New England Journal of Medicine June 06, 2013

Prone Positioning in Severe Acute Respiratory Distress Syndrome

Claude Guérin, Jean Reignier, Jean-Christophe Richard, Pascal Beuret, Arnaud Gacouin, Thierry Boulain, Emmanuelle Mercier, Michel Badet, Alain Mercat, Olivier Baudin, et al.

Source: View publication →

Bottom Line

In mechanically ventilated patients with severe ARDS, the early application of prolonged prone-positioning sessions of at least 16 hours per day significantly decreased 28-day and 90-day mortality compared to supine positioning.

Key Findings

1. At 28 days, all-cause mortality was significantly lower in the prone group compared to the supine group (16.0% vs. 32.8%; P<0.001), representing a hazard ratio of 0.39 (95% CI, 0.25 to 0.63). [1.2.1]

2. The survival benefit persisted at 90 days, with unadjusted mortality rates of 23.6% in the prone group versus 41.0% in the supine group (P<0.001) and a hazard ratio of 0.44 (95% CI, 0.29 to 0.67).

3. The rate of successful extubation by day 90 was significantly higher with prone positioning (80.5% vs. 65.0%; P<0.001).

4. The incidence of major complications did not differ significantly between the groups, with the exception of cardiac arrests, which were more frequent in the supine group.

Study Design

Design

RCT

Open-Label

Sample

466

Patients

Duration

28 days

Median

Setting

Multicenter, Europe

Population Adults intubated and mechanically ventilated for less than 36 hours with severe ARDS (PaO2/FiO2 ratio < 150 mm Hg, with FiO2 >= 0.6, PEEP >= 5 cm H2O, and tidal volume ~6 ml/kg predicted body weight).

Intervention Early application of prone positioning for at least 16 consecutive hours per day.

Comparator Maintenance in the semi-recumbent supine position.

Outcome All-cause mortality at 28 days.

Study Limitations

• The trial was conducted in centers with extensive experience in prone positioning (more than 5 years), meaning the safety and efficacy results might not be fully generalizable to less experienced hospitals. [1.2.4]

• Due to the nature of the intervention, the clinical staff could not be blinded, which introduces the potential for performance bias.

• A large proportion of screened patients were excluded from the trial, raising the possibility of selection bias.

• There were minor baseline imbalances between the groups, such as slightly higher SOFA scores and vasopressor use in the prone group at baseline, although multivariable adjustment did not alter the primary findings.

Clinical Significance

The PROSEVA trial was a landmark study that revolutionized the standard of care for severe acute respiratory distress syndrome (ARDS). Prior to this trial, prone positioning was recognized for improving oxygenation but had not definitively shown a survival benefit. By establishing strict protocols for early initiation (within 36 hours) and prolonged duration (at least 16 hours per day) alongside lung-protective ventilation, the study demonstrated an unprecedented relative reduction in 28-day mortality. Consequently, prone positioning was rapidly incorporated into international guidelines as a strong recommendation for managing severe ARDS.

Historical Context

The physiological benefits of prone positioning in ARDS, particularly the improvement of ventilation-perfusion matching, were first described in the 1970s. However, initial randomized controlled trials conducted in the early 2000s failed to show a consistent mortality benefit. These early trials often utilized shorter proning sessions (typically 7 to 8 hours daily), initiated the intervention relatively late in the disease course, and lacked strict lung-protective ventilation protocols across all groups. The PROSEVA trial successfully synthesized these historical lessons by enforcing early, prolonged prone positioning combined with standardized low-tidal-volume ventilation, thereby demonstrating a clear and substantial survival benefit.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Physiologically, how does prone positioning improve oxygenation and reduce ventilator-induced lung injury (VILI) in severe ARDS?

Key Response

Prone positioning unloads the dorsal lungs by relieving the weight of the heart and anterior chest wall, leading to recruitment of previously atelectatic dorsal alveoli. This creates a more homogeneous distribution of transpulmonary pressure and tidal volume, which improves ventilation-perfusion (V/Q) matching and decreases regional alveolar overdistension and cyclical opening and closing, ultimately reducing VILI.

Resident

A patient with severe ARDS is intubated with a PaO2/FiO2 ratio of 120. Based on the PROSEVA trial, what are the specific criteria, timing, and duration required to initiate and maintain prone positioning effectively?

Key Response

Based on PROSEVA, prone positioning should be initiated early (within 12 to 36 hours of intubation) for patients with a PaO2/FiO2 ratio < 150 mmHg, FiO2 >= 0.6, and PEEP >= 5 cmH2O. Crucially, the sessions must be prolonged, lasting at least 16 consecutive hours per day, as shorter durations in previous trials failed to show a mortality benefit.

