Corticosteroids for treating sepsis

Djillali Annane, Eric Bellissant, Pierre Edouard Bollaert, Josef Briegel, Didier Keh, Yizhak Kupfer, Djillali Annane, Eric Bellissant, Pierre Edouard Bollaert, Josef Briegel, Didier Keh, Yizhak Kupfer

Abstract

Background: Sepsis occurs when an infection is complicated by organ failures as defined by a sequential organ failure assessment (SOFA) score of two or higher. Sepsis may be complicated by impaired corticosteroid metabolism. Giving corticosteroids may benefit patients. The original review was published in 2004 and was updated in 2010 and again in 2015.

Objectives: To examine the effects of corticosteroids on death at one month in patients with sepsis, and to examine whether dose and duration of corticosteroids influence patient response to this treatment.

Search methods: We searched the Central Register of Controlled Trials (CENTRAL; 2014, Issue 10), MEDLINE (October 2014), EMBASE (October 2014), Latin American Caribbean Health Sciences Literature (LILACS; October 2014) and reference lists of articles, and we contacted trial authors. The original searches were performed in August 2003 and in October 2009.

Selection criteria: We included randomized controlled trials of corticosteroids versus placebo or supportive treatment in patients with sepsis.

Data collection and analysis: All review authors agreed on the eligibility of trials. One review author extracted data, which were checked by the other review authors, and by the primary author of the paper when possible. We obtained some missing data from trial authors. We assessed the methodological quality of trials.

Main results: We identified nine additional studies since the last update, for a total of 33 eligible trials (n = 4268 participants). Twenty-three of these 33 trials were at low risk of selection bias, 22 were at low risk of performance and detection bias, 27 were at low risk of attrition bias and 14 were at low risk of selective reporting.Corticosteroids reduced 28-day mortality (27 trials; n = 3176; risk ratio (RR) 0.87, 95% confidence interval (CI) 0.76 to 1.00; P value = 0.05, random-effects model). The quality of evidence for this outcome was downgraded from high to low for imprecision (upper limit of 95% CI = 1) and for inconsistency (significant heterogeneity across trial results). Heterogeneity was related in part to the dosing strategy. Treatment with a long course of low-dose corticosteroids significantly reduced 28-day mortality (22 trials; RR 0.87, 95% CI 0.78 to 0.97; P value = 0.01, fixed-effect model). The quality of evidence was downgraded from high to moderate for inconsistency (owing to non-significant effects shown by one large trial). Corticosteroids also reduced mortality rate in the intensive care unit (13 trials; RR 0.82, 95% CI 0.68 to 1.00; P value = 0.04, random-effects model) and at the hospital (17 trials; RR 0.85, 95% CI 0.73 to 0.98; P value = 0.03, random-effects model). Quality of the evidence for in-hospital mortality was downgraded from high to moderate for inconsistency and imprecision (upper limit of 95% CI for RR approaching 1). Corticosteroids increased the proportion of shock reversal by day seven (12 trials; RR 1.31, 95% CI 1.14 to 1.51; P value = 0.0001) and by day 28 (seven trials; n = 1013; RR 1.11, 95% CI 1.02 to 1.21; P value = 0.01) and reduced the SOFA score by day seven (eight trials; mean difference (MD) -1.53, 95% CI -2.04 to -1.03; P value < 0.00001, random-effects model) and survivors' length of stay in the intensive care unit (10 trials; MD -2.19, 95% CI -3.93 to -0.46; P value = 0.01, fixed-effect model) without inducing gastroduodenal bleeding (19 trials; RR 1.24, 95% CI 0. 92 to 1.67; P value = 0.15, fixed-effect model), superinfection (19 trials; RR 1.02, 95% CI 0.87 to 1.20; P value = 0.81, fixed-effect model) or neuromuscular weakness (three trials; RR 0.62, 95% CI 0.21 to 1.88; P value = 0.40, fixed-effect model). Corticosteroid increased the risk of hyperglycaemia (13 trials; RR 1.26, 95% CI 1.16 to 1.37; P value < 0.00001, fixed-effect model) and hypernatraemia (three trials; RR 1.64, 95% CI 1.28 to 2.09; P value < 0.0001, fixed-effect model).

Authors' conclusions: Overall, low-quality evidence indicates that corticosteroids reduce mortality among patients with sepsis. Moderate-quality evidence suggests that a long course of low-dose corticosteroids reduced 28-day mortality without inducing major complications and led to an increase in metabolic disorders.

Conflict of interest statement

The following review authors have been involved in randomized controlled trials of low‐dose hydrocortisone that are included in this updated review: Djillali Annane in Annane 2002 and Sprung 2008; Eric Bellissant in Annane 2002; Pierre Edouard Bollaert in Bollaert 1998 and Annane 2002; Josef Briegel in Briegel 1999 and Sprung 2008; Didier Keh in Keh 2003 and Sprung 2008; and Yizhak Kupfer in Chawla 1999.

Djillali Annane is involved with one ongoing study: NCT00625209 2008. This trial is funded by the French Ministry of Social Affairs, Health and Women Rights ‐ Programme Hospitalier de Recherche Clinique PHRC‐12‐002‐0030.

Didier Keh is involved with one ongoing study: NCT00670254 2008. This trial is funded by the Federal Ministry of Education and Research (01KG0701).

Yizhak Kupfer: I am a member of the Pfizer/BMS speakers' bureau for epixaban. This product has no relationship to steroids in sepsis.