Circulating Endothelial Signature: A Biomarker of Delirium Risk and Severity in Postoperative Patients

Justification: Delirium is a frequent complication in critically ill and septic patients and has been linked to endothelial dysfunction, microvascular injury and blood-brain barrier disruption. Circulating endothelial cells may reflect endothelial phenotypic alterations beyond soluble markers. We investigated the association between endothelial subsets and postoperative sepsis-related delirium in ICU patients. Objective: To investigate the role of circulating endothelial subsets in the development of delirium in post-surgical sepsis patients and their relationship with hypoperfusion and clinical outcomes, to identify potential prognostic biomarkers and mechanistic insights. Methods: In this prospective cohort study, 214 postoperative ICU patients were enrolled at the time of surgery or sepsis diagnosis and classified as non-septic ICU (n=77), sepsis (n=61) or septic shock (n=76) according to Sepsis-3 criteria. Blood samples were obtained within 24 hours of critical illness onset. Circulating endothelial subsets were characterized using high-dimensional flow cytometry with unsupervised clustering. Delirium was assessed daily using the CAM-ICU. Cox regression, ROC analysis and causal mediation models were applied to evaluate associations with 28-day delirium and organ-dysfunction related clinical events occurring after sampling. Results: Among 13 endothelial subpopulations identified, CD32b⁺ subset were independently associated with 28-day delirium (HR 2.41, 95% CI 1.32-4.40; p=0.004). CD32b⁺ subset demonstrated discriminative performance for delirium (AUC 0.79, 95% CI 0.60-0.98), which improved after adjustment for age and sex (AUC 0.89, 95% CI 0.82-0.98). Models based solely on organ-dysfunction related clinical events showed lower performance (AUC 0.69, 95% CI 0.52-0.86). Mediation analysis indicated that approximately 20% of the total effect was mediated through organ-dysfunction related events, suggesting partial mediation, while the remaining 80% may involve alternative endothelial and microvascular mechanisms not captured by conventional measures. Conclusions: Elevated CD32b⁺ subset are associated with postoperative delirium and organ-dysfunction related clinical events in critically ill patients, supporting an association between endothelial phenotypic alterations and vulnerability to brain dysfunction.