ExPress: PEEP Setting in ARDS (2008)

“In patients with ARDS, a multifaceted strategy aimed at maximizing alveolar recruitment and minimizing overdistention resulted in improved oxygenation and respiratory system compliance and a trend toward lower mortality, but it did not significantly reduce ventilator-free days.”

  • The ExPress Study Investigators

1. Publication Details

  • Trial Title: Positive End-Expiratory Pressure Setting in Adults With Acute Lung Injury and Acute Respiratory Distress Syndrome: A Randomized Controlled Trial
  • Citation: Mercat A, Richard JC, Vielle B, et al. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008;299(6):646-655. DOI: 10.1001/jama.299.6.646
  • Published: February 13, 2008, in The Journal of the American Medical Association (JAMA)
  • Author: Alain Mercat, M.D., Ph.D.
  • Funding: French Ministry of Health

2. Keywords

  • ARDS, Acute Lung Injury, Mechanical Ventilation, PEEP, Lung Protective Ventilation, Respiratory Mechanics, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with acute lung injury (ALI) or ARDS (Population), does a PEEP strategy based on respiratory mechanics to minimize lung stress (Intervention) compared to a conventional low-PEEP strategy (Comparison) increase the number of ventilator-free days at day 28 (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The ARDSNet ARMA trial (2000) had established low tidal volume ventilation as the standard of care. However, the optimal way to set positive end-expiratory pressure (PEEP) remained highly controversial. The ALVEOLI trial (2004) had shown no benefit of a protocolized high-PEEP over a low-PEEP strategy.
  • Knowledge Gap: It was unknown if a more individualized, physiology-based strategy for setting PEEP—specifically, one guided by measuring respiratory mechanics to estimate and limit lung stress—would be superior to the simple PEEP/FiO2 tables used in previous trials.
  • Proposed Hypothesis: The authors hypothesized that a PEEP strategy guided by respiratory mechanics would be superior to a conventional low-PEEP strategy in increasing the number of ventilator-free days.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: 37 intensive care units (ICUs) in France.
  • Trial Period: Enrollment ran from October 2004 to August 2006.
  • Population:
    • Inclusion Criteria: Adult patients intubated and ventilated for <48 hours with ALI or ARDS (PaO2:FiO2 ratio ≤ 300).
    • Exclusion Criteria: Included contraindications to high airway pressures (e.g., high intracranial pressure) and severe chronic respiratory disease.
  • Intervention: An “experimental” strategy. PEEP was set based on a full static pressure-volume curve of the respiratory system, with the goal of setting PEEP just above the lower inflection point to keep the lung open while keeping the plateau pressure below 30 cm H2O.
  • Control: A “minimal PEEP” or “control” strategy, where clinicians used the ARDSNet low PEEP/FiO2 table to set PEEP.
  • Management Common to Both Groups: All patients were managed with a low tidal volume ventilation strategy (6 ml/kg PBW).
  • Power and Sample Size: The authors calculated that a sample size of 750 patients would provide 80% power to detect a 2.5-day difference in ventilator-free days. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: The number of ventilator-free days at day 28.
    • Secondary Outcomes: Included 28-day and 90-day mortality, organ-failure-free days, and the incidence of barotrauma.

6. Key Results

  • Enrollment and Baseline: 767 patients were randomized (387 to the experimental group and 380 to the control group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the primary outcome. The median number of ventilator-free days was 7 in the experimental group and 5 in the control group (p=0.19).
  • Secondary Outcomes: There was no significant difference in 28-day or 90-day mortality. However, patients in the experimental (higher PEEP) group had significantly better oxygenation and respiratory system compliance.
  • Adverse Events: The incidence of barotrauma was similar in both groups.

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 Wilcoxon rank-sum test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the median number of ventilator-free days between the two groups.
  • Key Statistic(s) Reported: The key statistics were the median values for the primary outcome and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.19 for the primary outcome is higher than the 0.05 threshold, indicating that the result was not statistically significant and likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: In a post-hoc analysis of the subgroup of patients with the most severe ARDS (PaO2:FiO2 < 150), the experimental strategy was associated with a significant reduction in mortality. This finding is hypothesis-generating only.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design provided high-quality evidence. The use of a physiology-based intervention was a novel and important strength.
  • Generalizability: The inclusion of 37 diverse ICUs increases the applicability of the findings.
  • Statistical Power: The study was large and adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The primary outcome of ventilator-free days is a robust and patient-centered composite outcome.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which introduces a risk of performance bias.
  • External Validity (Generalizability): The measurement of a static pressure-volume curve is a complex procedure that is not available or routinely performed in all ICUs, which limits the generalizability of the intervention.
  • Other: The mortality rate in the control group was relatively high, and the separation in PEEP between the two groups was modest in the later days of the trial.

10. Conclusion of the Authors

  • The authors concluded that a strategy of setting PEEP based on respiratory mechanics, as compared with a conventional low-PEEP strategy, did not significantly improve the number of ventilator-free days in patients with ALI or ARDS.

11. To Summarize

  • Impact on Current Practice: This was an important trial that, like ALVEOLI before it, failed to show a benefit for a routine high-PEEP strategy in a broad ARDS population. It provided further evidence that a “one-size-fits-all” approach to PEEP is not effective.
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult patients with ARDS.
    • Actionable Intervention: The results do not support the routine use of this complex, physiology-based PEEP titration strategy for all patients with ARDS.
  • What This Trial Does NOT Mean: This trial does NOT mean that individualized PEEP setting is not important. It only suggests that this specific, complex method was not superior to a simpler approach in a heterogeneous population.
  • Implementation Caveats: The findings reinforce that while higher PEEP can improve physiological parameters like oxygenation, this does not automatically translate to improved patient-centered outcomes.

12. Context and Related Studies

  • Building on Previous Evidence: The ExPress trial (2008) was a direct follow-up to the neutral ALVEOLI trial (2004), testing a more sophisticated, individualized method for setting higher PEEP.
  • Influence on Subsequent Research: The neutral findings of this trial, along with ALVEOLI, were a major factor in the design of the subsequent ART trial (2017), which tested an even more aggressive recruitment and PEEP titration strategy and ultimately found harm. These trials collectively shifted the focus of research towards other parameters, like driving pressure, to guide ventilation.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question is how to best individualize PEEP for each patient to maximize benefit and minimize harm.
  • Future Directions: Subsequent research has focused on more advanced physiological parameters, such as driving pressure and lung recruitability, to guide PEEP titration in ARDS.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, attempting to refine a fundamental aspect of ARDS management.
  • Methods: The multicenter RCT design was appropriate. The main methodological weakness is the open-label design. The intervention, while physiologically sound, was complex and may have been difficult to perform consistently across all centers.
  • Results: The study reported a clear neutral finding for its primary outcome. The improvement in physiological variables without a corresponding improvement in patient-centered outcomes is a key finding. The post-hoc subgroup finding of a mortality benefit in severe ARDS is interesting but must be interpreted with extreme caution.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The trial provides strong evidence that this complex PEEP-setting strategy is not superior to a simpler approach for the general ARDS population.

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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