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Meta-Analysis
. 2015 Dec 3;2015(12):CD002243.
doi: 10.1002/14651858.CD002243.pub3.

Corticosteroids for treating sepsis

Djillali Annane  1 , Eric Bellissant, Pierre Edouard Bollaert, Josef Briegel, Didier Keh, Yizhak Kupfer
Affiliations
Meta-Analysis

Corticosteroids for treating sepsis

Djillali Annane et al. Cochrane Database Syst Rev. .

Update in

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.

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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.

Figures

Figure 1
Figure 1
Flow diagram.
Figure 2
Figure 2
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Figure 3
Figure 3
Figure represents the results from meta‐regression of log of risk ratio of dying and log of the dose of corticosteroids given at day 1 and expressed as equivalent mg of hydrocortisone. Estimates from each study are represented by circles. Circle sizes depend on the precision of each estimate (the inverse of its within‐study variance), which is the weight given to each study in the fixed‐effect model. Meta‐regression included 26 trials. The trial by Schummer et al was not included. REML estimate of between‐study variance tau2 = .01078. % residual variation due to heterogeneity: I2 res = 5.07% Proportion of between‐study variance explained Adj R2 = 11.16%
Figure 4
Figure 4
Figure represents results from meta‐regression of log of risk ratio of dying and log of cumulated dose of corticosteroids expressed as equivalent mg of hydrocortisone. Estimates from each study are represented by circles. Circle sizes depend on the precision of each estimate (the inverse of its within‐study variance), which is the weight given to each study in the fixed‐effect model. Meta‐regression included 26 trials. The trial by Schummer et al was not included. REML estimate of between‐study variance tau2 = .01183 % residual variation due to heterogeneity I2 res = 6.99% Proportion of between‐study variance explained Adj R2 = 2.49%
Figure 5
Figure 5
Funnel plot of comparison: 1 Steroids versus control, outcome: 1.1 28‐Day all‐cause mortality.
Figure 6
Figure 6
Contour‐enhanced funnel plot Log of risk ratio for 28‐day mortality is plotted against its standard error
Analysis 1.1
Analysis 1.1
Comparison 1 Steroids versus control, Outcome 1 28‐Day all‐cause mortality.
Analysis 1.2
Analysis 1.2
Comparison 1 Steroids versus control, Outcome 2 All‐cause mortality by subgroup based on mortality rate.
Analysis 1.3
Analysis 1.3
Comparison 1 Steroids versus control, Outcome 3 28‐Day all‐cause mortality by subgroups based on methodological quality.
Analysis 1.4
Analysis 1.4
Comparison 1 Steroids versus control, Outcome 4 28‐Day all‐cause mortality by subgroups based on treatment dose/duration.
Analysis 1.5
Analysis 1.5
Comparison 1 Steroids versus control, Outcome 5 28‐Day all‐cause mortality by subgroups based on targeted population.
Analysis 1.6
Analysis 1.6
Comparison 1 Steroids versus control, Outcome 6 28‐Day mortality in participants with critical illness‐related corticosteroid insufficiency.
Analysis 1.7
Analysis 1.7
Comparison 1 Steroids versus control, Outcome 7 Intensive care unit mortality.
Analysis 1.8
Analysis 1.8
Comparison 1 Steroids versus control, Outcome 8 Hospital mortality.
Analysis 1.9
Analysis 1.9
Comparison 1 Steroids versus control, Outcome 9 Number of participants with shock reversal at day 7.
Analysis 1.10
Analysis 1.10
Comparison 1 Steroids versus control, Outcome 10 Number of participants with shock reversal at 28 days.
Analysis 1.11
Analysis 1.11
Comparison 1 Steroids versus control, Outcome 11 SOFA score at day 7.
Analysis 1.12
Analysis 1.12
Comparison 1 Steroids versus control, Outcome 12 Length of ICU stay for all participants.
Analysis 1.13
Analysis 1.13
Comparison 1 Steroids versus control, Outcome 13 Length of ICU stay for survivors.
Analysis 1.14
Analysis 1.14
Comparison 1 Steroids versus control, Outcome 14 Length of hospital stay for all participants.
Analysis 1.15
Analysis 1.15
Comparison 1 Steroids versus control, Outcome 15 Length of hospital stay for survivors.
Analysis 1.16
Analysis 1.16
Comparison 1 Steroids versus control, Outcome 16 Number of participants with adverse events.
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Update of

References

References to studies included in this review

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Additional references

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References to other published versions of this review

    1. Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y. Corticosteroids for treating severe sepsis and septic shock. Cochrane Database of Systematic Reviews 2004, Issue 1. [DOI: 10.1002/14651858.CD002243.pub2] - DOI - PubMed
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    1. Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y. Corticosteroids for treating sepsis. Cochrane Database of Systematic Reviews 2015, Issue 12. [DOI: 10.1002/14651858.CD002243.pub3] - DOI - PMC - PubMed

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