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

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.

Conflict of interest statement

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.

Figures

Figure 1.. Patient Screening, Eligibility, and Enrollment in the RECOVERY-RS Trial

RECOVERY-RS indicates Randomized Evaluation of COVID-19 Therapy–Respiratory Support. aGiven the COVID-19 pandemic circumstances, investigators did not have hospitals track everyone who was approached or considered but not randomized. bFive patients were mistakenly randomized twice (3 to the conventional oxygen therapy group and 2 to the high-flow nasal oxygen group), but did not receive treatment. These patients were excluded from the analyses. cThere were 114 patients randomized to continuous positive airway pressure (CPAP) and 103 patients randomized to conventional oxygen therapy when high-flow nasal oxygen (HFNO) was not available; 109 patients randomized to HFNO and 113 to conventional oxygen therapy when CPAP was not available; and 266 patients randomized to CPAP, 309 to HFNO, and 259 to conventional oxygen therapy when all therapies were available. dTwo patients did not receive adequate treatment information or a crossover treatment (1 withdrew and 1 lost to follow-up). One patient withdrew and did not receive CPAP or a crossover treatment. eThe 2 patients who withdrew did not receive HFNO or a crossover treatment. One patient had insufficient data regarding receipt of HFNO or a crossover treatment (lost to follow-up). fAll 7 patients received treatment. Six patients (including the 4 patients who withdrew) did not receive a crossover treatment. One patient had insufficient data regarding receipt of a crossover treatment. gComparisons excluded patients who did not have an opportunity to be randomized to the alternative intervention based on hospital site availability.

Figure 2.. Unadjusted Subgroup Analyses for Tracheal Intubation or Mortality Within 30 Days in the Continuous Positive Airway Pressure (CPAP) Group vs the Conventional Oxygen Therapy Group

Fio2 indicates fraction of inspired oxygen. aThe P values were calculated using the test for the subgroup × treatment interaction. bComparison is limited to those who might have been randomized based on equipment availability. cCalculated as weight in kilograms divided by height in meters squared. Morbid obesity was defined as a body mass index greater than 35.

Figure 3.. Unadjusted Subgroup Analyses for Tracheal Intubation or Mortality Within 30 Days in the High-Flow Nasal Oxygen (HFNO) Group vs the Conventional Oxygen Therapy Group

Fio2 indicates fraction of inspired oxygen. aThe P values were calculated using the test for the subgroup × treatment interaction. bComparison is limited to those who might have been randomized based on equipment availability. cCalculated as weight in kilograms divided by height in meters squared. Morbid obesity was defined as a body mass index greater than 35.