Corticosteroids in the Treatment of Sepsis

Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids for treating sepsis in children and adults. Cochrane Database Syst Rev. 2019;12(12):CD002243.

Study Population: 12,192 adults and children with sepsis, from 61 trials

28-day, 90-day, long-term, in-hospital, and ICU mortality, shock reversal at 7 and 28 days, SOFA score at day 7, length of stay in ICU and hospital

Gastroduodenal bleeding, superinfection, hyperglycemia, hypernatremia, muscle weakness, neuropsychiatric event, stroke, cardiac event

Sepsis remains a major contributor to morbidity and mortality in the United States,1 and is now recognized as a dysregulated inflammatory response.2 There is laboratory evidence corticosteroids may affect this dysregulated response.3

The review summarized here by Annane et al4 found that corticosteroids may confer a short term, but not overall, mortality benefit for patients with sepsis. Specifically, they found moderate certainty evidence for reduced 28-day mortality (relative risk [RR] 0.91, 95% confidence interval [CI] 0.84 to 0.99; n=11233).

The review also found decreased intensive care unit (ICU) mortality (RR 0.89, 95% CI, 0.83-0.96; n=7267) and hospital mortality (RR 0.90, 95% CI, 0.82-0.99; n=8183) with high to moderate certainty evidence respectively. Annane et al suggested a signal of decreased 90-day mortality (RR 0.93, 95% CI, 0.87-1.00; n=5934), however it failed to reach statistical significance. Beyond 90 days, they found low certainty evidence that there is no mortality benefit (RR 0.97, 95% CI, 0.91-1.03; n=6236). The review found additional benefits of corticosteroids in sepsis including decreased intensive care unit length of stay (mean difference [MD] -1.07 days, 95% CI -1.95 to -0.19, n=7612) and hospital length of stay (MD -1.63 days, 95% CI -2.93 to -0.33, n=8795), decreased organ dysfunction or sequential organ failure assessment (SOFA) score at day 7 (MD -1.37, 95% CI - 1.84 to -0.90, n=2157), and increased number of patients with shock reversal at day 7 (RR 1.23, 95% CI, 1.13-1.34; n=6711) and day 28 (RR 1.06, 95% CI, 1.03-1.08; n=6779).

Complications of corticosteroids included an increase in hyperglycemia (RR 1.17, 95% CI, 1.13- 1.22; n=8594), hypernatremia (RR 1.66, 95% CI, 1.34-2.06; n=5069), and muscle weakness (RR 1.21, 95% CI, 1.01-1.44; n=6145). There were no statistically significant harms in other proposed complications of corticosteroids including gastroduodenal bleeding, superinfection, neuropsychiatric events, stroke or cardiac events.

We recognize that many systematic reviews and meta-analyses have explored the use of corticosteroids in sepsis. We chose to summarize the Cochrane Systematic review by Annane et al,4 as it includes the largest (61 trials including 12192 adults and children) and most recent data (including trials up to July 25, 2019), including trials in non-English language as well as unpublished data.

For the primary outcome of 28-day mortality, the review decreased the certainty of evidence from high to moderate for concerns of heterogeneity (I² =29.47%) across trial results. One reason for this significant heterogeneity may be broad inclusion criteria including trials dating back as early as 1972. A priori subgroup analyses found 28-day mortality benefit with long course (≥3 days) of low-dose (≤400mg hydrocortisone or equivalent) corticosteroids (RR 0.91, 95% CI, 0.87-0.97; n=9902) but not with short course of high-dose corticosteroids (RR 0.96, 95% CI, 0.8-1.16; n=910). Furthermore, differences in methodological quality may contribute to heterogeneity, with subgroup analysis of studies with low risk of bias demonstrating 28-day mortality benefit (RR 0.91, 95% CI, 0.84-0.98; n=7896).

Of note, the review includes secondary outcomes of 90-day and long-term (defined as “longest available follow-up beyond three months) mortality. While 28-day was mortality was the primary outcome for the majority of the 61 included trials, it is noteworthy that the two most recent and largest studies5^, 6 used 90-day mortality as their primary outcome. If the future studies continue to include 90-day mortality as a primary outcome, future systematic reviews may provide further clarity if patient-centered long-term benefits or harms truly exist.

The review identifies additional areas for future investigation. The review suggests a possible added benefit of mineralocorticoids, with 28-day mortality benefit of hydrocortisone plus fludrocortisone (RR 0.87, 95% CI, 0.77-0.98; n=1564). Secondly, investigation of the ideal modality of corticosteroid (intermittent bolus vs continuous infusion) found no significant difference (test for subgroup differences Chi² =0.41). Additionally, tapering of corticosteroids was not associated with 28-day mortality difference (RR 1.04, 95% CI, 0.92-1.18; n=2136) whereas absence of taper was (RR 0.87, 95% CI, 0.78-0.98; n=8770). Finally, this review does not find sufficient evidence to suggest the role of corticosteroids in children, different causes of sepsis(for example, ARDS vs community associated pneumonia), or in those with or without shock.

In summary, we assign a recommendation of yellow (potential benefits may outweigh harms) for the use of corticosteroids in patients with sepsis. This review demonstrates benefits in short term mortality, without clear long-term benefit, and at the expense of harms.

The original manuscript was published in Academic Emergency Medicine as part of the partnership between TheNNT.com and AEM.

See theNNT.com's previous reviews of this topic:
Systemic Steroids for Sepsis Syndromes , September 7, 2010

July 1, 2020