Corticosteroid therapy for acute lung injury, acute respiratory distress syndrome, and severe pneumonia: A meta-analysis of randomized controlled trials

Abstract

Background

Randomized trials investigating the effect of corticosteroids in the treatment of acute lung injury, acute respiratory distress syndrome, and severe pneumonia have had mixed results. We sought to determine whether systemic corticosteroids reduce hospital mortality from these illnesses.

Methods

We conducted a systematic review of published and unpublished randomized trials. We searched MEDLINE, EMBASE, CENTRAL, and CINAHL and reviewed proceedings from relevant society meetings. Two reviewers screened the literature and extracted data independently. For each outcome, we used Grading of Recommendations Assessments, Development and Evaluation (GRADE) criteria to evaluate the quality of the underlying evidence.

Results

We included 12 trials enrolling 966 patients. Pooling across all trials, corticosteroids did not significantly reduce hospital mortality (relative risk, 0.84; 95% confidence interval, 0.66-1.06). In a subgroup analysis by dose of corticosteroid, trials using the equivalent of 2 mg kg⁻¹ d⁻¹ or less of methylprednisolone (9 trials) found lower hospital mortality with corticosteroid therapy (relative risk 0.68; 95% confidence interval, 0.49-0.96). The quality of the evidence underlying the pooled estimate of effect on hospital mortality was low, downgraded for inconsistency and imprecision.

Conclusions

Low-dose corticosteroids administered within 14 days of disease onset may reduce all-cause mortality in patients with acute lung injury, acute respiratory distress syndrome, and severe pneumonia. However, the overall quality of the evidence precludes definitive conclusions regarding the use of corticosteroids in this population.

Introduction

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common complications of critical illness, affecting up to 20% of mechanically ventilated patients [1], [2]. Mortality estimates range from 30% to 40% [3].

These lung injuries typically appear 24 to 48 hours after a critical insult and persist for days to weeks [4], [5]. Current evidence suggests that excessive production of proinflammatory cytokines (tumor necrosis factor, interleukin [IL]-1, IL-6, IL-8) and neutrophil recruitment to the lungs mediate the disease process [6]. A similar pattern of excessive interleukin production may also play a role in the pathogenesis of pneumonias [7], [8], [9], [10]. Moreover, the duration of inflammatory cytokine production seems related to a worse outcome for patients with ARDS [11].

As our understanding of the pathophysiology progresses, the definitions for ALI and ARDS also evolve. An American-European consensus in 1994 [12] led to the adoption of the criteria currently in use (acute onset, bilateral pulmonary infiltrates, Pao₂/Fio₂ ratio less than 300 for ALI and less than 200 for ARDS, and absence of elevated end-diastolic left ventricular pressure). Studies published before their widespread adoption used other syndromal definitions. Regardless of the definition used, there is considerable overlap in the definitions for ALI and ARDS and the defining criteria for severe pneumonia, one of the most frequent causes of ALI and ARDS [2], [13], [14], [15], [16].

Corticosteroids modulate most steps of the inflammatory process. In ALI and ARDS, their administration causes significant reductions in tumor necrosis factor α and IL-1 through inhibitory effects on nuclear factor κB [17], [18]. Corticosteroid therapy may improve gas exchange and lung injury scores and reduce the requirement for mechanical ventilation by reducing the pulmonary and circulating levels of proinflammatory mediators [17], [18], [19], [20], [21], [22]. One recent review did not convincingly demonstrate that these biochemical effects translated into survival benefits (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.23-1.26) [23], whereas another found more compelling evidence that prolonged low-dose corticosteroids decreased mortality (relative risk [RR], 0.62; 95% CI, 0.43-0.90) [24].

Our primary objective was to elucidate the effects of systemic corticosteroid therapy, administered within 14 days of diagnosis, compared with placebo or standard care on hospital mortality in patients with ALI, ARDS, or severe pneumonia. We performed a systematic review and meta-analysis of published and unpublished randomized trials.