Glucocorticosteroids for sepsis: systematic review with meta-analysis and trial sequential analysis

Abstract

Introduction: Glucocorticosteroids (steroids) are widely used for sepsis patients. However, the potential benefits and harms of both high and low dose steroids remain unclear. A systematic review of randomised clinical trials with meta-analysis and trial sequential analysis (TSA) might shed light on this clinically important question.

Methods: A systematic review was conducted according to a published protocol and The Cochrane Handbook methodology including meta-analyses, TSA of randomised clinical trials, and external validity estimation (GRADE). Randomised clinical trials evaluating steroids were included for sepsis patients (systemic inflammatory response syndrome, sepsis, severe sepsis or septic shock) aged >18 years. Cochrane Central Register of Controlled Trials (CENTRAL), PubMed/Medline, Embase, Web of Science and Cinahl were searched until 18 February 2015. No language restrictions were applied. Primary outcomes were mortality at longest follow-up and serious adverse events.

Results: A total of 35 trials randomising 4682 patients were assessed and reviewed in full text. All trials but two had high risk of bias. No statistically significant effect was found for any dose of steroids versus placebo or no intervention on mortality at maximal follow-up [relative risk (RR) 0.89; TSA adjusted confidence interval (CI) 0.74-1.08]. Two trials with low risk of bias also showed no statistically significant difference (random-effects model RR 0.38, 95% CI 0.06-2.42). Similar results were obtained in subgroups of trials stratified according to high (>500 mg) or low (≤ 500 mg) dose hydrocortisone (or equivalent) (RR 0.87; TSA-adjusted CI 0.38-1.99; and RR 0.90; TSA-adjusted CI 0.49-1.67, respectively). There were also no statistically significant effects on serious adverse events other than mortality (RR 1.02; TSA-adjusted CI 0.7-1.48). The effects did not vary according to the degree of sepsis. TSA showed that many more randomised patients are needed before definitive conclusions may be drawn.

Conclusion: Evidence to support or negate the use of steroids in any dose in sepsis patients is lacking. The results of ongoing and future well-designed, large randomised clinical trials are needed.

Fig. 1

Randomised clinical trials with mortality data showing for each trial the hydrocortisone dose (on the first day) (white bars) and the time interval from sepsis/septic shock onset until randomisation/start treatment (black bars); a high dose steroids (>500 mg hydrocortisone or equivalent) and b low dose (≤500 mg hydrocortisone or equivalent). When other steroids were used, the equivalent hydrocortisone dose was calculated using the table in the Oxford Handbook of Critical Care [17]. When doses were expressed in milligrams per kilogram body weight, daily doses were calculated assuming a body weight of 75 kg. The trials by Hoffman [37], Klastersky [29], Scarborough [30], Schumer [43], Snijders [40], Rinaldi [58], Ruolan [59] and Wan [31] did not provide information on the time interval. The trials by Schumer [43] and Sprung [44] included two intervention groups using different doses of steroids: D dexamethasone, MP methylprednisolone

Fig. 1

Randomised clinical trials with mortality data showing for each trial the hydrocortisone dose (on the first day) (white bars) and the time interval from sepsis/septic shock onset until randomisation/start treatment (black bars); a high dose steroids (>500 mg hydrocortisone or equivalent) and b low dose (≤500 mg hydrocortisone or equivalent). When other steroids were used, the equivalent hydrocortisone dose was calculated using the table in the Oxford Handbook of Critical Care [17]. When doses were expressed in milligrams per kilogram body weight, daily doses were calculated assuming a body weight of 75 kg. The trials by Hoffman [37], Klastersky [29], Scarborough [30], Schumer [43], Snijders [40], Rinaldi [58], Ruolan [59] and Wan [31] did not provide information on the time interval. The trials by Schumer [43] and Sprung [44] included two intervention groups using different doses of steroids: D dexamethasone, MP methylprednisolone

Fig. 2

Forest plot of mortality at longest follow-up of all trials evaluating steroids for sepsis with subgroups according to risk of bias (random-effects model)

Fig. 3

Forest plot of serious adverse events of all trials evaluating steroids for sepsis with subgroups according to risk of bias (random-effects model)

Fig. 4

Forest plot of mortality at longest follow-up of low dose steroids (≤500 mg hydrocortisone or equivalent) use according to risk of bias subgroups (random-effects model)