risk of tracheal intubation or mortality among hospitalized adults with acute hypoxemic respiratory failure due to COVID-19?

Findings  In this randomized clinical trial of 1273 patients, the composite primary outcome of tracheal intubation or mortality within 30 days occurred in 36% of the patients in the CPAP group compared with 44% in the conventional oxygen therapy group, a difference that was statistically significant, and occurred in 44% in the HFNO group compared with 45% in the conventional oxygen therapy group, a difference that was not significantly different.

Meaning  Among patients with acute hypoxemic respiratory failure and COVID-19, an initial strategy of CPAP significantly reduced the risk of tracheal intubation or mortality compared with conventional oxygen therapy, but there was no significant difference between an initial strategy of HFNO compared with conventional oxygen therapy.

Abstract

Importance  Continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO) have been recommended for acute hypoxemic respiratory failure in patients with COVID-19. Uncertainty exists regarding the effectiveness and safety of these noninvasive respiratory strategies.

Objective  To determine whether either CPAP or HFNO, compared with conventional oxygen therapy, improves clinical outcomes in hospitalized patients with COVID-19–related acute hypoxemic respiratory failure.

Design, Setting, and Participants  A parallel group, adaptive, randomized clinical trial of 1273 hospitalized adults with COVID-19–related acute hypoxemic respiratory failure. The trial was conducted between April 6, 2020, and May 3, 2021, across 48 acute care hospitals in the UK and Jersey. Final follow-up occurred on June 20, 2021.

Interventions  Adult patients were randomized to receive CPAP (n = 380), HFNO (n = 418), or conventional oxygen therapy (n = 475).

Main Outcomes and Measures  The primary outcome was a composite of tracheal intubation or mortality within 30 days.

Results  The trial was stopped prematurely due to declining COVID-19 case numbers in the UK and the end of the funded recruitment period. Of the 1273 randomized patients (mean age, 57.4 [95% CI, 56.7 to 58.1] years; 66% male; 65% White race), primary outcome data were available for 1260. Crossover between interventions occurred in 17.1% of participants (15.3% in the CPAP group, 11.5% in the HFNO group, and 23.6% in the conventional oxygen therapy group). The requirement for tracheal intubation or mortality within 30 days was significantly lower with CPAP (36.3%; 137 of 377 participants) vs conventional oxygen therapy (44.4%; 158 of 356 participants) (absolute difference, −8% [95% CI, −15% to −1%], P = .03), but was not significantly different with HFNO (44.3%; 184 of 415 participants) vs conventional oxygen therapy (45.1%; 166 of 368 participants) (absolute difference, −1% [95% CI, −8% to 6%], P = .83). Adverse events occurred in 34.2% (130/380) of participants in the CPAP group, 20.6% (86/418) in the HFNO group, and 13.9% (66/475) in the conventional oxygen therapy group.

Conclusions and Relevance  Among patients with acute hypoxemic respiratory failure due to COVID-19, an initial strategy of CPAP significantly reduced the risk of tracheal intubation or mortality compared with conventional oxygen therapy, but there was no significant difference between an initial strategy of HFNO compared with conventional oxygen therapy. The study may have been underpowered for the comparison of HFNO vs conventional oxygen therapy, and early study termination and crossover among the groups should be considered when interpreting the findings.

Trial Registration  isrctn.org Identifier: ISRCTN16912075

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Corresponding Author: Daniel F. McAuley, MD, Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, 97 Lisburn Rd, Belfast BT9 7BL, Northern Ireland (d.f.mcauley@qub.ac.uk).

Accepted for Publication: January 4, 2022.

Published Online: January 24, 2022. doi:10.1001/jama.2022.0028

Author Contributions: Drs Ji and Lall had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Perkins, Connolly, Couper, Baillie, Bradley, Dark, De Soyza, Gorman, Hart, Regan, Simonds, Stallard, Yeung, McAuley.

Acquisition, analysis, or interpretation of data: Perkins, Ji, Connolly, Couper, Lall, Bradley, Dark, Dave, De Soyza, Dennis, Devrell, Fairbairn, Ghani, Green, Hart, Hee, Kimbley, Madathil, McGowan, Messer, Naisbitt, Norman, Parekh, Parkin, Patel, Regan, Ross, Rostron, Saim, Skilton, Stallard, Steiner, Vancheeswaran, Yeung, McAuley.

Drafting of the manuscript: Perkins, Connolly, Couper, Lall, De Soyza, Devrell, Hart, Naisbitt, Parekh, Parkin, Patel, Regan, Stallard, Steiner, McAuley.

Critical revision of the manuscript for important intellectual content: Perkins, Ji, Connolly, Couper, Baillie, Bradley, Dark, Dave, De Soyza, Dennis, Fairbairn, Ghani, Gorman, Green, Hart, Hee, Kimbley, Madathil, McGowan, Messer, Norman, Parekh, Patel, Ross, Rostron, Saim, Simonds, Skilton, Stallard, Steiner, Vancheeswaran, Yeung, McAuley.

