Ultra-early versus early adjunctive vasopressin initiation after norepinephrine escalation in septic shock: a target trial emulation.

Abstract

Purpose: The optimal timing of adjunctive vasopressin after norepinephrine escalation in septic shock remains uncertain. We emulated a target trial comparing ultra-early vasopressin initiation within 0-3 h with early initiation within > 3-6 h after the norepinephrine infusion rate reached 0.25 μg/kg/min or higher.

Methods: We emulated a target trial using electronic health record databases (MIMIC-IV 2008-2022 and eICU-CRD 2014-2015). Adults with septic shock who reached the norepinephrine threshold before vasopressin use were eligible. We used the clone-censor-weight method to estimate cumulative incidence curves under the ultra-early and early initiation strategies and compared them via the weighted Cox model.

Results: Among 3810 eligible patients, after cloning, 744 clones adhered to the ultra-early strategy and 293 clones adhered to the early strategy. The weighted 28-day mortality risk was 48.1% under the ultra-early strategy and 53.0% under the early strategy (risk difference, - 5.0 percentage points; 95% confidence interval [CI] - 6.8 to - 3.2), with a restricted mean survival time difference of 1.58 days (95% CI 1.21-1.92) and a hazard ratio (HR) of 0.82 (95% CI 0.78-0.85). Ultra-early initiation was associated with lower renal replacement therapy (HR, 0.68; 95% CI 0.63-0.74), continuous renal replacement therapy (HR, 0.61; 95% CI 0.55-0.68), and medically treated arrhythmia (HR, 0.91; 95% CI 0.83-0.99), but not with lower acute kidney injury.

Conclusions: Among adults with septic shock whose norepinephrine infusion reached 0.25 μg/kg/min or higher before vasopressin use, vasopressin initiation within 0-3 h was associated with lower 28-day mortality than initiation within > 3-6 h.