COVID-19 patients can develop hypoxaemic respiratory failure, potentially necessitating hospitalisation for supplemental oxygen or ICU for mechanical ventilation, and although most will have mild disease, some develop severe disease, including acute respiratory distress syndrome.
Interventions aimed at limiting illness severity and reducing the need for invasive mechanical ventilation are needed, and non-pharmacological interventions, like prone positioning, are life-saving for those with moderate-severe acute respiratory distress syndrome receiving mechanical ventilation.
However, although high certainty evidence exists for the use of prone positioning in patients receiving invasive ventilation for non-COVID-19 related acute respiratory distress syndrome, it is unclear whether awake prone positioning improves outcomes in spontaneously breathing non-intubated patients with COVID-19.
Previous systematic reviews and meta-analyses of observational studies suggested that awake prone positioning was linked to improved oxygenation and low endotracheal intubation rates.
Despite these outcomes, the tolerability, safety and efficacy of awake prone positioning remains unclear in patients with COVID-19 related hypoxaemic respiratory failure.
A prospective meta-analysis of six individual randomised controlled trials reported a reduction in the risk of treatment failure (i.e. a composite outcome of intubation or death) and a reduction in the risk of endotracheal intubation. The results of this prospective meta-analysis must be interpreted cautiously as the effect was probably driven by one of the included randomised controlled trials.
Two recent systematic reviews and meta-analyses had limitations, such as being driven by the results of the prospective meta-analysis or combining both observational and randomised studies.
Moreover, a comprehensive systematic review on awake prone positioning in patients with COVID-19 that also incorporates recent trials is needed.
Given the uncertainty about the clinical benefits of awake prone positioning and recent evidence from three trials with more than 900 additional patients, a collaboration by Canadian, Saudi Arabian and US scientists performed a systematic review and meta-analysis.
They used both frequentist and Bayesian methods to evaluate the efficacy and safety of awake prone positioning compared with usual care in trials of non-intubated adults with hypoxaemic respiratory failure due to COVID-19.
The authors, whose study was published in The BMJ, concluded that awake prone positioning, compared with usual care, reduces the risk of endotracheal intubation in adults with hypoxaemic respiratory failure due to COVID-19 but probably has little to no effect on mortality or other outcomes.
In an editorial published in response to the study, in The BMJ, Toronto scientists Amol Verma, Fahad Razak, Laveena Munshi and Michael Fralick, wrote an article titled Safely reduces intubation for patients with hypoxaemia.
In a linked paper, they wrote, Weatherald and colleagues offer the most up-to-date evidence synthesis evaluating the use of awake prone positioning in adults with COVID-19 related hypoxaemia, finding that awake prone positioning reduced the risk of endotracheal intubation but not mortality.
Their systematic review and meta-analysis was performed more than 40 years after a 1976 study observed that prone positioning improved oxygenation in five patients who were mechanically ventilated for acute respiratory distress syndrome (ARDS).
A year later another study described similar effects in five patients with ARDS who were mechanically ventilated and also found that prone positioning allowed intubation to be deferred in one patient who was breathing spontaneously.
In subsequent clinical trials prone positioning was found to reduce mortality in patients with moderate-to-severe ARDS who were mechanically ventilated, particularly in trials that targeted a duration of prone positioning for more than 12 hours daily.
In the decades that followed the observation in a single spontaneously breathing patient, the use of awake prone positioning remained limited. Two small uncontrolled studies with a total of 35 patients suggested that prone positioning improved oxygenation in those who were not intubated.
The COVID-19 pandemic urgently resurfaced questions about the utility of prone positioning, given the surges in patients with hypoxaemia, the limited treatment options, and the constrained supply of ventilators.
A series of small observational reports replicated the prepandemic observations, suggesting that awake prone positioning might improve oxygenation. Despite the lack of high quality evidence, awake prone positioning was eagerly adopted for patients with COVID-19 related hypoxaemia worldwide.
With the inclusion of 17 randomised trials involving 2 931 patients, Weatherald and colleagues captured several studies that were published after another recent systematic review and meta-analysis. The results of both meta-analyses are similar, showing that awake prone positioning in patients with COVID-19 related hypoxaemia reduces the need for endotracheal intubation.
Weatherald and colleagues observed a reduction of 55 fewer intubations per 1 000 patients (95% confidence interval 87 to 19 fewer intubations) compared with usual care, suggesting a “number needed to prone” of 18 to prevent one intubation. Prone positioning had no significant effect on mortality, although these results were inconclusive (relative risk 0.90, 95% confidence interval 0.76 to 1.07) and do not rule out the possibility that a mortality effect could emerge in future studies.
In clinical trials with selected populations and increased monitoring, awake prone positioning was found to be safe, with infrequent dislodgement of vascular catheters (2.5%) and skin breakdown or ulcers (0.7%). Given that the definitive reductions were in endotracheal intubation and not mortality, it is worth noting that participants and clinicians could not be masked and this could bias decisions about intubation.
Whether due to bias or physiological effects, high quality evidence now shows that awake prone positioning can safely reduce endotracheal intubation in patients with COVID-19 related hypoxaemia without increasing the risk of mortality.
