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. This is an update of a review originally published in 2004 and previously updated in 2010, 2015 and 2019.
OBJECTIVES: To examine the benefits and harms of corticosteroids 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 31 December 2023. In addition, we conducted reference checking and citation research, and contacted study authors, to identify additional studies as needed. We updated this search in December 2024, but these results have not yet been incorporated.
SELECTION CRITERIA: We included randomised 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: We used the same methods in comparisons of corticosteroids versus placebo or usual care, and of continuous infusion versus intermittent bolus administration of corticosteroids. The primary outcome was all-cause mortality at 28 days. The most critical secondary outcomes were (i) all-cause mortality in the long term (last follow-up from 90 days to one year) and in the hospital; (ii) length of stay in the intensive care unit and in hospital; (iii) adverse effects, i.e. superinfection and muscle weakness (within 28 days). 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. For this update, we used Covidence software for screening and selection of studies and abstraction of data by paired review authors, with discrepancies resolved by a third review author. We obtained unpublished data from the authors of some trials. We assessed the risk of bias in trials using the Cochrane risk of bias tool (RoB 1) and applied GRADE to assess the certainty of evidence. The review authors did not contribute to the assessment of eligibility or risk of bias, nor to data extraction, for the trials they had participated in.
MAIN RESULTS: We included 87 trials (24,336 participants), of which six included only children, two included children and adults, and the remaining trials included only adults. Seventeen additional trials are ongoing and will be considered in future versions of this review. We judged 25 trials as being at low risk of bias. Corticosteroids versus placebo or usual care Compared to placebo or usual care, corticosteroids probably reduce 28-day mortality (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.84 to 0.95; 72 trials, 22,915 participants; moderate-certainty evidence). We downgraded the certainty of evidence for this outcome from high to moderate for inconsistency (significant heterogeneity across trial results). Corticosteroids may result in little to no difference in long-term mortality (RR 0.97, 95% CI 0.91 to 1.03; 12 trials, 8468 participants; low-certainty evidence) and probably reduce in-hospital mortality (RR 0.90, 95% CI 0.84 to 0.97; 40 trials, 17,459 participants; moderate-certainty evidence). Corticosteroids may reduce length of intensive care unit (ICU) stay for all participants (mean difference (MD) -0.86 days, 95% CI -1.67 to -0.05; 25 trials, 8069 participants; low-certainty evidence) and may reduce length of hospital stay for all participants (MD -1.09 days, 95% CI -1.85 to -0.34; 31 trials, 16,954 participants; low-certainty evidence). The evidence is uncertain about the effect of corticosteroids on the risk of muscle weakness (RR 1.09, 95% CI 0.78 to 1.53; 7 trials, 6729 participants; very low-certainty evidence). Corticosteroids may result in little to no difference in the risk of superinfection (RR 0.96, 95% CI 0.86 to 1.07; 36 trials, 7961 participants; low-certainty evidence). Continuous infusion of corticosteroids versus intermittent bolus Four trials reported data for this comparison, and the certainty of evidence for all outcomes was very low. We are uncertain about the effects of continuous infusion of corticosteroids compared with intermittent bolus administration on 28-day mortality (RR 1.03, 95% CI 0.81 to 1.32; 3 trials, 310 participants). We downgraded the certainty of evidence to very low due to high risk of bias in all except one trial and due to imprecision. Compared to bolus administration, we are uncertain of the effects of continuous infusion of corticosteroids on long-term mortality (RR 1.36, 95% CI 1.02 to 1.81; 1 trial, 70 participants; very low-certainty evidence), in-hospital mortality (RR 0.92, 95% CI 0.71 to 1.19; 3 trials, 352 participants; very low-certainty evidence), ICU length of stay amongst all participants (MD -0.56 days, 95% CI -3.44 to 2.32; 4 trials, 422 participants; very low-certainty evidence), hospital length of stay amongst all participants (MD -0.21 days, 95% CI -4.72 to 4.30; 4 trials, 422 participants; very low-certainty evidence), risk of muscle weakness (RR 0.89, 95% CI 0.13 to 5.98; 1 trial, 70 participants; very low-certainty evidence) and risk of superinfection (RR 1.12, 95% CI 0.37 to 3.33; 2 trials, 193 participants; very low-certainty evidence).
AUTHORS' CONCLUSIONS: Moderate-certainty evidence indicates that corticosteroids probably reduce 28-day, 90-day and hospital mortality amongst patients with sepsis. Corticosteroids may shorten ICU and hospital length of stay (low-certainty evidence). There may be little or no difference in the risk of superinfection. The risk of muscle weakness is uncertain. The effects of continuous versus intermittent bolus administration of corticosteroids are uncertain.
| Discipline Area | Score |
|---|---|
| Hospital Doctor/Hospitalists |  |
| Internal Medicine | |
| Infectious Disease | |
| Intensivist/Critical Care | |
| Emergency Medicine |  |
| Pediatric Emergency Medicine | |
This Cochrane analysis of the effectiveness of corticosteroids in mortality from sepsis for patients in the ICU was done using strict Cochrane methodology. Summary: *Steroids probably reduce mortality in hospital and at 28 days (RR=0.89, 95% CI 0.84-0.95)but little difference is seen beyond 3 months. *Steroids may reduce ICU and hospital length of stay. *Whether steroids are given intermittently or by continuous infusion made no real difference. *There were multiple areas where steroids seem to make little or no difference: muscle weakness, superinfection, long-term mortality. Summary: ICU use of steroids in sepsis might decrease mortality. This is unlikely to make a difference in the Emergency Department where we don't know for certain which patients have sepsis (i.e., if steroids help septic patients as in this study, they may not make any difference in the group that the ED treats for presumed sepsis, many of whom don't have sepsis.
The findings of this Cochrane review align with the 2024 Society for Critical Care Medicine clinical practice guideline recommendations in support of corticosteroids to reduce 28-day mortality for sepsis patients https://journals.lww.com/ccmjournal/fulltext/2024/05000/2024_focused_update__guidelines_on_use_of.23.aspx so probably does not alter management for most emergency medicine physicians.
The devil is always in the details. Generally, steroids likely help in sepsis.
Steroids in sepsis. Help! This is known but good to review in kids as well.
Major concern: This study used the very broad term "sepsis" to include several different sepsis definitions among non-comparable eras (1972-2023) of sepsis usual care, including the conflation with septic shock, which is not comparable to sepsis. The evidence is consistent regarding the inefficacy of steroids in patients with sepsis, explaining why the surviving sepsis guideline does not recommend it for sepsis, but only for refractory septic shock. Actually, the full version of this new meta-analysis shows that steroids may be harmful for patients with sepsis since the main estimate is in the opposite direction - RR is above 1 with most 95% CIs on the harm side (increased mortality), while it may be beneficial for septic shock - RR is below 1 with most 95% CIs on the benefit side (decreased mortality) - analysis 1.8. Thus, this study's conclusion should be: "Low-certainty evidence suggests that corticosteroids probably reduce mortality amongst patients with septic shock."
This Cochrane review examined the effects of steroid in sepsis in both adult and pediatric patients. The results were that steroids may reduce 28-day mortality but not long-term mortality. Although this result is rated as moderate certainty by the authors, it is not new. However, the authors did an extra step and investigated infusion vs IV push dose. The evidence for this was low certainty and there was no statistically significant difference. Thus, this result will likely not be applicable to clinical practice.
An excellent systematic review. The data on this topic has not changed much in the past few years, and this review does not add much to clinical practice.
This large systematic review is still not conclusive about the role of corticosteroids in sepsis. I think this is of limited relevance to peds ED physicians.
