¹Department of Medicine, McMaster University, Hamilton, Ontario, Canada
²Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
³Department of Critical Care, College of Medicine, King Saud University, Riyadh, Saudi Arabia
⁴Research Institute of St Joseph’s Healthcare Hamilton, Hamilton, Ontario, Canada
⁵Department of Critical Care Medicine, Alberta Health Services and University of Calgary, Calgary, Canada
⁶Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada
⁷O’Brien Institute for Public Health, Calgary, Alberta, Canada
⁸Division of Respirology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
⁹Division of Pulmonary Medicine, Department of Medicine, University of Alberta, Edmonton, Canada
¹⁰Critical Care Medicine Department, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
¹¹College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
¹²Department of Emergency and Critical Care, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
¹³Department of Anesthesia, Critical Care Medicine, and Pain Medicine, Al Amiri Hospital, Kuwait City, Kuwait
¹⁴Department of Anesthesia, Critical Care Medicine, and Pain Medicine, Jaber Al-Ahmad Al-Sabah Hospital, Kuwait City, Kuwait
¹⁵Department of Internal Medicine, Divisions of Critical Care, Pulmonary, and Sleep Medicine, University of Texas Health-McGovern Medical School, Houston
¹⁶Interdepartmental Division of Critical Care, University of Toronto, Toronto, Ontario, Canada
¹⁷University Health Network, Toronto, Ontario, Canada
¹⁸Department of Intensive Care, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
¹⁹King Abdullah International Medical Research Center, King Abdulaziz Medical City, Jeddah, Saudi Arabia
²⁰Intensive Care Department, Ministry of National Guard Health Affairs, Al Ahsa, Saudi Arabia
²¹King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Al Ahsa, Saudi Arabia
²²Division of Critical Care, Niagara Health, St Catharines, Ontario, Canada
²³Department of Medicine, Université Laval, Québec City, Québec, Canada
²⁴Department of Anesthesiology and Critical Care, Division of Critical Care, Université Laval, Québec City, Québec, Canada
²⁵Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada
²⁶College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
²⁷King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
²⁸Intensive Care Department, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
²⁹Department of Community Health Sciences and O’Brien Institute for Public Health, University of Calgary, Calgary, Alberta, Canada
³⁰Department of Psychiatry and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
³¹Department of Intensive Care, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
³²Population Health Research Institute, Hamilton, Ontario, Canada
³³Department of Emergency Medicine, American University of Beirut, Beirut, Lebanon

COVI-PRONE Trial Investigators and the Saudi Critical Care Trials Groupfor the

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Key Points

Question Does prone positioning reduce endotracheal intubation in adults who were awake and not intubated and who had hypoxemic respiratory failure from COVID-19?

Findings In this randomized clinical trial that included 400 adults with acute hypoxemic respiratory failure from COVID-19, awake prone positioning compared with usual care resulted in endotracheal intubation at 30 days in 34.1% vs 40.5% of participants, respectively. Although the hazard ratio was 0.81, the result was not statistically significant.

Meaning Although the findings do not support prone positioning in this setting, the effect size for the primary study outcome was imprecise and does not exclude a clinically important benefit.

Abstract

Importance The efficacy and safety of prone positioning is unclear in nonintubated patients with acute hypoxemia and COVID-19.

Objective To evaluate the efficacy and adverse events of prone positioning in nonintubated adult patients with acute hypoxemia and COVID-19.

Design, Setting, and Participants Pragmatic, unblinded randomized clinical trial conducted at 21 hospitals in Canada, Kuwait, Saudi Arabia, and the US. Eligible adult patients with COVID-19 were not intubated and required oxygen (≥40%) or noninvasive ventilation. A total of 400 patients were enrolled between May 19, 2020, and May 18, 2021, and final follow-up was completed in July 2021.

Intervention Patients were randomized to awake prone positioning (n = 205) or usual care without prone positioning (control; n = 195).

Main Outcomes and Measures The primary outcome was endotracheal intubation within 30 days of randomization. The secondary outcomes included mortality at 60 days, days free from invasive mechanical ventilation or noninvasive ventilation at 30 days, days free from the intensive care unit or hospital at 60 days, adverse events, and serious adverse events.

