Effectiveness of Fludrocortisone Plus Hydrocortisone versus Hydrocortisone Alone in Septic Shock: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials

Rationale: The use of hydrocortisone in adult septic shock is controversial, and effectiveness of adding fludrocortisone to hydrocortisone remains uncertain. Objective: To assess comparative effectiveness and safety of fludrocortisone plus hydrocortisone, hydrocortisone alone and placebo/usual care in adults with septic shock. Methods: Systematic review and Bayesian network meta-analysis of peer-reviewed randomized trials. The primary outcome was all-cause mortality at last follow-up. Treatment effects were presented as relative risks (RR) with 95% credible intervals (CrI). Placebo/usual care was the reference treatment. Main Results: Out of 7,553 references, we included 17 trials (7,688 patients). All-cause mortality at last follow-up was lowest with fludrocortisone plus hydrocortisone (RR: 0.85, 95% CrI: 0.72-0.99, 98.3% probability of superiority, moderate-certainty evidence), followed by hydrocortisone alone (RR: 0.97, 95% CrI: 0.87-1.07, 73.1% probability of superiority, low-certainty evidence). The comparison of fludrocortisone plus hydrocortisone versus hydrocortisone alone was primarily based on indirect evidence (only two trials with direct evidence). Fludrocortisone plus hydrocortisone was associated with a 12% lower risk of all-cause mortality compared to hydrocortisone alone (RR: 0.88, 95% CrI: 0.74-1.03, 94.2% probability of superiority, moderate-certainty evidence). Conclusions: In adult septic shock patients, fludrocortisone plus hydrocortisone was associated with lower risk of all-cause mortality at last follow-up than placebo and hydrocortisone alone. The scarcity of head-to-head trials comparing fludrocortisone plus hydrocortisone versus hydrocortisone alone led our network meta-analysis to rely primarily on indirect evidence for this comparison. Though we undertook several sensitivity analyses and assessments, these findings should be considered while also acknowledging the heterogeneity of included trials.