Supplementary Material for: Continuous versus Intermittent Hydrocortisone for the Treatment of Septic Shock: A Systematic Review and Meta-Analysis

Objectives: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) and comparative cohort studies comparing continuous with intermittent intravenous hydrocortisone in adults with septic shock. Subjects and Methods: Searches of MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were conducted till July 2025. The primary outcome was all-cause mortality; secondary outcomes included hospital and ICU length of stay, shock reversal, hypernatremia, hypokalemia, and vasopressor use. Risk of bias was assessed using Cochrane RoB 2.0 for RCTs and the Newcastle–Ottawa Scale for cohort studies. A random-effects model was applied, and certainty of evidence was graded with GRADE. Results: Eight studies (five RCTs, three cohort studies) including 609 patients were analyzed. Continuous infusion was not associated with a significant reduction in mortality compared with intermittent infusion (RR 0.83, 95% CI 0.65–1.06; p=0.13; I²=36%). No significant differences were observed in hospital stay (MD 0.10 days, 95% CI –1.40 to 1.61), ICU stay (MD –0.02 days, 95% CI –0.63 to 0.58), shock reversal (RR 0.94, 95% CI 0.61–1.46), hypernatremia (RR 1.05, 95% CI 0.51–2.16), hypokalemia (RR 0.64, 95% CI 0.40–1.03), or vasopressor duration (MD –0.97 days, 95% CI –4.00 to 2.05). Certainty of evidence ranged from very low to moderate. Conclusion: Continuous and intermittent hydrocortisone infusion demonstrated comparable clinical outcomes in septic shock. Large, multicenter RCTs are warranted to determine the optimal administration strategy.