PROSEVA: Prone Positioning in Severe ARDS (2013)

“In patients with severe ARDS, early application of prolonged prone-positioning sessions significantly decreased 28-day mortality.”

  • The PROSEVA Study Group

1. Publication Details

  • Trial Title: Prone Positioning in Severe Acute Respiratory Distress Syndrome
  • Citation: Guérin C, Reignier J, Richard JC, et al. Prone Positioning in Severe Acute Respiratory Distress Syndrome. N Engl J Med. 2013;368(23):2159-2168. DOI: 10.1056/NEJMoa1214103
  • Published: June 6, 2013, in The New England Journal of Medicine
  • Author: Claude Guérin, M.D., Ph.D.
  • Funding: French Ministry of Health

2. Keywords

  • ARDS, Prone Positioning, Mechanical Ventilation, Critical Care, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with severe ARDS (Population), does an early and prolonged prone-positioning strategy (Intervention) compared to standard semi-recumbent (supine) positioning (Comparison) reduce 28-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Prone positioning was known to have a strong physiological rationale for improving oxygenation in ARDS by recruiting dorsal lung regions and improving ventilation-perfusion matching. However, previous clinical trials had yielded conflicting results and had failed to show a consistent survival benefit.
  • Knowledge Gap: The clinical community was uncertain about which specific patients, if any, truly benefited from the maneuver, and what the optimal duration and timing of proning should be.
  • Proposed Hypothesis: The authors hypothesized that a specific protocol of applying prone positioning early in the course of illness and for a prolonged duration in patients with severe ARDS would be superior to supine positioning in reducing 28-day mortality.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 27 intensive care units (ICUs) in France and Spain.
  • Trial Period: Enrollment ran from January 2008 to July 2011.
  • Population:
    • Inclusion Criteria: Adult patients intubated and ventilated for severe ARDS for less than 36 hours, defined by a PaO2:FiO2 ratio <150 mm Hg, with an FiO2 of at least 0.6, a PEEP of at least 5 cm H2O, and a tidal volume set at approximately 6 ml per kilogram of predicted body weight.
    • Exclusion Criteria: Morbid obesity, contraindications to prone positioning (e.g., facial trauma, unstable spine, recent thoracic surgery), pregnancy, and decision to withhold life-sustaining treatment.
  • Intervention: Patients were placed in the prone position for sessions of at least 16 consecutive hours. They were returned to the supine position for a maximum of 8 hours, during which staff could perform necessary care. To facilitate this, patients were deeply sedated, and neuromuscular blocking agents were used as needed.
  • Control: Patients were maintained in a semi-recumbent (supine) position.
  • Management Common to Both Groups: All patients were managed with a standardized lung-protective ventilation strategy (tidal volume ~6 ml/kg PBW) and followed protocols for sedation and weaning.
  • Power and Sample Size: The authors calculated that a sample of 456 patients would be required to have 90% power to detect a 15% absolute risk reduction in mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: All-cause mortality at day 28.
    • Secondary Outcomes: Included mortality at day 90, ventilator-free days, organ-failure-free days, and the incidence of complications such as unplanned extubation, endotracheal-tube obstruction, pressure sores, and arrhythmias.

