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

Our take —

Although awake prone positioning has gained favor in clinical practice for treatment of COVID-19 patients requiring high-flow oxygen supplementation, no clinical trials to date had assessed its efficacy. This large meta-trial of 1,121 patients (including six individual randomized trials from Canada, France, Ireland, Mexico, Spain, and the USA) evaluated the efficacy of awake prone positioning, in addition to standard high-flow nasal cannula, for preventing intubation or death among COVID-19 patients with acute hypoxemic respiratory failure. Patients in the intervention arm were 14% less likely to have treatment failure (intubation or death by 28 days after enrollment) and more likely to be weaned off high-flow nasal cannula compared to the standard of care. On the other hand, among those who survived, the two groups spent a similar amount of time in the hospital (16.4 vs. 16.5 days in intervention vs. control groups, respectively) and, among those intubated, on invasive mechanical ventilation (12.4 vs. 12.4 days). Despite some possible sources of bias, this study provides strong evidence of the benefits for awake prone positioning among patients with severe COVID-19 pneumonia in six upper-middle and high-income settings.

Study design

Randomized Controlled Trial

Study population and setting

This collaborative, prospective meta-trial combined individual-level data from six randomized clinical trials in hospitals from six countries (Ireland, USA, Mexico, Spain, Canada and France) to evaluate the efficacy of awake prone positioning for COVID-19 patients between April 2, 2020 and January 26, 2021. The study included patients with acute hypoxemic respiratory failure (requiring respiratory support with high-flow nasal cannula and with a ratio of peripheral arterial oxygen saturation to the fraction of expired oxygen (SpO2: FiO2) of 315 or lower) due to clinically confirmed or suspected COVID-19 pneumonia. The study excluded those with body mass index above 40 kg/m2, pregnant women, hemodynamically unstable patients, those unable to provide consent, and those with a contraindication to awake prone positioning. The primary outcome was treatment failure, defined as intubation or death. Secondary outcomes included intubation, death, use of noninvasive mechanical ventilation, time to weaning off high-flow nasal cannula, time to treatment failure, time to intubation, and time to death. The relative risk for the primary outcome was estimated with a mixed effect log-binomial model. Proportional hazards models were used to estimate differences in times to events. For intubation, mortality was considered as a competing risk. Analyses were pre-specified, including a subgroup analysis among patients who had SpO2/FiO2 less than 190.

Summary of Main Findings

Among the 1,126 patients in the study, 564 were randomized to the awake prone positioning arm and 557 to the standard of care arm. The median duration of awake prone positioning was 5 hours. In intention-to-treat analysis, 40% of the patients assigned to the intervention arm had been intubated or died by day 28 of enrollment compared to 46% in the standard of care arm (RR=0.86, 95% CI: 0.75 to 0.98). The estimated number of patients who need to be treated with awake prone positioning to prevent one intubation or death was 15 (95%CI: 8 to 156).  Regarding secondary outcomes, patients in the intervention arm were less likely to be intubated (33% vs. 40%) and were more likely to be weaned off high-flow nasal cannula. There were no differences in 28-day mortality, time to death, length of hospital stay, or time for weaning off mechanical ventilation. In the intervention arm, those who were able to maintain prone positioning daily for at least 8 hours were less likely to be intubated or die compared to those who had less than 8 hours of daily prone position (17% vs. 48%).  There was no difference in the incidence of central or arterial line dislodgement between the two groups, and none of the patients had cardiac arrest due to prone positioning.

Study Strengths

This was a large meta-trial including six randomized clinical trials, with a large sample size, coordination across study protocols, and pre-specified analytical plans. The study included trials from six different countries with wide variation in their health care systems, allowing greater confidence in the generalizability of the findings.

Limitations

There was significant variability in the median duration of awake prone positioning across trials, with a total median duration of only 5 hours. It is possible that longer durations could have led to better outcomes. Also, one in ten patients in the control group were treated with awake prone positioning. This, combined with the intention-to-treat analysis, could have resulted in underestimating the true effect of prone positioning in preventing intubation or death. Also, no stratification for the duration of prone positioning was done at study enrollment, which limits the interpretation of lower rates of intubation and death among patients who had eight hours or more of awake prone positioning. The trial could not be blinded, and treatment assignment may have affected clinical decision-making. For example, mechanical ventilation may have been delayed in the intervention arm due to temporary improvement of respiratory parameters during prone positioning. Finally, despite coordination, there were variations across trials in inclusion criteria that may have had unpredictable effects on results.

Value added

This is the first prospective randomized study to evaluate the efficacy of awake prone positioning for COVID-19 patients requiring high flow oxygen supplementation.

This review was posted on: 25 September 2021