Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids for treating sepsis in children and adults. Cochrane Database Syst Rev. 2019 Dec 6;12:CD002243. doi: 10.1002/14651858.CD002243.pub4. (Systematic review)

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 We obtained unpublished data from the authors of some trials.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.

Discipline Area Score
Pediatric Emergency Medicine 5 / 7
Emergency Medicine 6 / 7
Hospital Doctor/Hospitalists 6 / 7
Internal Medicine 6 / 7
Infectious Disease 6 / 7
Intensivist/Critical Care 6 / 7
Pediatric Hospital Medicine 5 / 7
Comments from MORE raters

Emergency Medicine rater

This Cochrane review evaluates corticosteroids in sepsis, including 61 studies (12,192 patients). Only 6 evaluated pediatric patients. Investigators found steroids may reduce death at 28 days, but this may not be present beyond this time period. They also reduce length-of-stay, but may increase muscle weakness. They were uncertain concerning infusion vs bolus dosing. Further study on infusion vs bolus dosing and pediatric patients is required.

Emergency Medicine rater

Very useful article that provides suggestions and evidence for a significant clinical issue!

Infectious Disease rater

In the eternal question of whether corticosteroids have a role to play in the management of sepsis, this Cochrane review gives a rousing, "maybe, maybe not" answer. There is fairly good evidence that steroids can modify the course of sepsis with some early parameters showing a measurable benefit. As always, there is a price to pay for the early benefit and this is manifest as an increased rate of muscle weakness. For a hospitalist, the early benefits are helpful, but for a patient it's a hard call. In a better world, we might someday have sufficiently personalized medicine to predict who has the greatest likelihood of benefit and the lowest risk and model treatment according to that. Alternatively, we might learn about the way in which steroid modulate the dysregulation surrounding sepsis and address that. For now, ongoing confusion and uncertainty with a slight edge to using steroids.

Intensivist/Critical Care rater

Given the results of the ADRENAL and APROCCHSS studies, this is what I would I have expected the results of an updated MA and SR to show. Considerable clinical heterogeneity exists between the included studies with regard to the inclusion criteria. The MA includes trials that enrolled participants with sepsis (as well as septic shock). No analyses of these subgroups or according to severity of septic shock (vasopressor dose) is provided. The APPROCCHSS trial included participants who required at least 0.25 mcg/kg/min of norepinephrine or epinephrine. As a practicing intensivist, my interpretation is that the benefits of corticosteriods probably outweigh the risks in critically ill adult patients with septic shock who require moderate to high doses of vasopressor therapy. In patients not in septic shock or who require a low dose of vasopressor, uncertainty exists.

Intensivist/Critical Care rater

Hydrocortisone treatment is used during sepsis and may improve hemodynamic status; however, divergent results led to uncertainty. This large meta-analysis included 61 trial and 12,192 patients. The results are positive for mortality and length of ICU and hospital stay despite an increase in the risk for muscle weakness. Future work is needed to elucidate the mechanisms of shock reversal.

Pediatric Emergency Medicine rater

I'm unable to tease out the pediatric data from the adult data to have a meaningful understanding of the conclusion drawn.

Pediatric Hospital Medicine rater

This article supports only that corticosteroids probably have little effect on the evolution of sepsis in children.

Pediatric Hospital Medicine rater

Extremely useful for hospital doctors who deal with sepsis in children.
Comments from EvidenceAlerts subscribers

Dr. marco confalonieri (1/1/2020 10:26 AM)

This is a very interesting review on a topic of great interest.