Noradrenaline-trajectory phenotypes in septic shock: derivation and external validation in two independent cohorts

Background: Septic shock is heterogeneous, and noradrenaline (NA) requirements evolve over time in ways that reflect vascular responsiveness and shock biology. Whether long-horizon NA dose-trajectory phenotypes are reproducible across healthcare systems and identifiable early in the clinical course remains uncertain. Methods: We retrospectively analyzed 1111 adults with septic shock at Sheba Medical Center (Israel) and 9343 adults from MIMIC-IV. Hourly NA infusion trajectories were reconstructed for 10 days. A fully prespecified clustering pipeline combining static-feature K-means with dynamic time warping refinement was derived in Sheba and applied unchanged to MIMIC-IV. The primary outcome was 90-day mortality; 30-day mortality was analyzed as a supportive secondary outcome. Secondary analyses included feature interpretability, multivariable landmark Cox models (24–144 h), and early phenotype prediction using exposure features available at 24–96 h. Results: Five stable phenotypes emerged in Sheba and six in MIMIC-IV. Despite this numerical difference and somewhat more prolonged high-dose exposure in Sheba sustained/late-escalating patterns, both cohorts exhibited the same core families of trajectory shapes with preserved mortality gradients (90-day mortality 37–89% in Sheba; 16–69% in MIMIC-IV). Mortality gradients were preserved at both 30 and 90 days across cohorts. Across cohorts, exposure-persistence features—particularly time to maximal NA dose and cumulative NA burden during days 2–4—were key determinants of phenotype structure and mortality. Early-prediction models identified final phenotypes using 24-h data with 85% accuracy in Sheba and 86% in MIMIC-IV, improving by 48 h to 89% and 88%, respectively; high-confidence assignments achieved approximately 91%–95% accuracy. Conclusions: Long-horizon NA dose-trajectory phenotypes are clinically interpretable hemodynamic exposure/response patterns, prognostically coherent, and externally reproducible. Their defining features were detectable within the first 24 h and showed stronger discrimination by 48 h. At present, these phenotypes should be interpreted as descriptive hemodynamic-response patterns that may support dynamic risk stratification, prognostic enrichment for future trials, and hypothesis generation; whether early phenotype identification can improve management or outcomes requires prospective evaluation.