Purpose To evaluate the efficacy and safety of hydrocortisone combined with fludrocortisone in the treatment of septic shock in adults. Methods We searched PubMed, Embase, Web of Science, and the Cochrane Library for studies on hydrocortisone combined with fludrocortisone in the treatment of septic shock in adults. Two investigators independently screened studies, extracted data, and assessed the risk of bias of the included studies. A meta-analysis was performed using RevMan 5.3 and STATA 17.0 software. Results A total of eight studies (5 RCTs and 3 N-RCTs) were included. Stratified analysis by study design and comparator type revealed that in the HC + FC vs. Placebo subgroup (derived solely from RCTs), the combination significantly reduced 28-day mortality RR 0.84; 95% CI (0.76, 0.94); p = 0.002, 90-day mortality RR 0.82; 95% CI (0.71, 0.94); p = 0.006, and in-hospital mortality RR 0.85; 95% CI (0.77, 0.94); p = 0.002. In contrast, for the HC + FC vs. HC alone subgroup (addressing incremental benefit), no significant survival advantage was observed in either RCTs ( n = 553) or N-RCTs ( n = 88,666, 28-day mortality RR 0.99, p = 0.79). Regarding safety, HC + FC was associated with a higher reinfection rate compared to placebo (RR 1.13, p = 0.03) but not when compared to HC alone ( p = 0.19). No significant increase in gastrointestinal bleeding or reduction in ICU/hospital length of stay was identified across all tiers of evidence. Conclusion Evidence primarily from RCTs indicates that HC + FC is associated with improved survival compared to placebo in septic shock. However, large-scale observational data suggest no significant incremental benefit over hydrocortisone alone. While the combination appears safe regarding gastrointestinal bleeding, the increased reinfection risk compared to placebo warrants caution. Given the non-causal nature of observational findings, these results are suggestive rather than definitive. Future head-to-head trials are essential to confirm the marginal efficacy of fludrocortisone supplementation. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420251001999 , Identifier: CRD420251001999
Sun et al. (2026) studied this question.