Meta-analysis strengthens case for awake prone positioning in COVID-19 with AHRF

Placing awake COVID-19 patients with acute hypoxaemic respiratory failure (AHRF) in a prone position is an efficacious intervention in terms of both reducing mortality and preventing intubation, according to an individual participant data (IPD) meta-analysis.

Pooled data from 14 randomized controlled trials showed that compared with supine positioning, awake prone positioning (APP) was associated with 42-percent increased odds of survival without intubation (odds ratio [OR], 1.42, 95 percent confidence interval [CI], 1.20–1.68), the primary study outcome. [JAMA Intern Med 2025;185:572-581]

Furthermore, APP reduced the odds of intubation (OR, 0.70, 95 percent CI, 0.59–0.84) and hospital mortality (OR, 0.77, 95 percent CI, 0.63–0.95) and delayed the time to intubation (mean difference, 0.93 days, 95 percent CI, 0.43–1.42) relative to supine positioning.

Results of time-to-event analysis also favoured APP, with reduced 30-day risks of the composite outcome of mortality or intubation (HR, 0.75, 95 percent CI, 0.65–0.86), intubation (HR, 0.74, 95 percent CI, 0.64–0.86) and mortality (HR, 0.81, 95 percent CI, 0.67–0.98).

The total population comprised 3,019 patients, including 1,542 in the APP group (mean age 59.3 years, 68.0 percent male) and 1,477 in the supine positioning group (mean age 59.9 years, 66.3 percent male).

Who benefits most?

These findings confirm the beneficial effect of APP in most patients receiving advanced respiratory support reported in earlier meta-analyses, the authors said. What’s more is “our exploratory subgroup analyses revealed new insights.” [Lancet Respir Med 2022;10:573-583; BMJ 2022;379:e071966]

Specifically, APP had a pronounced effect on the primary outcome for patients younger than age 68 years (55–68 years: OR, 1.57; <55 years: OR, 1.67), those with a BMI of 26–30 kg/m² (OR, 1.57), those who were subjected to APP within 1 day from hospitalization (1.8–1 day: OR, 1.60; <0.8 days: OR, 1.50), those with a pulse saturation to inhaled oxygen fraction (SpO₂:FiO₂) ratio of 155–232 (OR, 1.85), those with respiratory rate of 20–26 breaths per minute (OR, 1.53), and those receiving advanced respiratory support at enrolment (OR, 1.46).

“Although interaction analyses did not show significant treatment effect modification by any of these factors potentially due to limited sample size, the treatment effect in these subgroups remained significant after adjusting for multiple comparisons using the Bonferroni method,” the authors noted. 

“These findings may help identify the patients most likely to benefit from APP but should not preclude implementation of APP in patients who do not exhibit these beneficial characteristics since no significant increase of severe adverse events were observed with APP,” they continued.

The longer, the better

“APP duration is an independent factor associated with treatment success,” the authors said.

Pooled data from 11 trials with data on APP duration indicated a 3-percent increase in the odds of survival without intubation for every hour increase in APP duration (OR, 1.03, 95 percent CI, 1.00–1.07). Notably, patients who underwent APP for at least 10 hours in a day had higher odds of survival without intubation (OR, 1.85, 95 percent CI, 1.37–2.49), especially those who did so for the first 3 days of hospitalization (OR, 2.59, 95 percent CI, 1.30–5.14). Patients with ≥10 h of APP per day had a significantly lower baseline SpO₂:FiO₂ ratio compared with those with <10 h of APP per day, with similar baseline respiratory rates.

“Although this finding aligns with previous studies, our study analysed data at the individual participant level after adjustment for other confounding factors, highlighting the importance of sustained prone positioning for optimal clinical outcomes, with a preferred daily duration of at least 10 hours in the first 3 days,” according to the authors.  [Lancet Respir Med 2021;9:1387-1395; Crit Care 2022;26:16; Crit Care 2022;26:84]

“Efforts should be made to improve patient compliance and comfort in the prone position in order to extend APP duration,” they said.

Potential new standard of care

In an accompanying editorial, Dr Michael Matthay from the University of California, San Francisco in San Francisco, California, US, and colleagues noted that the rigorous IPD meta-analysis yielded “encouraging” findings, suggesting that APP, especially for 8 or more hours per day, could represent a new standard of care in severe COVID-19 pneumonia.”

There are practical challenges associated with implementing prone positioning, but “these considerations should not discourage its clinical implementation in appropriate patients,” according to Matthay and colleagues.  

Prone positioning in awake patients can lead to discomfort, demands regular repositioning to mitigate tissue injury risk, and requires further training for nursing and respiratory therapy personnel, they said. Then again, contraindications to prone positioning such as unstable trauma, elevated intracranial pressure, severe haemodynamic instability, or recent chest/abdominal surgery are typically uncommon in spontaneously breathing patients, they added.

Matthay and his team explained that switching from a supine to prone position can improve oxygenation by optimizing ventilation-perfusion matching and enhance ventilation by reducing the dead space fraction. Furthermore, the prone position may mitigate lung injury by preventing the cyclic opening and closing of dependent alveoli and avoiding the overdistension of ventral alveoli seen in the supine position.

They emphasized that APP may be an advantage in settings where ventilator access is limited.

The next step in APP research is to determine the intervention’s potential for improving outcomes in spontaneously breathing patients with acute respiratory distress syndrome who have lung injury from various causes beyond COVID-19, such as sepsis, bacterial or viral pneumonia, or aspiration of gastric contents AHRF, according to Matthay and colleagues.