MEDURI 2007: Prolonged Methylprednisolone in ARDS (2007)

“In patients with severe early ARDS, prolonged administration of methylprednisolone was associated with a significant improvement in pulmonary and multiple-organ dysfunction and a reduction in mortality.”

— The Meduri et al. Study Group

1. Publication Details

  • Trial Title: Methylprednisolone Infusion in Early Severe ARDS: Results of a Randomized Controlled Trial.
  • Citation: Meduri GU, Golden E, Freire AX, et al. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest. 2007;131(4):954-963. doi:10.1378/chest.06-2101.
  • Published: April 2007, in Chest.
  • Author: G. Umberto Meduri, M.D.
  • Funding: University of Tennessee Health Science Center.

2. Keywords

Acute Respiratory Distress Syndrome (ARDS), Corticosteroids, Methylprednisolone, Inflammation, Mechanical Ventilation, Lung Injury Score.

3. The Clinical Question

In adult patients with severe, early-phase ARDS (Population), does a prolonged, tapering course of methylprednisolone (Intervention) compared to placebo (Comparison) improve lung function and reduce mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The pathophysiology of ARDS involves a severe, dysregulated inflammatory response in the lungs. While short courses of high-dose corticosteroids had not shown benefit, it was theorized that a prolonged, lower-dose regimen might be able to modulate the persistent inflammation seen in non-resolving ARDS.
  • Knowledge Gap: The efficacy and safety of a prolonged, tapering course of methylprednisolone started in the early phase of severe ARDS had not been established in a randomized controlled trial.
  • Proposed Hypothesis: The authors hypothesized that prolonged administration of methylprednisolone would reduce systemic inflammation, improve lung function, and reduce mortality in patients with severe early ARDS.

5. Study Design and Methods

  • Design: A prospective, single-center, randomized, double-blind, placebo-controlled trial.
  • Setting: A single medical-surgical ICU at a university-affiliated hospital in the United States.
  • Trial Period: Enrollment from January 2003 to January 2006.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with severe ARDS (PaO2:FiO2 ratio <200 and a Lung Injury Score [LIS] >2.5) who had been intubated for <72 hours.
    • Exclusion Criteria: Major contraindications to corticosteroids, pregnancy, or conditions with a life expectancy of <28 days.
  • Intervention: Methylprednisolone, administered as a loading dose of 1 mg/kg, followed by a continuous infusion of 1 mg/kg/day, which was slowly tapered over 14 days or more.
  • Control: Matching placebo (saline) administered in the same manner.
  • Management Common to Both Groups: All patients were managed with a standardized lung-protective ventilation strategy and a sedation protocol.
  • Power and Sample Size: The trial was powered to detect a 3-point difference in the change in LIS over 14 days, requiring 90 patients.
  • Outcomes:
    • Primary Outcome: Change in the Lung Injury Score (LIS) from baseline to day 14.
    • Secondary Outcomes: Included 28-day mortality, ventilator-free days, and ICU-free days.

6. Key Results

  • Enrollment and Baseline: 91 patients were randomized (63 to methylprednisolone, 28 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: The methylprednisolone group had a significantly greater improvement (reduction) in the Lung Injury Score compared to the placebo group.
  • Secondary Outcomes: The methylprednisolone group had significantly lower 28-day mortality (20.6% vs 42.9%; P=0.03), more ventilator-free days (median 13 vs 5 days), and more ICU-free days (median 11 vs 2 days).
  • Adverse Events: There was no significant difference in the rate of new infections. Hyperglycemia was more common in the methylprednisolone group.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using repeated-measures analysis. Mortality was compared using a chi-square test.
  • Primary Outcome Analysis: The change in LIS over time was compared between the two groups.
  • Key Statistic(s) Reported (for 28-day mortality): 28-day mortality: 20.6% (13/63) in the methylprednisolone group vs 42.9% (12/28) in the placebo group; P=0.03.
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: RR = 20.6% / 42.9% = 0.48.
      • Clinical Meaning: An RR of 0.48 means there was a 52% lower relative risk of death at 28 days in the methylprednisolone group compared to the placebo group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The calculated 95% CI for the RR is approximately 0.26 to 0.89.
      • Clinical Meaning: Since the 95% CI does not cross the line of no effect (1.0), the result is statistically significant.
    • P-value:
      • Calculation: The reported p-value was 0.03.
      • Clinical Meaning: The p-value of 0.03 is less than the conventional threshold of 0.05, indicating that the observed difference in mortality is unlikely to be due to chance.
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group).
      • Calculation: ARR = 42.9% – 20.6% = 22.3%.
      • Clinical Meaning: For every 100 patients with early severe ARDS treated with prolonged methylprednisolone, about 22 fewer died by day 28.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR.
      • Calculation: NNT = 1 / 0.223 = 4.5.
      • Clinical Meaning: Approximately 5 patients with early severe ARDS need to be treated with this prolonged methylprednisolone regimen to prevent one additional death at 28 days.
  • Subgroup Analyses: Not reported.

