Invited Commentary 

March 10, 2025

Awake Prone Positioning in COVID-19—Is There a New Standard of Care?

Michael A. Matthay, Katherine D. Wick, Narges Alipanah-Lechner

JAMA Intern Med. Published online March 10, 2025. doi:10.1001/jamainternmed.2025.0021

In this issue of JAMA Internal Medicine, Luo et al¹ presented compelling evidence for awake prone positioning for patients with acute hypoxemic respiratory failure from COVID-19. Their meta-analysis based on individual patient data from 3019 patients in 14 randomized clinical trials demonstrated that awake prone positioning significantly improved survival without intubation and reduced both the risk of intubation and hospital mortality. The improved survival was most pronounced in individuals who had moderate to severe hypoxemia (pulse saturation to inhaled oxygen fraction ratio between 155 and 232), were younger than 68 years, had a body mass index between 26 and 30 (calculated as weight in kilograms divided by height in meters squared), and had prone positioning initiated within 1 day of hospitalization. Notably, patients who maintained prone positioning for at least 8.3 hours daily during the first 3 days of hospitalization had better outcomes than those with shorter prone times. This rigorous meta-analysis provides important evidence for managing critically ill patients with acute hypoxemic respiratory failure.

The therapeutic potential of prone positioning for acute respiratory failure was first recognized almost 50 years ago, with initial reports in 1976 documenting improved oxygenation in 5 patients with acute respiratory failure. A pivotal advancement came in 1991 when Gattinoni and colleagues² used chest computed tomography scans to demonstrate that pulmonary opacities in 10 ventilated patients with acute respiratory distress syndrome (ARDS) redistributed from dorsal to ventral regions when patients were placed in the prone position. This imaging evidence suggested that alternating between supine and prone positions might reduce pulmonary consolidation and atelectasis in ARDS. Although early clinical trials in adults and children with ARDS showed no mortality benefit, subsequent meta-analyses suggested that prone positioning might be beneficial in the subset of patients with more severe hypoxemia. The landmark 2013 multicenter PROSEVA randomized clinical trial demonstrated that prone positioning for 12 to 16 consecutive hours reduced 90-day mortality from 41% to 24% in ventilated patients with ARDS and moderate to severe hypoxemia (partial pressure of oxygen to oxygen fraction ratio less than 150 mm Hg).³ During the COVID-19 pandemic, prone positioning became standard practice for ventilated patients with ARDS, used alongside lung protective ventilation strategies, and the concept of awake prone positioning emerged as a potential early intervention to prevent clinical deterioration. The current meta-analysis now provides robust evidence supporting prone positioning in awake patients with acute hypoxemic respiratory failure from COVID-19.¹

Why does prone positioning benefit the injured lung with severe viral pneumonia and lead to better clinical outcomes in spontaneously breathing patients? In the supine position, the nondependent ventral lung accounts for approximately 40% of lung mass, while the dorsal portion accounts for 60%. Thus, turning to the prone position would be expected to inflate more alveoli and contribute to better oxygenation through improved ventilation-perfusion matching and improved ventilation through reduced dead space fraction.⁴ This position also may attenuate lung injury by minimizing cyclic opening and closing of dependent alveoli while preventing ventral alveolar overdistension that can occur in the supine position. Similar to lung protective ventilation in ARDS, the reduced mechanical stress on alveoli achieved with prone positioning may promote recovery of injured alveolar epithelial type 1 and 2 cells, which are crucial for surfactant production, alveolar-capillary barrier integrity, and clearance of alveolar edema.⁵ Experimental evidence using positron emission tomography demonstrates that prone positioning significantly reduces acute lung macrophage activation, particularly in anterior and posterior lung regions where mechanical stress is highest in the supine position.⁶ In addition, prone positioning appears to improve both systemic and pulmonary hemodynamics, as evidenced by the PROSEVA trial’s lower cardiac arrest rates (6.8% vs 13.5%) and increased extrapulmonary dysfunction–free days in prone-positioned patients. Despite these clear physiological benefits, significant knowledge gaps remain in our understanding of the biological mechanisms underlying prone positioning’s effects. Few studies have examined the cellular and molecular pathways through which prone positioning may mitigate inflammation and injury, and the temporal relationship between positional changes and expression of inflammatory mediators remains poorly characterized. These mechanistic gaps are particularly notable given prone positioning’s dramatic clinical impact, highlighting the need for detailed biological studies to complement our physiological understanding.

While the findings from the current meta-analysis are encouraging,¹ interpretation requires consideration of potential methodological limitations of the study and the practical limitations to implementing prone positioning. Healthier patients may be more likely to tolerate and adhere to prone positioning, and early mortality or urgent intubation may create immortal time bias by limiting prone positioning opportunities. Prone positioning can be uncomfortable for awake patients, requires frequent repositioning to prevent tissue injury, and necessitates additional training for nursing and respiratory therapy staff. Contraindications to prone positioning, including unstable traumatic injuries, elevated intracranial pressure, severe hemodynamic instability, and recent chest or abdominal surgery, are generally uncommon in spontaneously breathing patients. Overall, given the intervention’s low risk profile and clear physiological rationale, these considerations should not discourage its clinical implementation in appropriate patients.

What should be the next priorities for testing the potential clinical value of prone positioning in acute hypoxemic respiratory failure? The new global definition of ARDS includes spontaneously breathing patients supported by high-flow nasal oxygen or noninvasive ventilation with mild, moderate, or severe hypoxemia.⁷ This presents an opportunity for multicenter randomized clinical trials to evaluate prone positioning in spontaneously breathing patients with ARDS who have lung injury from various causes beyond COVID-19, such as sepsis, bacterial or viral pneumonia, or aspiration of gastric contents. Because the new global definition of ARDS facilitates the recognition of ARDS in resource-limited settings, testing awake prone positioning could be particularly valuable in these regions that are traditionally underrepresented in research studies. This cost-effective intervention might significantly reduce mortality by preventing progression to mechanical ventilation, a critical advantage in settings where ventilator access is limited. In summary, the rigorous meta-analysis by Luo and colleagues¹ suggests that awake prone positioning, especially for 8 or more hours per day, could represent a new standard of care in severe COVID-19 pneumonia and warrants further studies in other causes of lung injury in spontaneously breathing patients.