LOVS: Low vs. Higher PEEP for Acute Lung Injury (2008)

“In patients with ARDS, a ventilation strategy using higher PEEP and recruitment maneuvers did not reduce mortality compared to a strategy using lower PEEP.”

— The LOVS Investigators

1. Publication Details

  • Trial Title: A Trial of Lower versus Higher Tidal Volumes in Adults with Acute Lung Injury and Acute Respiratory Distress Syndrome.
  • Citation: The Acute Respiratory Distress Syndrome Network. A Trial of Lower versus Higher Tidal Volumes in Adults with Acute Lung Injury and Acute Respiratory Distress Syndrome. N Engl J Med. 2008;359(20):2113-2124. doi:10.1056/NEJMoa0804116.
  • Published: November 13, 2008, in The New England Journal of Medicine.
  • Author: The LOVS (Lung Open Ventilation Study) Investigators.
  • Funding: Canadian Institutes of Health Research.

2. Keywords

Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury (ALI), Mechanical Ventilation, Low Tidal Volume, Lung Protective Ventilation, Open Lung Approach, PEEP.

3. The Clinical Question

In adult patients with acute lung injury (ALI) or ARDS (Population), does a lung-protective strategy using low tidal volumes combined with high PEEP (Intervention) compared to the ARDSNet low tidal volume strategy with lower PEEP (Comparison) reduce 28-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The landmark ARMA trial (2000) established that a low tidal volume (6 mL/kg) strategy was superior to a high tidal volume (12 mL/kg) strategy for ARDS. However, the optimal way to set Positive End-Expiratory Pressure (PEEP) remained controversial. Some advocated for an “open lung” approach, using higher levels of PEEP to recruit collapsed lung tissue.
  • Knowledge Gap: It was unknown if a strategy combining low tidal volumes with an aggressive “open lung” high-PEEP strategy would be superior to the established ARDSNet low tidal volume protocol, which used more moderate levels of PEEP.
  • Proposed Hypothesis: The authors hypothesized that a strategy of low tidal volume ventilation combined with higher PEEP and recruitment maneuvers would reduce 28-day mortality compared to the standard ARDSNet low tidal volume protocol.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, controlled trial.
  • Setting: 30 intensive care units in Canada, Australia, and Saudi Arabia.
  • Trial Period: Enrollment from April 2004 to March 2008.
  • Population:
    • Inclusion Criteria: Adult patients with ALI or ARDS (defined by PaO2/FiO2 ratio ≤ 300) who were expected to require mechanical ventilation for at least 48 hours.
    • Exclusion Criteria: Included patients with contraindications to high PEEP (e.g., elevated intracranial pressure, severe obstructive lung disease).
  • Intervention: LOVS (High PEEP) Group: Ventilated with a tidal volume of 6 mL/kg, with PEEP set according to a specific table designed to achieve higher levels of PEEP for any given FiO2, and recruitment maneuvers were encouraged.
  • Control: ARDSNet (Lower PEEP) Group: Ventilated with a tidal volume of 6 mL/kg, with PEEP set according to the original ARDSNet low tidal volume trial’s PEEP-FiO2 table.
  • Management Common to Both Groups: All patients were managed with a low tidal volume strategy. Sedation and other supportive care were at the discretion of the treating clinicians.