8. Strengths of the Study

  • Study Design and Conduct: The randomized, double-blind, placebo-controlled design provided high-quality evidence.
  • Physiologic Rationale: The trial tested a specific, physiologically-based intervention (prolonged anti-inflammatory therapy) with a clear rationale.
  • Standardized Co-interventions: The use of standardized protocols for ventilation and sedation in both groups was a major strength.

9. Limitations and Weaknesses

  • Internal Validity (Bias): No major limitations to internal validity.
  • External Validity (Generalizability): The most significant limitation is that this was a single-center study with a relatively small sample size. The findings require confirmation in a larger, multicenter trial.
  • Other: The mortality rate in the placebo group (43%) was quite high, which may have made it easier to show a large treatment effect.

10. Conclusion of the Authors

“In patients with severe early ARDS, a prolonged infusion of methylprednisolone, as compared with placebo, was associated with a significant reduction in the duration of mechanical ventilation and ICU stay, and a significant improvement in survival.”

11. To Summarize

  • Impact on Current Practice: This trial was highly influential and controversial. It provided the strongest evidence to date for a mortality benefit from corticosteroids in ARDS and suggested that a prolonged, tapering regimen was key. However, its single-center nature and the memory of previous negative steroid trials meant it did not immediately change practice for everyone. Its main impact was to reignite the debate and provide the strong justification for larger, definitive multicenter trials.
  • Specific Recommendations:
    • Patient Selection: For adult patients with severe ARDS (PaO2:FiO2 <200) within the first 72 hours of intubation.
    • Actionable Intervention: This study provides evidence to consider a prolonged, tapering course of methylprednisolone.
    • Expected Benefit: A significant reduction in 28-day mortality, with an NNT of approximately 5.
  • What This Trial Does NOT Mean: This trial does not mean that all patients with ARDS should receive steroids. The benefit was seen in patients with severe, early ARDS.
  • Implementation Caveats: Patients treated with corticosteroids require close monitoring for side effects, particularly hyperglycemia.

12. Context and Related Studies

  • Building on Previous Evidence: This trial was a direct response to the negative results of the ARDSNet LaSRS trial (2006), which tested a similar regimen but started it much later in the course of ARDS (after 7 days). Meduri’s trial tested the hypothesis that starting the intervention early was critical.
  • Influence on Subsequent Research: This trial was the direct impetus for the large, multicenter DEXA-ARDS trial (2020), which tested a similar prolonged steroid strategy (using dexamethasone) in patients with moderate-to-severe ARDS and confirmed a significant benefit in reducing mortality and ventilator-free days.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: Can the positive findings of this single-center trial be replicated in a large, multicenter setting? What is the optimal corticosteroid, dose, and duration?
  • Future Directions: The positive findings of this trial, largely confirmed by DEXA-ARDS, have solidified the role of corticosteroids in moderate-to-severe ARDS. Future research is focused on personalizing therapy using biomarkers to identify which patients are most likely to respond.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was highly relevant, re-examining the role of corticosteroids in ARDS with a novel, physiologically-driven protocol.
  • Methods: The randomized, double-blind, placebo-controlled design was methodologically strong.
  • Results: The trial showed a surprisingly large and statistically significant benefit for its primary and key secondary outcomes, including a dramatic reduction in mortality.
  • Conclusions and Applicability: The authors’ conclusion is a direct interpretation of their data. However, the single-center nature and small size of the trial are major limitations to its immediate, widespread applicability. The results are best viewed as compelling, hypothesis-generating findings that required (and largely received) confirmation in a larger, multicenter trial before being adopted as a standard of care.

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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