Awake prone positioning for COVID-19 acute hypoxaemic respiratory failure: a randomised, controlled, multinational, open-label meta-trial

Abstract

Background: Awake prone positioning has been reported to improve oxygenation for patients with COVID-19 in retrospective and observational studies, but whether it improves patient-centred outcomes is unknown. We aimed to evaluate the efficacy of awake prone positioning to prevent intubation or death in patients with severe COVID-19 in a large-scale randomised trial.

Methods: In this prospective, a priori set up and defined, collaborative meta-trial of six randomised controlled open-label superiority trials, adults who required respiratory support with high-flow nasal cannula for acute hypoxaemic respiratory failure due to COVID-19 were randomly assigned to awake prone positioning or standard care. Hospitals from six countries were involved: Canada, France, Ireland, Mexico, USA, Spain. Patients or their care providers were not masked to allocated treatment. The primary composite outcome was treatment failure, defined as the proportion of patients intubated or dying within 28 days of enrolment. The six trials are registered with ClinicalTrials.gov, NCT04325906, NCT04347941, NCT04358939, NCT04395144, NCT04391140, and NCT04477655.

Findings: Between April 2, 2020 and Jan 26, 2021, 1126 patients were enrolled and randomly assigned to awake prone positioning (n=567) or standard care (n=559). 1121 patients (excluding five who withdrew from the study) were included in the intention-to-treat analysis. Treatment failure occurred in 223 (40%) of 564 patients assigned to awake prone positioning and in 257 (46%) of 557 patients assigned to standard care (relative risk 0·86 [95% CI 0·75-0·98]). The hazard ratio (HR) for intubation was 0·75 (0·62-0·91), and the HR for mortality was 0·87 (0·68-1·11) with awake prone positioning compared with standard care within 28 days of enrolment. The incidence of prespecified adverse events was low and similar in both groups.

Interpretation: Awake prone positioning of patients with hypoxaemic respiratory failure due to COVID-19 reduces the incidence of treatment failure and the need for intubation without any signal of harm. These results support routine awake prone positioning of patients with COVID-19 who require support with high-flow nasal cannula.

Funding: Open AI inc, Rice Foundation, Projet Hospitalier de Recherche Clinique Interrégional, Appel d'Offre 2020, Groupement Interrégional de Recherche Clinique et d'Innovation Grand Ouest, Association pour la Promotion à Tours de la Réanimation Médicale, Fond de dotation du CHRU de Tours, Fisher & Paykel Healthcare Ltd.

Conflict of interest statement

Declaration of interests SE discloses consultancies from Aerogen Ltd, research support from Aerogen Ltd, Fisher & Paykel Healthcare Ltd, Hamilton medical, travel reimbursements from Aerogen Ltd and Fisher & Paykel Healthcare Ltd. JL discloses research funding from Fisher & Paykel Healthcare Ltd, Aerogen Ltd, and Rice Foundation, and speaker fees from AARC and Fisher & Paykel Healthcare Ltd. IP discloses a research grant and speaker fees from Fisher & Paykel Healthcare Ltd. YP discloses research support from Fisher & Paykel Healthcare Ltd. OR discloses a research grant from Hamilton Medical and speaker fees from Hamilton Medical, Ambu and Aerogen Ltd, and non-financial research support from Timpel and Masimo Corporation. His institution received fees for consultancy from Hamilton Medical. DV discloses research funding from Teleflex Medical, Inc and Rice Foundation, and speaker fees from Theravance Biopharma. MWT discloses consulting fees from Fisher and Paykel. JRM discloses research support from Fisher & Paykel, and speaker fees from Fisher & Paykel, Gilead, Dextro, and Linet. JGL discloses consulting fees from Baxter Healthcare and Glaxosmithkline. All other authors have no competing interests to disclose.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Screening, enrolment, randomisation, and follow-up of trial participants BMI=body-mass index. *Could have more than one reason. †Other trial specific reasons for exclusion were: initiation of awake prone positioning on treating physicians' orders before inclusion in the trial, physician decision not to include the patient, respiratory support with high-flow nasal cannula for more than 48 h before enrolment, no insurance coverage.

Figure 2

Kaplan-Meier probabilities estimates in the intention-to-treat population over 28 days after enrolment (A) Probability of treatment failure (intubation or death). (B) Probability of intubation. (C) Probability of survival. (D) Probability of successful weaning of high-flow nasal cannula, with death, intubation, and non-invasive ventilation as competing events. The criteria for weaning were protocolised in each individual trial and are described in the appendix 1 p 7.

Figure 3

Physiological effects of awake prone positioning Means are indicated by points, with standard deviation indicated by the shaded area. (A) Ratio of peripheral arterial oxygen saturation to the fraction of inspired oxygen (SpO2:FiO2). (B) Respiratory rate in breaths per minute. (C) The ROX index is equal to SpO2:FiO2 divided by the respiratory rate. Lower values indicate more severe respiratory compromise. Values were recorded 1 h to immediately before the first awake prone positioning session, during the session 30 min to 1 h after the patient was placed into prone position and 30 min to 1 h after the patient had returned into the supine position.

Figure 4

Daily mean duration of prone positioning and outcomes in patients allocated to awake prone positioning Each bar represents the total number of patients having received a mean daily duration of awake prone positioning indicated on the horizontal axis in the population of patients with treatment success (patient was alive and did not require intubation after 28 days) and treatment failure (intubation or death by day 28).