Statistical analysis: Ji, Lall, Hee, Stallard.

Obtained funding: Perkins, Dark, De Soyza, Stallard, McAuley.

Administrative, technical, or material support: Perkins, Connolly, Couper, Bradley, Dark, Dave, De Soyza, Devrell, Ghani, Gorman, Green, Hart, McGowan, Norman, Regan, Ross, Rostron, Simonds, Skilton, Steiner, McAuley.

Supervision: Perkins, Connolly, Baillie, Dark, Dave, De Soyza, Ghani, Green, Regan, Rostron, Saim, Steiner, Vancheeswaran, McAuley.

Conflict of Interest Disclosures: Dr Perkins reported being supported by the National Institute for Health Research (NIHR) West Midlands Applied Research Collaboration and serving as co-director of research for the Intensive Care Society until recently (term ended in June 2021). Dr Connolly reported receiving grants from the NIHR; receiving personal fees from Fisher & Paykel Healthcare; and serving as the director of research for the Intensive Care Society. Dr Baillie reported receiving grants from the Wellcome Trust, the Biotechnology and Biological Sciences Research Council, and the Medical Research Council. Dr Dark reported receiving grants from the Manchester NIHR Biomedical Research Centre and being a national specialty cluster lead for the NIHR. Dr Dave reported receiving personal fees from Chiesi. Dr De Soyza reported being a national specialty cluster lead for the NIHR and receiving personal fees from AstraZeneca, Bayer, Chiesi, Gilead, GlaxoSmithKline, Forest Labs, Novartis, Insmed, Teva, Zambon, and Pfizer. Mrs Devrell reported receiving personal fees from the NIHR. Dr Gorman reported receiving grants from the NIHR and Wellcome Trust. Dr Hart reported receiving a UK Research and Innovation grant from the Medical Research Council; receiving unrestricted grants and equipment from Philips-Respironics, Fisher & Paykel Healthcare, and ResMed; receiving institutional funding for his role on the Philips Global medical advisory board; receiving personal fees from Philips-Respironics, Philips, ResMed, and Fisher & Paykel Healthcare; and receiving financial support from Philips for the development of the Myotrace technology that has a patent approved in Europe and in the US. Dr Hee reported receiving grants from the British Heart Foundation and the NIHR West Midlands Research Design Service. Mr Messer reported receiving personal fees from Fisher & Paykel Healthcare. Dr Parekh reported receiving a UK Research and Innovation grant from the Medical Research Council and receiving grants from the NIHR. Dr Steiner reported receiving personal fees from GlaxoSmithKline. Dr McAuley reported receiving personal fees from GlaxoSmithKline, Boehringer Ingelheim, Bayer, Novartis, Sobi, Eli Lilly, Vir Biotechnology, and Faron Pharmaceuticals; receiving grants from the NIHR, Randox, Wellcome Trust, Innovate UK, the Medical Research Council, and the Northern Ireland Health and Social Research and Development Division; holding a patent for an anti-inflammatory treatment issued to Queen’s University Belfast; and serving as co-director of research for the Intensive Care Society until recently (term ended in June 2021) and as program director for the NIHR Efficacy and Mechanism Evaluation program. No other disclosures were reported.

Funding/Support: This study was funded by grant COVID-19-RSC from the National Institute for Health Research.

Role of the Funder/Sponsor: The National Institute for Health Research approved the design of the study and monitored the conduct of the study. They played no role in the collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The RECOVERY-RS Collaborators appear in Supplement 3.

Disclaimer: The views expressed are those of the authors and do not necessarily represent those of the National Institute for Health Research or the Department of Health and Social Care.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We are grateful to all the patients and families who supported the trial, together with the physicians, nurses, and allied health professionals across all participating hospitals who supported both trial recruitment and delivery of trial interventions in extremely challenging conditions. We thank the National Institute for Health Research Clinical Research Network and the Northern Ireland Clinical Research Network. We also thank Health Data Research UK, the Office for National Statistics, and the Intensive Care National Audit and Research Centre for support with the data linkage. In addition, we are indebted to the following members of both the trial steering and data and safety monitoring committees: Kathy Rowan, PhD (Intensive Care National Audit and Research Centre, London, England), Duncan Young, DM (Oxford University, Oxford, England), Marion Campbell, PhD (University of Aberdeen, Aberdeen, Scotland), Susie Hennings, MSc (Keele University, Keele, England), John Laffey, MD (National University of Ireland, Galway), Martin Landray, PhD (Oxford University, Oxford, England), Gillian McCarmack (patient and public representative), Gary Overton (patient and public representative), Marion Thompson, PhD (patient and public representative), B. Taylor Thompson, MD (Massachusetts General Hospital and Harvard Medical School, Boston), and Timothy Walsh, MD (University of Edinburgh, Edinburgh, Scotland). Mr Overton and Dr Marion Thompson received personal fees for their contribution to the study as patient and public representatives. All others listed did not receive compensation.

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