Corticosteroids in ARDS: A Counterpoint

Abstract

Meduri et al highlight the nature of the ongoing debate over the value of corticosteroids in acute lung injury/ARDS. The study by Confalonieri and colleagues1Confalonieri M Urbino R Potena A et al.Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study.Am J Respir Crit Care Med. 2005; 171: 242-248Crossref PubMed Scopus (530) Google Scholar was not included in our review because the study population had severe pneumonia, not ARDS. The retrospective study by Annane et al2Annane D Sebille V Bellissant E Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome.Crit Care Med. 2006; 34: 22-30Crossref PubMed Scopus (230) Google Scholar was a secondary analysis of a randomized controlled trial of corticosteroids in septic shock; benefit was noted in the subgroup of patients with sepsis-associated ARDS who failed to respond to a corticotropin stimulation test. The benefits of corticosteroids in this group likely derive from their beneficial effects in the overall population of nonresponders in this study rather than from an effect specific to ARDS; no statistical test of interaction between corticosteroid therapy and ARDS was reported in the article. In addition, while post hoc subgroup analysis may be useful for hypothesis generation, generalizing the findings to patient treatment can be perilous.3Assmann SF Pocock SJ Enos LE et al.Subgroup analysis and other (mis)uses of baseline data in clinical trials.Lancet. 2000; 355: 1064-1069Abstract Full Text Full Text PDF PubMed Scopus (867) Google Scholar The 2007 study by Meduri et al was not published at the time of our review; however, this trial4Meduri GU Golden E Freire AX et al.Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial.Chest. 2007; 131: 954-963Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar has significant limitations as well. For one, the majority of patients randomized to placebo who remained on mechanical ventilation at day 9 of the study were crossed over to open-label methylprednisolone, making outcomes analysis after that point (such as mortality and ventilator-free days) very difficult to interpret. In our review,5Calfee CS Matthay MA Non-ventilatory management of acute lung injury and the acute respiratory distress syndrome.Chest. 2007; 131: 913-920Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar we focused on the largest and most rigorous trial on this issue: the prospective, randomized controlled trial performed by the ARDS Network, which demonstrated no mortality benefit to corticosteroids.6The Acute Respiratory Distress Syndrome Network Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome.N Engl J Med. 2006; 354: 1671-1684Crossref PubMed Scopus (1064) Google Scholar We agree that the size of the subgroup of patients randomized after day 14 in this study is small, and that conclusions drawn from this subgroup, albeit a prespecified one, should be tempered by this consideration; however, most of the baseline imbalances cited by the letter were not statistically significant. We also question the validity of the authors' approach of pooling data from the five studies cited in their letter. Since the trials did not have similar inclusion criteria (ie, ARDS vs pneumonia, early vs late ARDS), they would be poor candidates for a traditional metaanalysis.7Bent S Shojania KG Saint S The use of systematic reviews and meta-analyses in infection control and hospital epidemiology.Am J Infect Control. 2004; 32: 246-254Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Moreover, the authors do not describe their meta-analysis methods (ie, fixed vs random-effects model, statistical tests for heterogeneity). For these reasons, we also disagree with their calculation of a number needed to treat based on this data. The heterogeneity of prior studies was a primary driving force behind the creation of the ARDS Network's large randomized controlled trial, which has rendered the most definitive verdict in this field. Corticosteroids in ARDS: A CounterpointCHESTVol. 132Issue 3PreviewThe review article by Calfee and Matthay (March 2007)1 provides an incomplete picture of the recent literature on prolonged glucocorticoid treatment in ARDS. Five randomized trials (n = 518) have been published investigating prolonged glucocorticoid (hydrocortisone, 200 to 240 mg/d; methylprednisolone, 1 mg/kg/d) treatment in early acute lung injury (ALI) [Pao2/fraction of inspired oxygen (Fio2) < 300],2 early ARDS (Pao2/Fio2 < 200),34 and unresolving ARDS (methylprednisolone, 2 mg/kg/d).56 These trials consistently reported that prolonged glucocorticoid treatment was associated with significant improvement in Pao2/Fio2,23456 and a significant reduction in markers of systemic inflammation,23456 BAL neutrophilia,67 duration of mechanical ventilation,23456 and ICU stay. Full-Text PDF