Concise Critical Appraisal: Awake Prone Positioning For COVID-19 Acute Hypoxemic Respiratory Failure

Early in the COVID-19 pandemic, awake prone positioning in nonintubated patients was thought to be a beneficial intervention for patients with acute hypoxemic respiratory failure, but the theoretical benefit was based on low-quality evidence.¹ Clinicians were willing to try awake prone positioning for patients with COVID-19 because of the concern that invasive mechanical ventilation would become a limited resource and that it came with associated harms. An earlier Concise Critical Appraisal reviewed the observational cohort study by Caputo et al that showed improved oxygenation with awake prone positioning for emergency department patients with respiratory failure due to COVID-19.² There have also been ICU-based studies of similar quality evidence showing benefit.³
 
This Concise Critical Appraisal explores an article by Ehrmann et al, who aimed to evaluate the efficacy of awake prone positioning to prevent intubation or death in patients with severe COVID-19.⁴ This meta-trial investigated COVID-19-induced acute hypoxemic respiratory failure using a new study design that allowed for the combination of six simultaneous national randomized, controlled, open-label trials. Investigators from trials in Canada, France, Ireland, Mexico, the United States, and Spain agreed to combine individual patient data a priori while simultaneously avoiding the logistical obstacles of setting up a multinational trial, thus harnessing the benefits of prospective design and high power. Investigators agreed to report data collaboratively and conduct ongoing interim data analysis and, if necessary, end enrollment in each national trial once equipoise was lost.
 
Before this meta-trial, there had been conflicting lower-quality evidence regarding the benefits of awake prone positioning in nonintubated patients. There also remained a question as to whether it was harmful to delay intubation even if there was transient improvement in oxygenation during awake prone positioning.
 
Enrolled patients were adults with hypoxemic respiratory failure (Pao₂/Fio₂ ≤ 300 mm Hg) due to COVID-19 pneumonia requiring high-flow nasal cannula. In total, 1126 patients were randomized after exclusion criteria (e.g., hemodynamic instability, pregnancy). A total of 564 patients were assigned to the awake prone positioning group and 559 were assigned to standard care. The two groups were well-balanced with regard to age, sex, BMI, clinical parameters, location, and comorbidities. Patients in the awake prone positioning group were encouraged to lie in the prone position “for as long and as frequently as possible each day.” Prone positioning in the standard care group was considered a protocol violation.
 
Investigators from each nation agreed to harmonize criteria for intubation: worsening respiratory failure (respiratory rate > 40 breaths/min, respiratory muscle fatigue, respiratory acidosis with pH < 7.25, copious tracheal secretions, severe hypoxemia with Spo₂ < 90% despite Fio₂ ≥ 0.8), hemodynamic instability, or deteriorating mental status. Outcomes were also consistent among the various national trials with the primary outcome defined as treatment failure at 28 days (intubation or death). Secondary outcomes included intubation and death separately, as well as important safety-related events.
 
Results showed that awake prone positioning reduced the incidence of treatment failure within 28 days of enrollment, from 46% to 40%. The primary composite outcome was intubation or death. The benefit was seen primarily in prevention of intubation. For every 14 patients who underwent awake prone positioning, one intubation was prevented. It is important to note that mortality alone was not significantly different, although there was a slight trend toward increased deaths in the control group (21% vs. 24%). Notably, there was no detected interaction between initial oxygenation requirements and effect on primary outcome, although the study was not meant to evaluate this correlation.
 
Interestingly, patients who had longer mean daily duration of awake prone positioning were more likely to have treatment success demonstrating a dose-response relationship. Those who were proned for a mean of more than 8 hours a day had a failure rate of only 17% compared to 48% failure rate in patients who were proned for less than 8 hours a day. A high duration of prone positioning was instituted primarily in the Mexico trial and is hypothesis generating at this point. The authors suspected commitment to longer prone positioning sessions may have more benefit than these data show but note that further studies are needed to see this effect.
 
Physiologic effects were noted too, with oxygenation improvements noted during initial prone positioning sessions for the intervention group. There was also a reduction in respiratory rate. The authors suggest that, as has been previously theorized, the benefit comes from reduced alveolar shunt and self-inflicted lung injury as well as improved recruitment, but more studies are needed to confirm this.
 
The intervention is safe, with similar rates of skin breakdown, vomiting, and line dislodgment. Cardiac arrests did not occur during awake prone positioning and, since mortality was similar in this study, there are no data to suggest harm with the intervention.
 
Appropriate limitations were noted by the authors. There was no way to blind clinicians to this intervention, which could have had an unseen effect on clinical decision-making. The authors acknowledge the possibility that, despite clear intubation criteria, treating clinicians may have had a lower threshold for intubation in the standard care group. The authors also note that a protocol violation occurred in 10% of the standard care group, who underwent at least one session of awake prone positioning. This would only underestimate the benefit of the intervention in the intention-to-treat analysis.
 
Ehrmann et al appear to show clear evidence that awake prone positioning has patient-centered benefit. Awake prone positioning is beneficial in preventing intubation in adult patients with hypoxemic respiratory failure from COVID-19 pneumonia requiring high-flow nasal cannula. While patients must be able to cooperate with this intervention, this study confirms that adverse effects are low and it does not increase mortality in patients who ultimately require intubation.

References

1. Scaravilli V, Grasselli G, Castagna L, et al. Prone positioning improves oxygenation in spontaneously breathing nonintubated patients with hypoxemic acute respiratory failure: a retrospective study. J Crit Care. 2015 Dec;30(6):1390-1394. https://pubmed.ncbi.nlm.nih.gov/26271685/
2. Caputo ND, Strayer RJ, Levitan R. Early self-proning in awake, non-intubated patients in the emergency department: a Single ED’s experience during the COVID-19 pandemic. Acad Emerg Med. 2020 May;27(5):375-378. https://pubmed.ncbi.nlm.nih.gov/32320506/
3. Prud’homme E, Trigui Y, Elharrar X, et al. Effect of prone positioning on the respiratory support of nonintubated patients with COVID-19 and acute hypoxemic respiratory failure: a retrospective matching cohort study. Chest. 2021 Jul;160(1):85-88. https://pubmed.ncbi.nlm.nih.gov/33516704/
4. Ehrmann S, Li J, Ibarra-Estrada M, et al; Awake Prone Positioning Meta-Trial Group. Awake prone positioning for COVID-19 acute hypoxaemic respiratory failure: a randomised, controlled, multinational, open-label meta-trial. Lancet Respir Med. 2021 Aug 20;S2213-2600(21)00356-8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378833/#