Journal Article

Analysis of the heterogeneous treatment effect of vasoactive drug dosage and time on hospital mortality across different sepsis phenotypes: a retrospective cohort study

Fang, Kun, Li, Li, Shen, Jiacheng, Xie, Jianhong, Sun, Dongsheng

2025

Overview

Background The heterogeneity of sepsis poses challenges for the individualized treatment of vasoactive drugs. Methods This study used data from ICUs in MIMIC-IV (2008–2019) and eICU (2014–2015) databases, identified sepsis by sepsis-3 criteria, and stratified sepsis into phenotypes by consensus K-means. The norepinephrine equivalence (NEE) formula balance treatment of different vasoactive drugs, with NEE captured hourly for up to 72 h to record both time of use and dosage. The logistic regression model, including phenotype–dosage–time interactions, examined heterogeneous treatment effects on hospital mortality. To address confounding, three models were fitted: Model 1 unadjusted, Model 2 adjusted for age and sex, and Model 3 additionally included 7 clinical variables identified via machine learning and directed acyclic graph. Nonlinear dosage was further analyzed based on restricted cubic splines. P values and P for interaction were Bonferroni-adjusted. Results A total of 54,673 sepsis patients were included for phenotype identification, and 8,803 patients were further analyzed to evaluate heterogeneous treatment effect of vasoactive drugs. Four sepsis phenotypes were identified: A, B, C and D. Phenotype D was the most severe subgroup, followed by phenotype C, while phenotypes A and B were mild subgroups. In Model 3, each 0.05 μg/kg/min increase in NEE dosage was linked to higher hospital mortality (OR 1.328, 95% CI 1.314–1.342; p  < 0.001). Longer NEE time of use also significantly increased mortality risk (OR 1.006, 95% CI 1.005–1.007; p  < 0.001). In addition, these associations varied significantly by phenotype ( P for interaction < 0.001). In RCS model, phenotype A consistently showed higher mortality than the other phenotypes at NEE dosages of 0.1–0.5 µg/kg/min, with this gap increasing over time, showing a clear dosage–time dependence. Phenotype B displayed lower overall mortality but the steepest relative risk of hospital mortality increased as dosage and time (OR of dosage: 1.309; OR of time: 1.005) in Model 3. Phenotype C reached the highest mortality risk when dosages exceeded 0.5 µg/kg/min, which was dosage dependence. Finally, phenotype D followed a U-shaped curve in RCS model, and minimum mortality was around 20% at 0.03–0.05 µg/kg/min. Conclusions Sepsis phenotypes differ significantly in their treatment effects of vasoactive drug dosage and time of use, indicating the need for phenotype-specific treatment strategies to improve outcomes.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Aged / Analysis / Biomedicine / Clustering / Combination therapy / Critical care / Dosage and administration / Dose-Response Relationship, Drug / Drug dosages / Drugs / Female / Gene expression / Genotype & phenotype / Hospital Mortality / Hospital patients / Hospitals / Humans / Immunotherapy / Infection / Infectious Diseases / Intensive care / Internal Medicine / Male / Medicine / Medicine & Public Health / Middle Aged / Mortality / Norepinephrine - administration & dosage / Norepinephrine - therapeutic use / Norepinephrine equivalence / Oncology / Patient outcomes / Patients / Phenotype / Phenotypes / Retrospective Studies / Sepsis / Sepsis - drug therapy / Sepsis - mortality / Surgery / Time Factors / Treatment Effect Heterogeneity / Variables / Vasoactive drugs / Vasoconstrictor Agents - administration & dosage / Vasoconstrictor Agents - therapeutic use