BACKGROUND: The optimal timing of vasopressor initiation in septic shock remains uncertain, and mixed trial results may reflect unmeasured hemodynamic heterogeneity. We hypothesized that the association between early norepinephrine and mortality differs by bedside hemodynamic phenotype, as characterized by diastolic blood pressure (DBP) and pulse pressure (PP). METHODS: We conducted a retrospective analysis of prospectively collected data from a national sepsis registry (2019–2024). Adults with septic shock presenting to emergency departments were included. Time-to-vasopressor was defined as the time from triage to norepinephrine initiation; restricted cubic splines supported an a priori classification of “early” use as ≤ 25 min. The primary outcome was in-hospital mortality. Patients were stratified by pre-vasopressor DBP (< 50 vs. ≥ 50 mmHg) and, secondarily, by PP (< 25 vs. ≥ 25 mmHg). Multivariable models adjusted for demographics, comorbidities, illness severity (SOFA), three-hour sepsis bundle completion, and mechanical ventilation. Sensitivity analyses explored alternative DBP thresholds (< 40, < 44 mmHg), and subgroup analyses assessed effect consistency. RESULTS: Among 1,104 patients, early norepinephrine was associated with lower mortality only in those with low DBP; there was no mortality benefit when DBP was ≥ 50 mmHg. Mortality associations were stronger at more extreme diastolic hypotension thresholds (< 40 and < 44 mmHg). Hemodynamic phenotyping with PP further refined risk: within the low-DBP group, a wide PP (≥ 25 mmHg) was associated with the most pronounced survival association from immediate vasopressors, whereas a narrow PP showed no clear benefit. Results were directionally consistent across sensitivity and subgroup analyses. CONCLUSIONS: The relationship between vasopressor timing and outcomes in septic shock is hemodynamic phenotype dependent. Early norepinephrine appears beneficial when DBP is markedly low, particularly with wide PP, and less critical when DBP is preserved or PP is narrow. Simple bedside measurements (DBP and PP) can guide individualized resuscitation, helping clinicians decide whether to initiate vasopressors or initially emphasize preload or inotropy. TRIAL REGISTRATION: Not applicable.
Keywords: Diastolic blood pressure; Norepinephrine; Phenotype; Pulse pressure; Septic shock.