Supplementary Material for: Efficacy and safety of hydrocortisone, ascorbic acid, and thiamine combination therapy for the management of sepsis and septic shock: A systematic review and meta-analysis of randomised controlled trials

Introduction This systematic review aimed to assess the efficacy and safety of hydrocortisone, ascorbic acid, and thiamine (HAT) combination therapy in patients with sepsis and septic shock. Methods We conducted a database search in MEDLINE, Embase, CENTRAL, Web of Science, and CNKI for randomised controlled trials (RCTs) comparing HAT against placebo/standard of care or against hydrocortisone in sepsis/septic shock patients. Outcomes included mortality, ICU/hospital length of stay (LOS), vasopressor durations, mechanical ventilation durations, change in SOFA at 72 hours, and adverse events. RCT results were pooled in random-effects meta-analyses. Quality of evidence was assessed using GRADE. Results Fifteen RCTs (N=2,594) were included. At 72 hours, HAT reduced SOFA scores from baseline (MD -1.16, 95% CI -1.58 to -0.74, I2=0%) compared to placebo/SoC, based on moderate quality of evidence. HAT also reduced the duration of vasopressor use (MD -18.80 hours, 95% CI -23.67 to -13.93, I2=64%) compared to placebo/SoC, based on moderate quality of evidence. HAT increased hospital LOS (MD 2.05 days, 95% CI 0.15 to 3.95, I2=57%) compared to placebo/SoC, based on very low quality of evidence. HAT did not increase incidence of adverse events compared to placebo/SoC. Conclusions HAT appears beneficial in reducing vasopressor use and improving organ function in sepsis/septic shock patients. However, its advantages over hydrocortisone alone remain unclear. Future research should use hydrocortisone comparators and distinguish between sepsis-specific and comorbidity- or care-withdrawal-related mortality.