The reduction in intubation was driven mainly by trials that achieved longer duration of prone positioning (median ≥5 hours per day), targeted patients with more severe hypoxaemia (median peripheral oxygen saturation to fraction of inspired oxygen ratio <150), and focused on patients requiring high flow oxygen or non-invasive ventilation.
It is not possible to distinguish which of these features is more important based on the current trial evidence. The cut-points used to define these subgroups were chosen based on post hoc observations and should be interpreted cautiously as they may not have specific physiological significance.
Nevertheless, prone positioning in patients receiving mechanical ventilation for ARDS is also most beneficial in those with more severe hypoxaemia and longer duration of prone positioning, strengthening the plausibility of these findings.
Overall, patients with COVID-19 related hypoxaemia find it difficult to tolerate awake prone positioning – the patients in Weatherald and colleagues’ analyses spent a median of just 2.8 hours (interquartile range 2.2-5) daily prone, despite careful patient selection and many trials targeting at least six hours of prone positioning daily.
Trials used numerous potentially resource intensive strategies to help improve adherence, including frequent reminders to patients and clinical staff and 24-hour availability of an intensivist.
Given that the benefits of prone positioning in patients with COVID-19 may be confined to those receiving more advanced respiratory support and with more severe hypoxaemia, it may be wise to focus efforts on these subgroups.
Several unanswered questions remain, including the ideal daily duration of treatment, the level of hypoxaemia that should prompt prone positioning, and how best to improve patient comfort and encourage adherence.
These questions may never be answered definitively in patients with COVID-19 as, fortunately, far fewer are experiencing hypoxaemic respiratory failure or critical illness.
The pandemic should, however, renew interest and encourage further evaluation of awake prone positioning – an intervention that may benefit a wide range of patients with hypoxaemia.
Study details
Efficacy of awake prone positioning in patients with COVID-19 related hypoxaemic respiratory failure: systematic review and meta-analysis of randomised trials
Jason Weatherald, Ken Kuljit Parhar, Zainab Al Duhailib, Derek Chu, Anders Granholm, Kevin Solverson, Kimberley Lewis, Morten Hylander Møller, Mohammed Alshahrani, Emilie Belley-Cote, Nicole Loroff, Edward Qian, Cheryl Gatto, Todd Rice, Dan Niven, Henry Stelfox, Kirsten Fiest, Deborah Cook, Yaseen M Arabi, Waleed Alhazzani.
Published in The BMJ on 7 December 2022
Abstract
Objective
To determine the efficacy and safety of awake prone positioning versus usual care in non-intubated adults with hypoxaemic respiratory failure due to COVID-19.
Design
Systematic review with frequentist and bayesian meta-analyses.
Study eligibility
Randomised trials comparing awake prone positioning versus usual care in adults with COVID-19 related hypoxaemic respiratory failure. Information sources were Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to 4 March 2022.
Data extraction and synthesis
Two reviewers independently extracted data and assessed risk of bias. Random effects meta-analyses were performed for the primary and secondary outcomes. Bayesian meta-analyses were performed for endotracheal intubation and mortality outcomes. GRADE certainty of evidence was assessed for outcomes.
Main outcome measures
The primary outcome was endotracheal intubation. Secondary outcomes were mortality, ventilator-free days, intensive care unit (ICU) and hospital length of stay, escalation of oxygen modality, change in oxygenation and respiratory rate, and adverse events.
Results
17 trials (2931 patients) met the eligibility criteria. 12 trials were at low risk of bias, three had some concerns, and two were at high risk. Awake prone positioning reduced the risk of endotracheal intubation compared with usual care (crude average 24.2% v 29.8%, relative risk 0.83, 95% confidence interval 0.73 to 0.94; high certainty). This translates to 55 fewer intubations per 1000 patients (95% confidence interval 87 to 19 fewer intubations). Awake prone positioning did not significantly affect secondary outcomes, including mortality (15.6% v 17.2%, relative risk 0.90, 0.76 to 1.07; high certainty), ventilator-free days (mean difference 0.97 days, 95% confidence interval −0.5 to 3.4; low certainty), ICU length of stay (−2.1 days, −4.5 to 0.4; low certainty), hospital length of stay (−0.09 days, −0.69 to 0.51; moderate certainty), and escalation of oxygen modality (21.4% v 23.0%, relative risk 1.04, 0.74 to 1.44; low certainty). Adverse events related to awake prone positioning were uncommon. Bayesian meta-analysis showed a high probability of benefit with awake prone positioning for endotracheal intubation (non-informative prior, mean relative risk 0.83, 95% credible interval 0.70 to 0.97; posterior probability for relative risk <0.95=96%) but lower probability for mortality (0.90, 0.73 to 1.13; <0.95=68%).
Conclusions
Awake prone positioning compared with usual care reduces the risk of endotracheal intubation in adults with hypoxaemic respiratory failure due to COVID-19 but probably has little to no effect on mortality or other outcomes.
BMJ article – Awake prone positioning and COVID-19 (Open access)
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