ALVEOLI: Higher versus Lower PEEP in ARDS (2004)

“In patients with acute lung injury and the acute respiratory distress syndrome, a clinical trial of mechanical ventilation with higher levels of positive end-expiratory pressure (PEEP) did not show a significant improvement in survival.”

  • The ARDS Clinical Trials Network

1. Publication Details

  • Trial Title: Higher versus Lower Positive End-Expiratory Pressures in Patients with the Acute Respiratory Distress Syndrome
  • Citation: The Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Higher versus Lower Positive End-Expiratory Pressures in Patients with the Acute Respiratory Distress Syndrome. N Engl J Med. 2004;351(4):327-336. DOI: 10.1056/NEJMoa032193
  • Published: July 22, 2004, in The New England Journal of Medicine
  • Author: The Acute Respiratory Distress Syndrome (ARDS) Network
  • Funding: National Heart, Lung, and Blood Institute (NHLBI).

2. Keywords

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

3. The Clinical Question

  • In patients with acute lung injury (ALI) and ARDS already receiving low tidal volume ventilation (Population), does a strategy using higher levels of PEEP (Intervention) compared to a strategy with lower PEEP levels (Comparison) decrease mortality and increase ventilator-free days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The ARDSNet ARMA trial (2000) had already established low tidal volume ventilation as the standard of care to prevent over-distention injury. The next major question was how to optimize PEEP. The “open lung” hypothesis suggested that higher PEEP levels could prevent the cyclical collapse and reopening of alveoli (atelectrauma), thereby reducing VILI and improving survival.
  • Knowledge Gap: While physiologically plausible, it was unknown if a routine strategy of applying higher PEEP to all ARDS patients would translate into a meaningful clinical benefit, such as improved survival, or if it would cause more harm through side effects like hypotension and barotrauma.
  • Proposed Hypothesis: The authors hypothesized that a ventilation strategy using higher levels of PEEP would be superior to a strategy using lower levels of PEEP in reducing mortality and increasing the number of days breathing without assistance.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: The ARDS Clinical Trials Network sites, comprised of multiple university-affiliated medical centers in the United States.
  • Trial Period: Enrollment ran from August 2000 to May 2003.
  • Population:
    • Inclusion Criteria: Adult patients intubated and receiving mechanical ventilation who met criteria for ALI or ARDS (PaO2:FiO2 ratio ≤ 300) for less than 36 hours.
    • Exclusion Criteria: Included contraindications to the ventilation protocols, severe chronic liver disease, increased intracranial pressure, and conditions with a very high short-term mortality risk.
  • Intervention: Patients were managed with a protocol that set higher levels of PEEP based on their FiO2 requirement, following a specific PEEP/FiO2 table.
  • Control: Patients were managed with a protocol that set lower levels of PEEP for a given FiO2 requirement, following a different PEEP/FiO2 table.
  • Management Common to Both Groups: All patients were managed with the proven low tidal volume ventilation strategy (6 ml/kg PBW, plateau pressure ≤ 30 cm H2O) established by the ARMA trial.
  • Power and Sample Size: The authors calculated that a sample size of 549 patients would provide 85% power to detect a 10% absolute risk reduction in mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80-90% is considered standard).
  • Outcomes:
    • Primary Outcome: All-cause mortality before hospital discharge home breathing without assistance.
    • Secondary Outcomes: Included ventilator-free days, organ-failure-free days, and the incidence of barotrauma.