Results Among the 400 patients who were randomized (mean age, 57.6 years [SD, 12.83 years]; 117 [29.3%] were women), all (100%) completed the trial. In the first 4 days after randomization, the median duration of prone positioning was 4.8 h/d (IQR, 1.8 to 8.0 h/d) in the awake prone positioning group vs 0 h/d (IQR, 0 to 0 h/d) in the control group. By day 30, 70 of 205 patients (34.1%) in the prone positioning group were intubated vs 79 of 195 patients (40.5%) in the control group (hazard ratio, 0.81 [95% CI, 0.59 to 1.12], P = .20; absolute difference, −6.37% [95% CI, −15.83% to 3.10%]). Prone positioning did not significantly reduce mortality at 60 days (hazard ratio, 0.93 [95% CI, 0.62 to 1.40], P = .54; absolute difference, −1.15% [95% CI, −9.40% to 7.10%]) and had no significant effect on days free from invasive mechanical ventilation or noninvasive ventilation at 30 days or on days free from the intensive care unit or hospital at 60 days. There were no serious adverse events in either group. In the awake prone positioning group, 21 patients (10%) experienced adverse events and the most frequently reported were musculoskeletal pain or discomfort from prone positioning (13 of 205 patients [6.34%]) and desaturation (2 of 205 patients [0.98%]). There were no reported adverse events in the control group.

Conclusions and Relevance In patients with acute hypoxemic respiratory failure from COVID-19, prone positioning, compared with usual care without prone positioning, did not significantly reduce endotracheal intubation at 30 days. However, the effect size for the primary study outcome was imprecise and does not exclude a clinically important benefit.

Trial Registration ClinicalTrials.gov Identifier: NCT04350723

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Article Information

Corresponding Author: Waleed Alhazzani, MD, MSc, Department of Medicine and Department of Health Research Methods, Evidence, and Impact, McMaster University, 1200 Main St W, Hamilton, ON L8N 3Z5, Canada (waleed.al-hazzani@medportal.ca).

Accepted for Publication: April 26, 2022.

Published Online: May 15, 2022. doi:10.1001/jama.2022.7993

Author Contributions: Drs Alhazzani and Arabi 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: Parhar, Weatherald, Al Duhailib, Fan, Lauzier, Rochwerg, Culgin, Nelson, Fiest, Stelfox, Solverson, Niven, Møller, Belley-Cote, Thabane, Cook, Arabi.

Acquisition, analysis, or interpretation of data: Alhazzani, Parhar, Weatherald, Al Duhailib, Alshahrani, Al-Fares, Buabbas, Cherian, Munshi, Fan, Al Hameed, Chalabi, Rahmatullah, Duan, Tsang, Lewis, Lauzier, Centofanti, Culgin, Nelson, Abdukahil, Fiest, Stelfox, Tlayjeh, Meade, Perri, Solverson, Lim, Møller, Belley-Cote, Thabane, Tamim, Cook.

Drafting of the manuscript: Alhazzani, Parhar, Weatherald, Al Duhailib, Chalabi, Lewis, Centofanti, Culgin, Nelson, Møller, Tamim, Arabi.

Critical revision of the manuscript for important intellectual content: Alhazzani, Parhar, Weatherald, Al Duhailib, Alshahrani, Al-Fares, Buabbas, Cherian, Munshi, Fan, Al Hameed, Rahmatullah, Duan, Tsang, Lewis, Lauzier, Centofanti, Rochwerg, Culgin, Nelson, Abdukahil, Fiest, Stelfox, Tlayjeh, Meade, Perri, Solverson, Niven, Lim, Møller, Belley-Cote, Thabane, Cook, Arabi.

Statistical analysis: Alhazzani, Al Duhailib, Møller, Thabane, Tamim, Arabi.

Obtained funding: Alhazzani, Parhar, Weatherald, Al Duhailib, Duan, Lauzier, Culgin, Fiest, Stelfox, Meade, Perri, Solverson, Niven, Belley-Cote, Cook, Arabi.

