Mean arterial pressure-to-norepinephrine-equivalent dose ratio, rather than achieved mean arterial pressure alone, is associated with mortality in septic shock

BACKGROUND: Higher mean arterial pressure (MAP) is commonly pursued in septic shock, yet randomized trials have failed to demonstrate a survival benefit-and patients achieving higher MAP often exhibit paradoxically greater mortality. We hypothesized this reflects impaired vascular responsiveness requiring greater vasopressor support, quantifiable by the MAP-to-norepinephrine-equivalent dose ratio (MAP/NEQ). METHODS: We conducted a retrospective cohort study using two independent critical care databases (MIMIC‑IV and eICU). Adult patients with septic shock receiving vasopressors within 24 h of ICU admission were included. The primary exposure was the 24-h time-weighted average MAP (65-80 mmHg vs. ≥ 80 mmHg); the key secondary exposure was MAP/NEQ. The primary outcome was 28-day mortality. Cox regression, restricted cubic splines, and mediation analysis were performed. RESULTS: A total of 7433 patients were included (MIMIC‑IV: n = 4944; eICU: n = 2489). Despite being younger with fewer comorbidities, patients with MAP ≥ 80 mmHg had higher 28-day mortality (MIMIC-IV: 19.5% vs. 12.6%; eICU: 20.5% vs. 11.0%; both P < 0.001). After adjustment for MAP/NEQ, the association between high MAP and mortality became non-significant, while MAP/NEQ remained independently and inversely associated with mortality in both cohorts (AUC 0.81 and 0.72). Mediation analyses revealed a suppression effect (- 33% and - 26%), indicating higher MAP coexisted with impaired vascular responsiveness. Subgroup and sensitivity analyses were consistent. CONCLUSIONS: Higher achieved MAP was not independently associated with 28-day mortality after accounting for vascular responsiveness. MAP/NEQ may serve as a clinically accessible tool for early risk stratification and identification of a vasoplegic phenotype in septic shock, though prospective validation is needed before clinical application.