Key messages
• Compared to placebo or usual care, corticosteroids probably reduce the risk of death at 28 days and of in-hospital death, and may have little or no effect on the risk of dying beyond three months.
• We are uncertain about the effects of continuous intravenous infusion of corticosteroids compared with intermittent intravenous bolus (rapid injection) administration.
• Future studies should measure the benefits and harms of corticosteroids for the treatment of specific populations, including children, patients with sepsis without shock or with a mild form of septic shock, patients with acute respiratory distress syndrome (ARDS) and patients with different types of infections. Defining the optimal methods for corticosteroid administration, including the types of molecule - with or without producing sodium and fluid retention and potassium excretion (mineralocorticoid activity), timing of initiation, dose and duration, continuous infusion or intermittent intravenous boluses, and ending of treatment - with or without gradually decreasing the dose to zero, also requires additional studies. Future studies should measure the longer-term effects, i.e. longer than one year, on survival and complications of sepsis.
What is sepsis?
Sepsis is present when an infection is complicated by organ failure. People develop rapid breathing, hypotension (low blood pressure) and mental confusion. Sepsis can interfere with the effectiveness of the body’s corticosteroids, which control how your body recognises and defends itself against bacteria, viruses and substances that appear foreign and harmful.
What are corticosteroids (medicine)?
Corticosteroids are medicines used to stop excessive inflammation. However, these medicines may cause unwanted harms, such as increased blood sugar or salt levels, infections, bleeding in the stomach, agitation or delirium, and weakness of the limbs. Corticosteroids have been given for decades to people with infection resulting from various causes.
What did we want to find out?
We wanted to find out:
• the benefits of using corticosteroids in children and adults with sepsis; and
• the best ways to administer this treatment (including the best people to give it to).
We also wanted to know if corticosteroids can cause any unwanted effects.
What did we do?
We searched for studies that compared:
• corticosteroids administered intravenously against a 'dummy' treatment, or sham treatment, which does not contain any medicine but looks or tastes identical to corticosteroids, or usual care; or
• continuous infusion against intermittent rapid intravenous injections (boluses) of corticosteroids administration.
We compared and summarised their results, and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
This review includes 87 trials (24,336 participants). The biggest study was of 3800 people and the smallest study was of 21 people. Eighty-three trials compared corticosteroids to no corticosteroids (placebo or usual care in 59 and 24 trials, respectively). Four trials also compared continuous administration versus rapid intravenous injection (i.e. bolus) of corticosteroids given at fixed intervals of six or eight hours. Thirty-three trials were conducted in Europe, 15 in North America, 22 in Asia, six in the Middle East, six in Africa and three in Latin America; four were multinational trials.
Three trials were funded by a drug company, 27 by public organisations or through charitable funding and six by both a drug company and public organisations or charitable funding; 25 did not declare the source of funding.
Compared to placebo or usual care, corticosteroids probably reduce the risk of death at 28 days by 10% (72 trials; 22,915 participants), with consistent treatment effects between children and adults. There may be little or no effect of corticosteroids on the risk of dying over the long term (longer than three months), but these results are less certain. Corticosteroids probably reduce the risk of dying in hospital. Corticosteroids may result in a reduction in the length of stay in the intensive care unit (ICU) and in hospital. They may not increase the risk of superinfection (second infection). The evidence is very uncertain about the effect of corticosteroids on the risk of muscle weakness.
We are uncertain about the effects of continuous intravenous infusion of corticosteroids compared with intermittent intravenous bolus (rapid injection) administration. Four studies reported data for this comparison, and the certainty of evidence for all outcomes was very low.
What are the limitations of the evidence?
• Corticosteroids versus placebo or usual care
We have moderate confidence in our findings that corticosteroids reduced 28-day mortality. We found some differences amongst the study populations, the types of corticosteroids and how they were given, and the use of additional medicines.
• Continuous infusion versus bolus administration of corticosteroids
We have very little confidence in our findings about the absence of a difference in 28-day mortality between the administration of corticosteroids continuously and repeated rapid intravenous injections. We found only four studies that enrolled very few patients.
How up-to-date is this evidence?
The evidence provided in this review is current to December 2023.
Read the full abstract
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 strategy
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.
