Therapeutic role of norepinephrine infusion and 28-day mortality in aneurysmal subarachnoid hemorrhage: A pharmaco-epidemiological cohort study with overlap weighting

Abstract: Background: Aneurysmal subarachnoid hemorrhage (aSAH) is frequently complicated by hemodynamic instability and impaired cerebral perfusion, which may require vasoactive support. However, the association between norepinephrine (NE) exposure and short-term mortality in aSAH remains uncertain. Objectives: To evaluate the association between NE infusion and 28-day all-cause mortality among patients with aSAH treated with endovascular embolization, while accounting for baseline severity and measured confounding. Methods: This single-center retrospective cohort study included consecutive patients with aSAH who underwent endovascular embolization at The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China, from January 1, 2022 to August 31, 2025. Patients were classified according to NE administration during the acute hospitalization. The primary outcome was 28-day all-cause mortality. Survival was compared using Kaplan-Meier curves and log-rank tests. Cox proportional hazards models were fitted in crude, adjusted and fully adjusted forms. Propensity score-based overlap weighting was applied as a sensitivity analysis to improve covariate balance; balance was evaluated using standardized mean differences (SMDs). Results: A total of 259 patients were included in this study, of whom 67 received norepinephrine. The 28-day mortality rate was higher in the NE group than in the non-NE group (47.8% vs. 15.7%, P<0.001). After full adjustment for laboratory and other relevant covariates, NE use remained associated with an increased risk of 28-day mortality (HR=2.892, 95% CI: 1.566-5.338, P<0.001). Consistent results were observed in the overlap-weighted (OW) analysis (HR=2.211, 95% CI: 1.218-4.015, P=0.009). No significant interactions were identified in the subgroup analyses.Conclusion: NE infusion was associated with higher 28-day mortality in patients with aSAH. Because NE use may also indicate severe hemodynamic instability, these findings should be interpreted as an association rather than proof of causality. Prospective studies with detailed dose-duration data are needed.