Fellow

Previous trials of prone positioning in ARDS failed to demonstrate a significant mortality benefit. What were the critical methodological differences in the PROSEVA trial design that unmasked the mortality benefit of proning?

Key Response

Earlier trials included less severe ARDS populations, initiated proning later in the clinical course, and utilized shorter daily prone sessions. PROSEVA selectively enrolled severe ARDS (P/F < 150), intervened early (<36 hours), mandated prolonged sessions (>16 hours/day), and rigorously protocolized lung-protective ventilation in both arms, minimizing confounding from VILI and maximizing the synergistic benefit of proning.

Attending

Despite the dramatic absolute risk reduction in mortality demonstrated in PROSEVA, widespread implementation of prone positioning remains challenging. What are the key systemic and logistical barriers to initiating prone positioning, and how can an ICU team mitigate these risks?

Key Response

Barriers include staff unfamiliarity, perceived high risks of accidental extubation or central line dislodgement, pressure ulcers, and the sheer physical manpower required. Attendings must lead protocolized simulation training, utilize specialized positioning checklists, ensure adequate sedation/paralysis during the turn, and implement robust pressure-injury prevention strategies to safely translate this mortality benefit into routine practice.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The PROSEVA trial was stopped early for efficacy after a scheduled interim analysis. How does stopping a trial early for benefit potentially impact the effect size estimate, and what statistical safeguards were necessary to ensure the validity of this finding?

Key Response

Stopping early for efficacy (truncation) risks exaggerating the treatment effect size due to random high bias. To mitigate this, PROSEVA used predefined stopping boundaries (e.g., O'Brien-Fleming) that require a highly stringent p-value at interim analyses to declare significance. Researchers must interpret the 17 percent absolute risk reduction noting that early termination may slightly overestimate the true benefit, though the biological plausibility supports the core finding.

Journal Editor

As a reviewer evaluating the PROSEVA manuscript, how would you address the potential confounding effect of neuromuscular blockade (NMB), given that it was used in a high percentage of patients in both arms?

Key Response

The ACURASYS trial had previously shown that early NMB improves mortality in severe ARDS. In PROSEVA, most patients received NMB, raising the question of whether the benefit of proning is synergistic with or dependent on paralysis. A reviewer would look for subgroup analyses or multivariable adjustments to ensure the prone mortality benefit remained independent of NMB use, and flag whether the results are generalizable to non-paralyzed patients.

Guideline Committee

How should the results of the PROSEVA trial influence formal clinical practice guidelines regarding the standard of care for severe ARDS, specifically concerning the grading of the recommendation and the precise clinical triggers?

Key Response

PROSEVA provides high-quality, Level 1 evidence that shifting from conditional to a strong recommendation is warranted for early prone positioning (>16 hours/day) in patients with moderate-to-severe ARDS. Current ATS/ESICM/SCCM guidelines now strongly recommend this practice based heavily on this trial. Committees must specify exact triggers (P/F <150, PEEP >=5) and duration to prevent inappropriate generalization to mild ARDS where risks may outweigh benefits.

Clinical Landscape

Noteworthy Related Trials

2000

ARMA Trial

n = 861 · NEJM

Tested

Low tidal volume ventilation (6 mL/kg)

Population

Patients with acute lung injury and ARDS

Comparator

Traditional tidal volume ventilation (12 mL/kg)

Endpoint

Mortality before discharge home and breathing without assistance

Key result: Mortality was significantly lower in the lower tidal volume group compared to the traditional tidal volume group.

2010

ACURASYS Trial

n = 340 · NEJM

Tested

Early administration of cisatracurium besylate for 48 hours

Population

Patients with severe ARDS

Comparator

Placebo

Endpoint

90-day all-cause mortality

Key result: Early use of a neuromuscular blocking agent improved adjusted 90-day survival and increased time off the ventilator without increasing muscle weakness.

2018

EOLIA Trial

n = 249 · NEJM

Tested

Early venovenous extracorporeal membrane oxygenation (ECMO)

Population

Patients with very severe ARDS

Comparator

Conventional mechanical ventilation with optional ECMO crossover

Endpoint

60-day mortality

Key result: Early ECMO did not significantly lower 60-day mortality compared to a strategy of conventional mechanical ventilation that included prone positioning and crossover to ECMO.

Tailored to your role

Want this tailored to you?

Add your specialty or training stage to get role-specific takeaways and more questions.

Personalize this analysis