Effect of Prolonged Methylprednisolone Therapy in Unresolving Acute Respiratory Distress Syndrome

Meduri. JAMA 1998; 280(2):159-165

Clinical Question

• Does a prolonged course of intravenous methylprednisolone improve lung function and reduce mortality in patients with unresolving ARDS

Design

• Randomised and double-blinded
• Randomised in blocks of 3 according to a random number generator and stratified by site

Setting

• 4 Medical ICU’s in different hospitals in Memphis, US
• October 1994 – November 1996

Population

• Inclusion:
  • ARDS by criteria 1995  NEJM ref 2
  • Received 7 days of mechanical ventilation with a *Lung Injury Score (LIS) of 2.5 or greater and < 1 point reduction from day 1 of ARDS
  • No evidence of untreated infection
  • 18 years or older
• Exclusion:
  • Participation in any other research trial
  • ARDS > 3 weeks
  • Extensive burns
  • Life expectancy < 3 months
  • Pregnancy
  • Recent gastrointestinal bleed
  • Presence of disease requiring more than 1mg/kg/day of methylprednisolone
• 16 patients received methylprednisolone and 8 received placebo
• At study entry (day 9 [SD 3] of ARDS) both groups had similar LIS, PaO2/FiO2 ratio and MODS score 
  • 4 patients in each group had ARDS secondary to community acquired pneumonia
  • Other causes included drug interactions (TCA overdose and anaphylaxis), aspiration and pulmonary blastomycosis

Intervention

• Methylprednisolone for 32 days
  • Loading dose 2 mg/kg/day and then the same total daily dose for 14 days
  • Methylprednisolone dose was tapered from day 15 to 32
  • If the patient was extubated prior to day 14, treatment was advanced to day 15

Control

Outcome

• Primary outcome:
  • ICU mortality
    • 0 of 16 in intervention group vs. 5 of 8 patients in the control group (62%) p=0.002 NNT 2
  • Improvement in LIS (>1 point) in intervention group compared with placebo group after 10 days of treatment
    • 100% vs. 25% NNT 2
    • mean LIS (SEM) 1.7 (0.1) vs. 3.0 (0.2); p<0.001
• Secondary outcomes favoured the intervention group
  • Hospital mortality: 2 of 16 (13%) in intervention group vs. 5 of 8 patients in the control group (62%); p=0.03
  • Death associated with unresolving ARDS (PaO2/FiO2 of 75 or less at the time of death): 0 of 2 patients vs. 5 of 5 (100%)
  • PaO2/FiO2 ratio at study day 10: mean 262 vs. 148; p<0.001
  • Successful extubation by day 10: 7 patients (44%) vs. 0 patients
  • Mean MODS score at study day 10: 0.7 vs. 1.8; p=0.001
  • MODS-free days at study day 28: 16 (2%) vs. 6 (2%); p=0.005
  • Median duration of mechanical ventilation
    • 11.5 days vs. 23 days; p=0.001
  • Survival at study day 10: 16 (100%) vs 6 (75%), p=0.1
• Other outcomes
  • Infections per 100 days of treatment was similar
  • Ventilator associated pneumonia occurred more frequently in the intervention group but this did not reach statistical significance
  • survival in patients treated with placebo throughout the study period vs. survival in patients treated with methylprednisolone at any time
    • 2 (50%) vs. 23 (82%), p=0.2

Authors’ Conclusions

• ‘In this study, prolonged administration of methylprednisolone in patients with unresolving ARDS was associated with improvement in lung injury and MODS score and reduced mortality’

Strengths

• Prolonged treatment course
• Cross over provision for patients who did not respond to other treatment interventions
• Careful protocol for identifying infection including regular bronchoscopy
• Select patient group

Weaknesses

• Trial stopped early
• Sicker patients in the placebo group although not statistically significant (LIS 3 vs. 3.3, p=0.16; MODS score 1.5 vs. 2.5, p-0.22)
• Little explanation of methodology particularly with regards to ventilatory strategy
• CT or other radiological data would have been useful
• Instead of a traditional power analysis, the study used a sequential analysis of study results as data accumulated. This analysis led to an very small trial size of 24 patients  despite a long trial period. The original power calculation was for 99 patients to be recruited
• With only 8 patients in the placebo group
  • 3 of 8 (> 1/3) had causes other than community acquired pneumonia for developing ARDS (1 pulmonary blastocytosis; 1 anaphylactic reaction to urokinase; 1 chemical aspiration).
  • only 4 patients were treated with placebo throughout the study period as the other 4 patients were swapped to the intervention group at day 10

Metadata

Summary author: @stevemathieu75
Summary date: 8th August 2014
Peer-review editor: @davidslessor