Corticosteroids for treating sepsis

Review question

We reviewed the evidence on effects on survival at one month and on tolerance of systemic corticosteroids in people with sepsis.

Background

Sepsis, the most severe form of infection, is present when a site of infection is apparent and evidence suggests body-wide, systemic inflammation and organ failures. The person develops poor temperature control, an increase or decrease in white blood cells, an increase in heart rate and rapid breathing. Sepsis can interfere with effectiveness of the body’s own corticosteroids, which serve as key defence hormones against infection. Corticosteroids have been given for more than 60 years to people with severe infection resulting from various causes.

Search date

The evidence provided in this review was current to October 2014.

Study characteristics

This review included a total of 33 randomized controlled trials, accounting for 4268 hospitalized patients with sepsis. Three trials included children, and the remaining 30 trials included only adults. Corticosteroids were compared with placebo in all except five trials, in which they were compared with standard therapy alone.

Study funding sources

Ten out of 33 trials were funded by a drug company, 13 were funded by public organizations or received charitable funding and 10 stated no source of funding.

Key results

Corticosteroids reduced risk of death at 28 days by 13% (among 27 trials, 3176 participants). Both intensive care unit (ICU) and in-hospital deaths were reduced (13 and 17 trials, respectively). The review found that survival benefits were dependent on the dose of corticosteroids - the lower the dose (less than 400 mg of hydrocortisone or equivalent per day) for a longer duration of treatment (three or more days at the full dose) the better - and on the severity of illness. Corticosteroids increased the chance of recovery from septic shock by day seven (when drugs are required to support blood pressure) by 31% (from 12 trials) and the number of organs that were not functioning properly (organ failure) (from eight trials). Length of stay in the ICU was reduced by more than two days (10 trials). Corticosteroids did not cause harm, except for a mild increase in blood glucose and salt (sodium) levels (13 and three trials, respectively). Gastrointestinal bleeding and infection (19 trials) and neuromuscular weakness (three trials) were not increased.

We found sparse data on effects of corticosteroids in children with sepsis.

Quality of evidence

We judged the quality of evidence for 28-day mortality as low because of imprecision (the confidence interval of the statistical result approached no change) and inconsistency across trials. These findings were related in part to differences among study populations, type of corticosteroid given, dose and duration of treatment and use of additional interventions. The quality of evidence for 28-day mortality in the subgroup given a long course of low-dose corticosteroids was downgraded from high to moderate because one of the two largest trials on a long course of low-dose corticosteroids reported no survival benefit.

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.

Read the full 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 strategy: 

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).

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