Comparative efficacy and safety of hydrocortisone-based regimens in septic shock: A network meta-analysis.

BACKGROUND: The optimal corticosteroid regimen for septic shock, particularly the dosing and combination of hydrocortisone and fludrocortisone, remains uncertain due to inconsistent mortality findings across trials. METHODS: We conducted a PRISMA-compliant systematic review and network meta-analysis of randomized controlled trials evaluating hydrocortisone and/or fludrocortisone in adults with septic shock (PubMed, Embase, CENTRAL; inception-May 1, 2025; PROSPERO CRD420251015672). Interventions were grouped into six regimens (including placebo), and outcomes were analyzed using a frequentist random-effects model; the primary outcome was 28-day mortality. RESULTS: A total of 21 trials involving 7908 patients were included. Hydrocortisone ≥300 mg/day and hydrocortisone 200-299 mg/day combined with fludrocortisone 50 μg/day were associated with reduced 28-day mortality compared with placebo (OR 0.53, 95% CI 0.29-0.96; OR 0.78, 95% CI 0.64-0.96, respectively), with higher fludrocortisone doses showing numerically greater point estimates of benefit, though estimates were not statistically significant. Higher hydrocortisone doses were associated with increased superinfection risk, while fludrocortisone appeared to attenuate this effect. An increased risk of gastrointestinal hemorrhage was observed across regimens, although estimates were imprecise. CONCLUSIONS: Higher-dose hydrocortisone was associated with improved survival but also increased adverse events, whereas adjunctive fludrocortisone may provide additional benefit without substantially increasing complications. These findings should be interpreted with caution and highlight the need for further dose-specific trials.