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Corticosteroids in severe sepsis and septic shock—results of a recent meta-analysis

Severe sepsis and septic shock are both associated with a high rate of mortality.¹ Rapid therapy, begun shortly after recognition of the condition, is essential to improve outcomes. Current guidelines from the Society of Critical Care Medicine (SCCM) recommend fluid support (as resuscitation) and antibiotic therapy as initial treatment for severe sepsis or septic shock. Additional hemodynamic support can then be used, consisting of fluids (crystalloids or colloids), vasopressors, or inotropic therapies. In addition, corticosteroids can be considered. The current guidelines recommend that corticosteroids (as intravenous hydrocortisone) be given only to patients unresponsive to fluid resuscitation and vasopressor therapy (i.e., hypotension despite use of these measures). This recommendation for the use of corticosteroids is based in part on the results of the CORTICUS (Corticosteroid Therapy of Septic Shock) study, during which low-dose intravenous hydrocortisone (50 mg every 6 hours for 5 days, followed by a 6-day taper for 29 doses total) or placebo was given to 499 patients with septic shock.² At 28 days, no difference was seen in mortality between the 2 groups, regardless of patients’ response to corticotropin (34.3% mortality with hydrocortisone vs. 31.5% with placebo; p=0.51). The CORTICUS study did find that the use of hydrocortisone was associated with a significantly shorter duration to reversal of shock compared with placebo (3.3 days vs. 5.8 days), with no difference in the proportion of patients who underwent reversal (79.7% for hydrocortisone vs. 74.2% for placebo; p=0.18). However, other earlier, smaller studies have reported some beneficial effects of corticosteroids, including improvements in mortality, depending on the dose and duration used.^1-3

Meta-analysis findings
To further assess the efficacy or place of corticosteroids in the treatment of septic shock, Annane and colleagues conducted a meta-analysis of available trials using these agents for treatment of severe sepsis and septic shock.³ Included in the analysis were studies enrolling adult patients with severe sepsis or septic shock given corticosteroids (e.g., cortisone, hydrocortisone, methylprednisolone, betamethasone, or dexamethasone) at a low dose (≤ 300 mg daily of hydrocortisone or equivalent) or a high dose (> 300 mg daily). A long course of therapy was considered to be a full-dose course of treatment for at least 5 days; therapy for less than 5 days was considered a short course. The primary outcome used in the analysis was 28-day any cause mortality, comparing corticosteroid use to controls (standard therapies [e.g., fluids, vasopressor, antibiotics] excluding corticosteroids). Subgroup analyses were also conducted for dose (high vs. low) and duration (long vs. short). Twenty randomized (17 trials) or quasi-randomized (3 trials) trials were included for a total of 2384 patients; 16 trials were double-blinded. Most trials were small, with half enrolling 50 patients or less; however, 4 large trials (including the CORTICUS study) contributed a total of 1404 patients.

Rates for 28-day any cause mortality were 35.9% for patients given corticosteroids and 38.5% for control patients, for a relative risk (RR) of 0.84 (95% confidence interval [CI], 0.71-1.00; p=0.05) for the available 17 randomized trials (2138 patients); for the 3 remaining quasi-randomized trials, the RR for mortality was 1.05 (95% CI, 0.69-1.58; p=0.83). For all 20 trials included in the analysis, the RR for mortality was 0.87 (95% CI, 0.74-1.01), indicating no significant difference between the corticosteroid group and controls. However, significant differences were found between the 2 treatments after subgroup analyses based on dose and duration. A significantly lower 28-day mortality was seen with prolonged low-dose corticosteroids compared to controls; RR 0.84 (95% CI, 0.72-0.97; p=0.02) based on analysis of 12 studies. No difference was seen between short course, high-dose corticosteroids and controls (RR 0.94 [95% CI, 0.69-1.30]) in 7 trials.

For studies evaluating shock reversal by day 7, corticosteroids showed a significantly increased risk of shock reversal compared to controls (RR 1.29 [95% CI, 1.06-1.58; p<0.01]). This effect was maintained in trials using a prolonged course of low-dose corticosteroids (RR 1.35 [95% CI 1.06-1.58]). For all studies evaluating shock reversal at 28 days, significance was seen in favor of corticosteroids (RR 1.12 [95% CI, 1.02-1.23]). Corticosteroids also resulted in a significantly shorter length of intensive care unit stay (mean difference -4.49 days; p<0.001). No difference was seen between groups in regards to adverse events, such as gastrointestinal bleeding, neuromuscular weakness, or superinfections; the risk of hyperglycemia was greater with corticosteroids (RR 1.16 [95% CI, 1.07-1.25; p<0.001]).

Summary
Although corticosteroids did not have a significant effect on 28-day any cause mortality in patients with severe sepsis or septic shock, subgroup analyses of studies evaluating a prolonged, low-dose course of corticosteroids found a significant effect in favor of corticosteroids. Based on their findings, the authors concluded that a short course of high dose corticosteroids is not supported and suggested that corticosteroids should be considered at a dose of 200 to 300 mg of hydrocortisone (or equivalent) daily with a duration of at least 100 hours for patients with vasopressor-dependent shock. This dose is consistent with the current SCCM guidelines, which recommend against doses in excess of 300 mg daily.

References