Gavin D Perkins1,2, Chen Ji1, Bronwen A Connolly3,4,5,6, Keith Couper1,2, Ranjit Lall1, J Kenneth Baillie7,8,9, Judy M Bradley3, Paul Dark10,11, Chirag Dave2, Anthony De Soyza12,13, Anna V Dennis2, Anne Devrell1,14, Sara Fairbairn15, Hakim Ghani16, Ellen A Gorman3, Christopher A Green2, Nicholas Hart4,5, Siew Wan Hee17, Zoe Kimbley2, Shyam Madathil2, Nicola McGowan1, Benjamin Messer13, Jay Naisbitt18, Chloe Norman1, Dhruv Parekh2,19, Emma M Parkin18, Jaimin Patel2,19, Scott E Regan1, Clare Ross20, Anthony J Rostron21,22, Mohammad Saim2, Anita K Simonds23, Emma Skilton1, Nigel Stallard17, Michael Steiner24, Rama Vancheeswaran16, Joyce Yeung1,2, Daniel F McAuley3,25. 1. Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry, England. 2. University Hospitals Birmingham NHS Foundation Trust, Birmingham, England. 3. Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, Northern Ireland. 4. Lane Fox Clinical Respiratory Physiology Research Centre, Guy's and St Thomas' NHS Foundation Trust, London, England. 5. Centre for Human and Applied Physiological Sciences, King's College London, London, England. 6. Department of Physiotherapy, University of Melbourne, Melbourne, Australia. 7. Roslin Institute, University of Edinburgh, Midlothian, Scotland. 8. MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland. 9. Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, Scotland. 10. NIHR Manchester Biomedical Research Centre, University of Manchester, Manchester, England. 11. Salford Royal Hospital, Northern Care Alliance NHS Group, Manchester, England. 12. Population and Health Science Institute, NIHR Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, England. 13. Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, England. 14. Research Champion Team, West Midlands Clinical Research Network, Wolverhampton, England. 15. Grange University Hospital, Aneurin Bevan University Health Board, Cwmbran, Wales. 16. Watford General Hospital, West Hertfordshire Hospitals NHS Trust, Watford, England. 17. Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, England. 18. Fairfield General Hospital, Pennine Acute Hospitals NHS Trust, Northern Care Alliance NHS Group, Bury, England. 19. Institute of Inflammation and Ageing, School of Medical and Dental Sciences, University of Birmingham, Birmingham, England. 20. Imperial College Healthcare NHS Trust, London, England. 21. Sunderland Royal Hospital, South Tyneside and Sunderland NHS Foundation Trust, Sunderland, England. 22. Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, England. 23. Royal Brompton and Harefield Hospital, Guy's and St Thomas' NHS Foundation Trust, London, England. 24. Institute for Lung Health, NIHR Leicester Biomedical Research Centre, Department of Respiratory Sciences, University of Leicester, Leicester, England. 25. Royal Victoria Hospital, Belfast, Northern Ireland.
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.
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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