Background: Sepsis occurs when an infection is complicated by organ failure. Sepsis may be complicated by impaired corticosteroid metabolism. Thus, providing corticosteroids may benefit patients. The original review was published in 2004 and was updated in 2010 and 2015 prior to this update.
Objectives: To examine the effects of corticosteroids on death in children and adults with sepsis.
Search methods: We searched CENTRAL, MEDLINE, Embase, LILACS, ClinicalTrials.gov, ISRCTN, and the WHO Clinical Trials Search Portal, on 25 July 2019. In addition, we conducted reference checking and citation searching, and contacted study authors, to identify additional studies as needed.
Selection criteria: We included randomized controlled trials (RCTs) of corticosteroids versus placebo or usual care (antimicrobials, fluid replacement, and vasopressor therapy as needed) in children and adults with sepsis. We also included RCTs of continuous infusion versus intermittent bolus of corticosteroids.
Data collection and analysis: All review authors screened and selected studies for inclusion. One review author extracted data, which was checked by the others, and by the lead author of the primary study when possible. We obtained unpublished data from the authors of some trials. We assessed the methodological quality of trials and applied GRADE to assess the certainty of evidence. Review authors did not contribute to assessment of eligibility and risk of bias, nor to data extraction, for trials they had participated in.
Main results: We included 61 trials (12,192 participants), of which six included only children, two included children and adults, and the remaining trials included only adults. Nine studies are ongoing and will be considered in future versions of this review. We judged 19 trials as being at low risk of bias. Corticosteroids versus placebo or usual care Compared to placebo or usual care, corticosteroids probably slightly reduce 28-day mortality (risk ratio (RR) 0.91, 95% confidence interval (CI) 0.84 to 0.99; 11,233 participants; 50 studies; moderate-certainty evidence). Corticosteroids may result in little to no difference in long-term mortality (RR 0.97, 95% CI 0.91 to 1.03; 6236 participants; 7 studies; low-certainty evidence) and probably slightly reduce hospital mortality (RR 0.90, 95% CI 0.82 to 0.99; 8183 participants; 26 trials; moderate-certainty evidence). Corticosteroids reduced length of intensive care unit (ICU) stay for all participants (mean difference (MD) -1.07 days, 95% CI -1.95 to -0.19; 7612 participants; 21 studies; high-certainty evidence) and resulted in a large reduction in length of hospital stay for all participants (MD -1.63 days, 95% CI -2.93 to -0.33; 8795 participants; 22 studies; high-certainty evidence). Corticosteroids increase the risk of muscle weakness (RR 1.21, 95% CI 1.01 to 1.44; 6145 participants; 6 studies; high-certainty evidence). Corticosteroids probably do not increase the risk of superinfection (RR 1.06, 95% CI 0.95 to 1.19; 5356 participants; 25 studies; moderate-certainty evidence). Corticosteroids increase the risk of hypernatraemia (high-certainty evidence) and probably increase the risk of hyperglycaemia (moderate-certainty evidence). Moderate-certainty evidence shows that there is probably little or no difference in gastroduodenal bleeding, stroke, or cardiac events, and low-certainty evidence suggests that corticosteroids may result in little to no difference in neuropsychiatric events. Continuous infusion of corticosteroids versus intermittent bolus We are uncertain about the effects of continuous infusion of corticosteroids compared with intermittent bolus administration. Three studies reported data for this comparison, and the certainty of evidence for all outcomes was very low.
Authors' conclusions: Moderate-certainty evidence indicates that corticosteroids probably reduce 28-day and hospital mortality among patients with sepsis. Corticosteroids result in large reductions in ICU and hospital length of stay (high-certainty evidence). There may be little or no difference in the risk of major complications; however, corticosteroids increase the risk of muscle weakness and hypernatraemia, and probably increase the risk of hyperglycaemia. The effects of continuous versus intermittent bolus administration of corticosteroids are uncertain.
Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Conflict of interest statement
Djillali Annane is an author of the following studies included in this review: Aboab 2008; Annane 2002; Annane 2010; Annane 2018; Sprung 2008. He obtained funds from the French Minisitry of Health to conduct the following trials: Annane 2002; Annane 2010; and Annane 2018. He has been the chair of the international task force for elaborating 2017 guidelines for the diagnosis and treatment of critical illness‐related corticosteroid insufficiency.
Eric Bellissant is an author of the following studies included in this review: Annane 2002; Annane 2018.
Pierre Edouard Bollaert is an author of the following studies included in this review: Annane 2002; Bollaert 1998. He obtained public funds from the University of Nancy to conduct the trial (Bollaert 1998).
Josef Briegel is an author of the following studies included in this review: Briegel 1999; Keh 2016; Sprung 2008. He obtained public funds to conduct the trial (Briegel 1999). He contributed to the international task force for elaborating 2017 guidelines for the diagnosis and treatment of critical illness‐related corticosteroid insufficiency. He participated in the European Society of Intensive Care Medicine, the Deutsche interdisziplinäre Vereinigung Intensivmedizin, and the Deutsche Gesellschaft für Anästhesie und Intensivmedizin, and he has given lectures and talks on hydrocortisone treatment for septic shock.
Didier Keh is an author of the following studies included in this review: Keh 2003; Keh 2016; Sprung 2008. He obtained public funds from Charité–Universitätsmedizin Berlin and from the German Federal Ministry of Education and Research to conduct the following trials: Keh 2003; Keh 2016.
Yizhak Kupfer is an author of the following studies included in this review: Chawla 1999. He is a member of the Pfizer/BMS speakers' bureau for epixaban. This product has no relationship to steroids in sepsis. He obtained funds from his institution to conduct the trial (Chawla 1999).
Romain Pirracchio received funding for International Mobility from the Fulbright Foundation and from the Assistance Publique – Hôpitaux de Paris (APHP).
Bram Rochwerg is supported by McMaster University Department of Medicine early career research awards. He has contributed to the international task force for elaborating 2017 guidelines for the diagnosis and treatment of critical illness‐related corticosteroid insufficiency. He is a methodologist for American Thoracic Society, European Society of Intensive Care Medicine, and American Society of Haematology.
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