Clinical outcomes of norepinephrine-phenylephrine vs. norepinephrine-vasopressin in septic shock: a retrospective cohort study

Purpose: This study aims to compare the clinical outcomes of norepinephrine combined with phenylephrine (NE-PE) versus norepinephrine combined with vasopressin (NE-VP) in patients with septic shock. Materials and Methods: This retrospective cohort study included septic shock patients identified from the Medical Information Mart for Intensive Care (MIMIC-IV; 2008-2019) and the eICU Collaborative Research Database (eICU-CRD). Within the MIMIC-IV cohort, propensity score matching (PSM) and stabilized inverse probability of treatment weighting (IPTW) were carried out to balance baseline characteristics between groups, with outcomes compared across the crude, PSM, and IPTW cohorts. Multivariable logistic regression was further employed for subgroup analyses to assess the association between NE-VP versus NE-PE and in-hospital mortality. The observed association was subsequently validated using the external eICU-CRD cohort. Interaction and marginal effects were evaluated within the MIMIC-IV cohort to determine whether Shock Index modified the treatment effect of NE-VP versus NE-PE on in-hospital mortality. Results: The MIMIC-IV cohort comprised 753 patients (NE-PE: 238; NE-VP: 515), with an eICU-CRD validation cohort of 313 (NE-PE: 67; NE-VP: 246). After 1:1 PSM (336 patients; 168 pairs) and stabilized IPTW (weighted n = 724.7), both methods effectively reduced selection bias. Consistently across PSM/IPTW cohorts, the NE-PE group exhibited a shorter duration of dual vasopressor therapy and a lower in-hospital mortality rate. Multivariable regression analysis within the MIMIC-IV cohort confirmed reduced in-hospital mortality for NE-PE versus NE-VP, a finding further validated in the eICU-CRD cohort. Subgroup analyses with interaction testing within the MIMIC-IV cohort revealed that the mortality reduction associated with NE-PE was particularly pronounced in patients aged < 65 years and in those without hypertension. Marginal effect analysis further indicated that higher Shock Index values amplified the mortality risk associated with NE-VP versus NE-PE. Conclusion: In septic shock patients, NE-PE may be associated with reduced in-hospital mortality compared to NE-VP, especially among patients aged <65 years or those without hypertension. The Shock Index may serve as a valuable indicator for selecting a secondary vasopressor during vasopressor escalation.