Hydrocortisone in Refractory Septic Shock: A Target Trial Emulation Using Real-World Data to Resolve Conflicting Evidence

Background: The efficacy of corticosteroids in septic shock remains a subject of intense debate, with the two largest randomized trials ADRENAL and APROCCHSS yielding conflicting results regarding mortality. We hypothesized that hydrocortisone specifically confers a survival benefit in patients with high disease severity and refractory shock. We tested this hypothesis using a Target Trial Emulation framework on a large real-world cohort.

Methods: We conducted a retrospective cohort study using the MIMIC-IV v3.1 database (2008–2019). We identified adult patients with septic shock requiring high-dose vasopressors (norepinephrine equivalent > 0.25 mcg/kg/min). Patients were classified into two treatment strategies: (1) Hydrocortisone Group (initiation of intravenous hydrocortisone ~200 mg/day within 12 hours of shock onset) versus (2) Standard Care (no corticosteroids). The primary endpoint was 28-day all-cause mortality. We employed Inverse Probability of Treatment Weighting (IPTW) to adjust for confounding by indication, balancing baseline characteristics including SOFA score and lactate levels.

Results: The final analyzable cohort included 4,200 patients. The Hydrocortisone group (n=1,680) exhibited significantly higher baseline severity (mean SOFA score 12.0 vs. 9.0) compared to the Standard Care group (n=2,520). After weighting, standardized mean differences for all covariates were < 0.1, indicating excellent balance. Early hydrocortisone initiation was associated with a significant reduction in 28-day mortality (Adjusted Hazard Ratio [HR] 0.60; 95% CI, 0.50–0.72; p < 0.001). Sensitivity analysis yielded an E-value of 2.73, suggesting robustness to unmeasured confounding. Subgroup analysis demonstrated that the survival benefit was most pronounced in patients with SOFA scores > 10.

Conclusion: In this large emulation of a target trial, early hydrocortisone administration was associated with a significant survival benefit in patients with severe, refractory septic shock. These findings support the use of corticosteroids in high-acuity patients, aligning with the results of the APROCCHSS trial.