Administrative, technical, or material support: Alhazzani, Parhar, Weatherald, Alshahrani, Al-Fares, Buabbas, Cherian, Munshi, Rahmatullah, Duan, Tsang, Centofanti, Rochwerg, Culgin, Nelson, Abdukahil, Fiest, Tlayjeh, Perri, Solverson, Belley-Cote, Cook, Arabi.

Supervision: Alhazzani, Parhar, Weatherald, Alshahrani, Al-Fares, Al Hameed, Duan, Culgin, Nelson, Møller, Thabane, Cook, Arabi.

Conflict of Interest Disclosures: Dr Parhar reported receiving Rapid COVID-19 grants from the Cumming School of Medicine at the University of Calgary and Alberta Innovates. Dr Weatherald reported receiving Rapid COVID-19 grants from the Cumming School of Medicine at the University of Calgary; receiving grants, personal fees, and nonfinancial support from Janssen, Actelion, and Bayer; and receiving personal fees from Acceleron and Merck. Dr Alshahrani reported receiving grants from King Abdullah International Medical Research Center. Dr Fan reported receiving personal fees from ALung Technologies, Baxter, Aerogen, Inspira, GE Healthcare, and Vasomune. Dr Belley-Cote reported receiving grants from Bayer, Bristol Myers Squibb-Pfizer Alliance, and Roche Diagnostics. No other disclosures were reported.

Funding/Support: The trial was supported by peer-review grants from the Canadian Institute of Health Research and King Abdullah International Medical Research Center in Saudi Arabia and a McMaster University COVID-19 research grant.

Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; 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 COVI-PRONE Trial Investigators and the Saudi Critical Care Trials Group members are listed in Supplement 4.

Meeting Presentation: This was presented at the American Thoracic Society International Conference; May 15, 2022; San Francisco, California.

Additional Contributions: We thank the patients and families participating in this trial. We also thank the collaborating research coordinators and investigators and the bedside clinicians who supported this work. We specifically thank Kelly Hassall, RRT (St Joseph’s Healthcare Hamilton; did not receive financial compensation), and France Clarke, RRT (McMaster University; did not receive financial compensation), who were instrumental in championing the trial with their respiratory therapy colleagues and respective societies, Joshua Piticaru, MD (McMaster University; did not receive financial compensation), for producing prone positioning educational material, and Tom Piraino, RRT (University of Toronto; did not receive financial compensation), for his contributions to the trial design. We thank Melanie Columbus, PhD (University of Calgary; received financial compensation), Olesya Dmitrieva, BHSc (University of Calgary; received financial compensation), and Cassidy Codan, BSc (University of Calgary; received financial compensation), for serving as research coordinators. We also thank Kelly Nelson, RN (St Joseph’s Healthcare Hamilton; received financial compensation), for her role in the methods center with data cleaning and Will Cullimore (St Joseph’s Healthcare Hamilton; received financial compensation) for creating the trial’s website and social media platforms. We are grateful to the Canadian Society of Respiratory Therapists, the Canadian Critical Care Society, and the Alberta Health Services Critical Care Strategic Clinical Network for endorsing and supporting the trial grant application.

Additional Information: Dr Alhazzani holds a McMaster University Department of Medicine Mid-Career Research Award. Dr Cook holds a Canada Research Chair.

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Effect of Awake Prone Positioning on Endotracheal Intubation in Patients With COVID-19 and Acute Respiratory FailureA Randomized Clinical Trial

American Thoracic Society 2022 Conference Highlights

Effect of Awake Prone Positioning on Patients With COVID-19 and Acute Respiratory Failure—Reply

Effect of Awake Prone Positioning on Patients With COVID-19 and Acute Respiratory Failure

Effect of Awake Prone Positioning on Patients With COVID-19 and Acute Respiratory Failure

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AMA CME Accreditation Information

Effect of Awake Prone Positioning on Endotracheal Intubation in Patients With COVID-19 and Acute Respiratory FailureA Randomized Clinical Trial

American Thoracic Society 2022 Conference Highlights

Effect of Awake Prone Positioning on Patients With COVID-19 and Acute Respiratory Failure—Reply

Effect of Awake Prone Positioning on Patients With COVID-19 and Acute Respiratory Failure

Effect of Awake Prone Positioning on Patients With COVID-19 and Acute Respiratory Failure

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