Introduction: Vasopressin is suggested as the first-line adjunctive agent in patients with septic shock requiring escalating doses of norepinephrine. However, the optimal norepinephrine-equivalent (NEQ) dose at which vasopressin should be initiated remains unknown. Methods: A target trial was emulated using retrospective data pooled from the Cleveland Clinic electronic health record and the MIMIC-IV and eICU-CRD databases. Adult patients with septic shock admitted to an ICU receiving continuous infusion norepinephrine and adjunctive vasopressin were eligible. Two cohorts were compared: patients initiated on vasopressin at low NEQ doses (5-20 mcg/min) versus high doses (30-60 mcg/min). Additionally, patients were divided into weight-based NEQ cohorts: 0.05-0.2 mcg/kg/min vs 0.3-0.6 mcg/kg/min. Stabilized inverse probability of treatment weighting was applied to adjust for severity of illness markers and known confounders. To address residual imbalance, the linearized propensity score was included as a covariate in weighted models. The primary outcome was in-hospital mortality. Results: 2141 patients were included in the non-weight based NEQ cohorts: 1093 low NEQ vs 1048 high NEQ. Baseline SOFA score was 12.2±3.9, 54.8% of included patients were male, 68.8% were Caucasian, and 44.9% were admitted to a medical ICU. Before weighting, in-hospital mortality was lower in the low NEQ group: 46.1% vs 65.8% and remained lower after weighting: 50% vs 63.9%, adjusted OR 0.52 (95% CI 0.42-0.64). The adjusted median difference in ICU free days was 4.3 days (95% CI -0.4 to 9.0). SOFA Score at 48 hours was lower in the low NEQ group: adjusted mean difference -0.6 (95% CI -1.1 to -0.1). There were 1858 patients included in the weight-based NEQ cohorts: 729 low NEQ vs 1129 high NEQ. After weighting, in-hospital mortality was lower in the low NEQ group 45.4% vs 63.2%; adjusted OR 0.45 (95% CI 0.35-0.57). The adjusted median difference in ICU free days was adjusted median difference 2.5 days (95% CI -0.3 to 5.4). SOFA Score at 48 hours was lower in the low NEQ group: adjusted mean difference -0.6 (95% CI -1.0 to -0.2). Conclusions: Initiation of vasopressin at low NEQ doses, between 5-20 mcg/min or 0.05-0.2 mcg/kg/min, was associated with reduced ICU mortality compared to NEQ doses exceeding 30 mcg/min or 0.3 mcg/kg/min.
Sacha et al. (Sun,) studied this question.