6. Key Results

  • Enrollment and Baseline: 549 patients were randomized (272 to the higher-PEEP group and 277 to the lower-PEEP group). The groups were well-matched at baseline, with a mean age of 50 years and similar severity of illness.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no statistically significant difference in the primary outcome. Mortality was 25.1% in the higher-PEEP group versus 27.5% in the lower-PEEP group (p=0.48).
  • Secondary Outcomes: There was no significant difference in ventilator-free days or organ-failure-free days. Patients in the higher-PEEP group had better oxygenation (higher mean PaO2:FiO2 ratio) but also required more vasopressors to manage hypotension in the initial days of the trial.
  • Adverse Events: The incidence of barotrauma (e.g., pneumothorax) was similar in both groups (11% in the higher-PEEP group vs. 10% in the lower-PEEP 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.
  • Primary Outcome Analysis: The primary outcome was a comparison of proportions of death between the two groups.
  • Key Statistic(s) Reported: Relative risk of death: 0.90 (95% CI, 0.73 to 1.12; P-value: 0.48).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: The paper reports the result as 0.90.
      • Clinical Meaning: The RR of 0.90 suggests a non-significant 10% relative reduction in the risk of death with higher PEEP.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.73 to 1.12.
      • Clinical Meaning: Since this range crosses the line of no effect (1.0), it confirms that the result is not statistically significant. Clinically, this means the true effect could range from a 27% benefit to a 12% harm.
    • P-value: The p-value of 0.48 is much higher than the 0.05 threshold, indicating the result is not statistically significant and was 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: A post-hoc analysis suggested a possible benefit of higher PEEP in the subgroup of patients with more severe hypoxemia (PaO2:FiO2 < 200), but this was not a pre-specified finding and is considered hypothesis-generating only.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design provided high-quality evidence on a critical clinical question.
  • Generalizability: The multicenter design increases the applicability of the findings.
  • Statistical Power: The study was adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The primary outcome of mortality is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded to clinicians, which could introduce performance bias.
  • External Validity (Generalizability): The use of rigid PEEP/FiO2 tables does not allow for tailoring PEEP to individual patient physiology (e.g., based on lung mechanics or recruitment potential). This “one-size-fits-all” approach may have masked a benefit in certain subgroups.
  • Other: The “lower PEEP” arm still used moderate levels of PEEP, which may have diluted the potential difference between the two strategies.

10. Conclusion of the Authors

  • In a broad population of patients with ALI and ARDS, a routine strategy of ventilation with higher levels of PEEP does not improve survival or increase ventilator-free days compared to a strategy with lower PEEP levels.

11. To Summarize

  • Impact on Current Practice: This trial demonstrated that a “one-size-fits-all” high PEEP strategy is not superior to a lower PEEP strategy for all patients with ARDS.
  • Specific Recommendations:
    • Patient Selection: There is no evidence to support the routine use of high PEEP in all ARDS patients.
    • Actionable Intervention: PEEP settings should be individualized based on a patient’s specific physiology, considering both the potential benefits (improved oxygenation, lung recruitment) and risks (hypotension, barotrauma).
  • What This Trial Does NOT Mean: This trial does NOT mean that high PEEP is never beneficial. It only suggests that a protocolized high-PEEP strategy for all comers is not superior to a lower-PEEP strategy.
  • Implementation Caveats: While higher PEEP can improve oxygenation, clinicians must be aware that this does not automatically translate to a survival benefit and may increase the need for hemodynamic support.

12. Context and Related Studies

  • Building on Previous Evidence: The ALVEOLI trial (2004) was the logical next step after the ARMA trial (2000) established low tidal volume ventilation.
  • Influence on Subsequent Research: The neutral findings of this trial, along with others like the ExPress trial (2008), were instrumental in shifting the focus of research away from a “one-size-fits-all” PEEP approach and towards more individualized strategies for setting PEEP in ARDS, such as those guided by esophageal manometry or driving pressure.

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 as the logical next step after the ARMA trial. The hypothesis was clear.
  • Methods: The multicenter RCT design was appropriate. The major methodological critique is the use of a rigid, protocolized PEEP strategy rather than one tailored to individual patient mechanics. This may have led to some patients in the high-PEEP group receiving excessive PEEP, while some in the low-PEEP group may have received inadequate PEEP, potentially masking a true benefit of individualized “optimal” PEEP.
  • Results: The study reported a clear neutral finding for its primary outcome. The confidence interval was wide and crossed 1.0, reinforcing the conclusion of no definitive benefit. The finding of improved oxygenation but increased vasopressor use in the high-PEEP group is an important trade-off to consider clinically.
  • Conclusions and Applicability: The authors’ conclusion is a fair and accurate reflection of their data. The trial was instrumental in shifting the focus of research away from a “one-size-fits-all” PEEP approach and towards more individualized strategies for setting PEEP in ARDS.

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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