6. Key Results

  • Enrollment and Baseline: 983 patients were randomized (490 to the LOVS group, 493 to the ARDSNet group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 28-day all-cause mortality between the two groups (36.4% in the LOVS group vs. 40.4% in the ARDSNet group; P=0.19).
  • Secondary Outcomes: The LOVS group had significantly better oxygenation (higher PaO2/FiO2 ratio) and a lower rate of refractory shock. There was no significant difference in the rate of barotrauma.
  • Adverse Events: The incidence of adverse events was similar between the two groups.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Key Statistic(s) Reported:
    • Primary Outcome (28-day mortality): Relative Risk (RR) 0.90 (95% CI, 0.77 to 1.05; P=0.19).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: RR = 36.4% / 40.4% = 0.90.
      • Clinical Meaning: An RR of 0.90 means there was a 10% lower relative risk of death at 28 days in the high PEEP (LOVS) group, but this difference was not statistically significant.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI was 0.77 to 1.05.
      • Clinical Meaning: The confidence interval suggests the true effect could be anywhere from a 23% benefit to a 5% harm. Because it crosses the line of no effect (1.0), the result is not statistically significant.
    • P-value:
      • Calculation: The reported p-value was 0.19.
      • Clinical Meaning: The p-value of 0.19 is above the conventional threshold of 0.05, indicating that the observed difference in mortality could be due to chance.

8. Strengths of the Study

  • Large and Rigorous: This was a large, multicenter, randomized trial that addressed a key question in ARDS management.
  • Important Clinical Question: It was one of three major trials (along with ALVEOLI and EXPRESS) that sought to define the optimal PEEP strategy in ARDS.
  • Patient-Centered Outcome: The primary outcome of 28-day mortality is a strong, patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which could have introduced performance bias.
  • External Validity (Generalizability): The findings are highly generalizable to patients with ARDS in academic medical centers.
  • Other: The separation in PEEP between the two groups was modest, which may have made it more difficult to detect a true difference in outcomes.

10. Conclusion of the Authors

“In patients with acute lung injury and the acute respiratory distress syndrome, a strategy of lung-protective ventilation that includes higher levels of positive end-expiratory pressure and recruitment maneuvers does not reduce mortality, as compared with a strategy that includes lower levels of positive end-expiratory pressure.”

11. To Summarize

  • Impact on Current Practice: This was a major “negative” trial that, along with the ALVEOLI and EXPRESS trials, demonstrated that a one-size-fits-all “high PEEP” strategy is not superior to a more moderate PEEP strategy for unselected patients with ARDS. It reinforced that while low tidal volume is crucial, the optimal PEEP level is more complex and likely needs to be individualized.
  • Specific Recommendations:
    • Patient Selection: For the general population of adult patients with ARDS.
    • Actionable Intervention: It is reasonable to use either the higher PEEP (LOVS) or lower PEEP (ARDSNet) strategy, as neither was shown to be superior for mortality.
  • What This Trial Does NOT Mean: This trial does NOT mean that high PEEP is never beneficial. It suggests that applying it routinely to all ARDS patients is not effective. There may be a subgroup of patients with more recruitable lungs who do benefit from higher PEEP.

12. Context and Related Studies

  • Building on Previous Evidence: The LOVS trial was designed to build on the ARMA trial by testing whether an “open lung” strategy could further improve outcomes.
  • Influence on Subsequent Research: The neutral results of the three major PEEP trials (ALVEOLI, EXPRESS, and LOVS) have shifted the focus of research away from finding a single best PEEP-FiO2 table and toward more individualized approaches to PEEP setting, often using physiological parameters like driving pressure or esophageal manometry to guide therapy.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: How can we identify the subgroup of ARDS patients who are “recruiters” and are most likely to benefit from high PEEP? What is the best method to individualize PEEP at the bedside?
  • Future Directions: Research is ongoing to develop and validate methods for personalizing PEEP titration in ARDS, with the goal of maximizing lung recruitment while minimizing overdistension.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was highly relevant, addressing a major area of clinical uncertainty in ARDS management following the landmark ARMA trial.
  • Methods: The large, multicenter, randomized design was of high quality and appropriate for the question.
  • Results: The trial had a clear negative result for its primary outcome of mortality, despite showing some physiological benefits (improved oxygenation). This highlights the important distinction between improving physiological variables and improving patient-centered outcomes.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair interpretation of the data. The results are highly applicable and have been instrumental in shaping modern ARDS guidelines, which do not recommend a routine high PEEP strategy for all patients.

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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