6. Key Results

  • Enrollment and Baseline: 466 patients were randomized (237 to the prone group and 229 to the supine group). The baseline characteristics were well-matched, with a mean age of around 60 years and a mean PaO2:FiO2 ratio of approximately 100.
  • Trial Status: The trial was stopped early at the second interim analysis by the data monitoring committee due to a significant mortality benefit in the prone group.
  • Primary Outcome: The 28-day mortality was significantly lower in the prone group: 38 of 237 patients (16.0%) died, compared with 75 of 229 patients (32.8%) in the supine group (p<0.001).
  • Secondary Outcomes: The mortality benefit was sustained at 90 days (23.6% in the prone group vs. 41.0% in the supine group; p<0.001). Patients in the prone group also had significantly more ventilator-free days by day 28 (14.1 vs 11.4 days; p=0.03).
  • Adverse Events: The incidence of complications was broadly similar between the two groups. Notably, there was no significant increase in complications directly related to the proning procedure, such as unplanned extubation (1.7% in prone vs 1.8% in supine) or endotracheal tube obstruction. The rate of pressure sores was also similar. Interestingly, the rate of cardiac arrest was significantly lower in the prone group.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test. A log-rank test was used for the time-to-event analysis (90-day mortality).
  • Primary Outcome Analysis: The primary outcome was a comparison of proportions of death between the two groups.
  • Key Statistic(s) Reported: The hazard ratio for death at 90 days was 0.44 (95% CI, 0.29 to 0.67).
  • Interpretation of Key Statistic(s):
    • Hazard Ratio (HR):
      • Formula: Conceptually, HR = (Hazard Rate in Intervention Group) / (Hazard Rate in Control Group).
      • Calculation: The paper reports the result as 0.44.
      • Clinical Meaning: The HR of 0.44 means that at any given time, a patient in the prone group had a 56% lower risk of dying compared to a patient in the supine group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.29 to 0.67.
      • Clinical Meaning: Since this entire range is below the line of no effect (1.0), it confirms that the result is highly statistically significant. Clinically, this means we can be 95% confident that the true benefit of prone positioning is a risk reduction of somewhere between 33% and 71%.
    • P-value: The p-value of <0.001 for the primary outcome indicates that the observed difference in mortality is very unlikely to be due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 32.8% – 16.0% = 16.8%.
      • Clinical Meaning: For every 100 patients with severe ARDS treated with this proning protocol, about 17 additional deaths were prevented.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.168 = 5.95, which is rounded up to 6.
      • Clinical Meaning: You would need to treat only 6 patients with this protocol to prevent one additional death.
  • Subgroup Analyses: No significant subgroup analyses were reported in the primary publication.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design is the gold standard for minimizing selection bias and producing high-quality evidence.
  • Generalizability: The inclusion of 27 centers across two countries increases the external validity, making the results more applicable to a broad range of clinical settings than a single-center trial.
  • Statistical Power: The study was adequately powered to detect a clinically meaningful difference and ultimately found a very large treatment effect.
  • Patient-Centered Outcomes: The study focused on mortality, which is a robust, objective, and highly relevant outcome for patients, rather than relying solely on surrogate markers.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The primary limitation was the unavoidable lack of blinding. This introduces a risk of performance bias, as the knowledge of the intervention could lead clinicians to provide more attentive care or different co-interventions to the prone group. However, the objective nature of the primary outcome (mortality) helps to mitigate this concern.
  • External Validity (Generalizability): The participating ICUs were highly experienced with the prone positioning maneuver. This means the impressive safety profile and mortality benefit might not be fully replicable in centers with less experience or without a dedicated, trained proning team and protocol. Caution should be used when extrapolating these results to settings with limited resources or training.
  • Other: The trial was stopped early for benefit based on pre-specified rules. While ethically necessary, this statistical approach can sometimes lead to an overestimation of the true treatment effect compared to a trial that completes its full planned enrollment.

10. Conclusion of the Authors

  • In patients with severe ARDS, early application of prolonged prone-positioning sessions significantly decreased both 28-day and 90-day mortality without increasing the risk of adverse events.

11. To Summarize

  • Impact on Current Practice: This trial provided definitive evidence for a practice that was previously controversial, establishing early and prolonged prone positioning as a standard of care for severe ARDS.
  • Specific Recommendations:
    • Patient Selection: For adult patients with severe ARDS (PaO2:FiO2 < 150) within 36 hours of intubation, this intervention should be strongly considered.
    • Actionable Intervention: Initiate prone positioning for at least 16 consecutive hours per day.
    • Expected Benefit: This intervention can be expected to prevent approximately one death for every 6 patients treated.
  • What This Trial Does NOT Mean: This trial does NOT mean that prone positioning is beneficial for all patients with ARDS. Its findings are specific to the population studied: patients with severe ARDS who were proned earlyand for a long duration. The benefit in mild or moderate ARDS is not established by this study.
  • Implementation Caveats: The results are most applicable to centers with experienced staff and a clear proning protocol. Safe implementation requires a trained team.

12. Context and Related Studies

  • Building on Previous Evidence: The PROSEVA trial (2013) succeeded where earlier proning studies failed by addressing their limitations, specifically by focusing only on severe ARDS and mandating a longer, uninterrupted duration of proning (≥16 hours).
  • Influence on Subsequent Research: The definitive positive result of this trial solidified the role of prone positioning in severe ARDS, and it has since been incorporated as a standard of care in international guidelines. It also set the stage for the EOLIA trial (2018), which compared this optimized conventional strategy to ECMO.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: A primary unresolved question is whether the benefits of prone positioning extend to patients with moderate ARDS (PaO2:FiO2 150-200), a group not specifically studied here. The optimal duration beyond 16 hours also remains an area of discussion.
  • Future Directions: Future research could be directed at identifying which patients within the severe ARDS category are most likely to respond, and exploring the role of prone positioning in other forms of respiratory failure.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was clear, focused, and highly relevant to a critical problem in the ICU. The authors clearly justified the need for the study based on previous conflicting evidence.
  • Methods: The RCT design was the best choice for this question. The key strength was the very specific inclusion criteria, which targeted the sickest patients and likely explains why this trial succeeded where others failed. The control group received appropriate standard care. The primary outcome of mortality was objective and patient-centered. The main methodological weakness is the lack of blinding, which was unavoidable but introduces a risk of performance bias.
  • Results: The effect size was large and highly clinically meaningful (NNT of 6). The result was precise, as indicated by a narrow confidence interval. All outcomes, including adverse events, were reported honestly and clearly.
  • Conclusions and Applicability: The authors’ conclusions are a direct and fair reflection of the results. They honestly discuss the study’s limitations. The results can be realistically applied to most modern ICUs, provided that they invest in the training and protocols necessary to perform prone positioning safely, which is a key consideration for external validity.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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