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Methylprednisolone Infusion in Early Severe ARDS Results of a Randomized Controlled Trial

Methylprednisolone Infusion in Early Severe ARDS Results of a Randomized Controlled Trial

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Methylprednisolone Infusion in Early Severe ARDS Results of a Randomized Controlled Trial

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  1. Methylprednisolone Infusion in Early Severe ARDSResults of a Randomized Controlled Trial Meduri et all Chest 2007;131;954-963

  2. Background • Inflammation in the first week of MV determines resolving vs un-resolving • Un-resolving ARDS LIS by day 7 • PEEP • PaO2/FIO2 • Static Lung Compliance • CXR • Dysregulated systemic inflammation

  3. Background • Methylprednisolone (2 mg/kg/d) non-improvers after 9 days of • Sustained reductions in plasma and BAL inflammatory • Improvement in lung injury and MODS scores. • Reduction in duration of MV and ICU mortality Meduri GU, Headley S, Golden E, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA 1998; 280:159 –165

  4. Background These results do not support the routine use of methylprednisolone for persistent ARDS despite the improvement in cardiopulmonary physiology. In addition, starting methylprednisolone therapy more than two weeks after the onset of ARDS may increase the risk of death

  5. Hypothesis • Prolonged administration of low-dose methylprednisolone (1 mg/kg/d) initiated in early ARDS (within 72 h of diagnosis) downregulates systemic inflammation and leads to earlier resolution of pulmonary organ dysfunction and a reduction in duration of mechanical ventilation and ICU

  6. Design • April 1997 to April 2002 in 5 ICU’s • 2:1 methylprednisolone: placebo randomization • Loading dose of 1 mg/kg • 1 mg/kg/d from day 1 to day 14, • 0.5 mg/kg/d from day 15 to day 21, • 0.25 mg/kg/d from day 22 to day 25, • 0.125 mg/kg/d from day 26 to day 28. • 240 mL of normal saline solution and administered daily as an infusion at 10 mL/h

  7. Design • MV ARDSnet • Bronch + bl BAL was per- formed prior to study entry, and then every 5 to 7 days • Day 7 and 9, un-blinded methylpred- nisolone therapy (2 mg/kg/d) for un-resolving ARDS • Infection surveillance and avoidance of neuromuscular blocking agents

  8. Design • The primary outcome variable was • Improvement in LIS by study day 7 • For patients remaining intubated on study day 7 • a reduction in LIS 1 point • day 7 LIS ≤ 2.0 (for study entry LIS ≤ 2.9) or 2.5 (for study entry LIS ≥ 3.0)

  9. Statistical Analysis • The study was analyzed as intention-to- treat. • “Per protocol” analysis is recommended to reflect scientific methods of the protocol. • All statistical calculations were preformed using the SAS System for Windows • Significance was defined as a 2-tailed test with an alpha of .05.

  10. Results

  11. Baseline Characteristics

  12. Baseline Characteristics

  13. Results Among patients with and without shock, improvement in the primary variable was observed: methylprednisolone vs placebo, 67% vs 23% (p 0.03) and 71% vs 47% (p 0.09)

  14. Results

  15. Results

  16. Results

  17. Results • ICU mortality • Pts catecholamine-dependent shock was 73% vs 46% (p 0.24) • Pts w/o shock was 81% vs 67% (p 0.29). • In per-protocol analysis with catecholamine-dependent shock was 90% vs 71% (p 0.07) • Between day 7 - 9, 14 patients failed to meet criteria for improvement in LIS (8% vs 36%; p 0.002) and received open-label. • Day 14, 3 pts (5%) in the Rx group and 10 pts (36%) in the control group remained on MV (p 0.0001).

  18. Results • There were fewer-than-expected observed infections in the methylprednisolone group

  19. Discussion • The surrogate marker for pulmonary inflammation was LIS; the markers for systemic inflammation were CRP • By study day 7 twice the proportion of patients randomized to Rx achieving a 1-point reduction in LIS • Improvement was not significantly affected by the baseline imbalance in the proportion of patients with catecholamine-dependent shock

  20. Ventilator Free Days

  21. Discussion • In patients with un-resolving ARDS, premature discontinuation of methylpred-nisolone administration was associated with physiologic deterioration • In the recent ARDS network study, the large benefits observed during methylprednisolone treatment were partially lost after premature discontinuation of study drug

  22. Limitations • Small Sample size • Imbalances pts with catecholamine-dependent shock that may have biased the estimate of the treatment effect on mortality • Surviving sepsis • Ventilator protocol • Open label cross over