Landmark-based early perfusion phenotyping for prognostic stratification in septic shock: derivation in MIMIC-IV and fixed-parameter external transportability assessment in eICU.

Background: Septic shock is clinically heterogeneous, and early perfusion failure may not be adequately captured by any single bedside variable. We aimed to derive a clinically interpretable early perfusion phenotyping framework within a landmark design and assess whether the high-risk phenotype contour could be transferred across critical care databases. Methods: In this retrospective observational study, MIMIC-IV was used for phenotype derivation and the eICU Collaborative Research Database for fixed-parameter external transportability assessment. Adults in the first intensive care unit stay were eligible if they had early vasopressor exposure and baseline lactate greater than 2 mmol/L. At an 8-h landmark, phenotypes were derived using mean arterial pressure deficit burden, body-weight-standardized urine output, and lactate clearance. The primary outcome was in-hospital mortality, selected for cross-database harmonization because it was consistently available in both databases, whereas fixed-time 28- or 90-day mortality was not reliably harmonized. Secondary renal outcomes were summarized descriptively. Results: The MIMIC landmark cohort included 4,374 patients, of whom 2,671 had complete data for phenotype assignment. Four early perfusion phenotypes were identified. Phenotype 1 was characterized by greater hypotensive burden, poorer lactate clearance, and lower urine output. In-hospital mortality was 47.0% in Phenotype 1 versus 17.7% in Phenotype 4. Phenotype 1 remained associated with higher mortality after primary adjustment for age, sex, and pre-landmark SOFA score (OR 3.67, 95% CI 2.74-4.93), but this estimate attenuated after expanded pre-landmark case-mix adjustment (OR 2.56, 95% CI 1.85-3.53). In eICU, the same high-risk contour remained detectable under frozen transfer among measured complete-case patients. However, the strict and relaxed transfer cohorts were small, monitoring-dense subsets, and class-prevalence drift with measurement-dependent complete-case formation precluded robust conclusions about transportability of the entire four-class model, particularly for Phenotypes 2-4. Conclusions: A landmark-based early perfusion phenotype identified a high-risk perfusion-failure contour among septic shock patients with sufficient early monitoring density. In eICU, this contour was recoverable only within measured complete-case subsets, and the external data do not establish robust transportability of the entire four-class model. The framework should be interpreted as an observational, hypothesis-generating prognostic stratification approach rather than as an independently validated bedside decision tool.