Relationship between norepinephrine dose and outcome in septic shock: a retrospective study

Background High-dose norepinephrine (NE) is frequently required in septic shock, but the association of NE dose with outcome remains incompletely characterized. We aimed to evaluate the relationship between NE dosing, mortality and ischemic complications, and to identify clinically relevant NE dose ranges. Methods This retrospective single-center cohort study included adult patients admitted to the ICU with septic shock between 2016 and 2022. NE dosing variables, including initial dose, highest dose within 24 hours, and peak dose during ICU stay, were collected. An adjusted optimal binning approach was used to identify NE peak-dose ranges associated with ICU and in-hospital mortality. Multivariable logistic regression models were adjusted for age, APACHE II, and SOFA score at admission. Time-dependent Cox models were used to assess the association between NE peak dose and secondary ischemic outcomes. Results A total of 506 patients were included. Median NE peak dose was 0.5 [0.2–1.2] µg/kg*min. Four NE peak-dose ranges were identified: 0.05–0.6, 0.61–1.2, 1.2–3.0, and > 3.0 µg/kg*min. ICU and in-hospital mortality increased stepwise across these ranges, from 20.7% and 32.4% in the lowest group to 100% in patients receiving > 3.0 µg/kg*min. This association persisted after exclusion of patients with withdrawal of life-sustaining therapies. Adjusted odds ratios for ICU mortality were 1.88 [0.97–3.64] and 2.55 [1.38–5.57] in the 0.61–1.2 and 1.2–3.0 µg/kg*min groups, respectively. NE peak dose showed fair discrimination for ICU mortality (Area Under the Receiver Operating Characteristic curve of 0.75), with an optimal threshold of 0.78 µg/kg*min. Most ischemic complications were infrequent and not dose-dependent, except for myocardial ischemia and unexpected cardiac arrest, which were significantly associated with higher NE doses. Conclusions In septic shock, increasing NE peak doses are associated with a marked, stepwise increase in ICU and in-hospital mortality across four distinct dose ranges. Ischemic complications are uncommon and largely independent of NE dose. NE dose stratification may improve risk assessment and harmonization of outcome reporting in future studies.