Blood-brain barrier penetration determines link between beta blockers and reduced mortality in patients with sepsis-associated encephalopathy: A multicenter cohort study and an effect heterogeneity tool

Clinical evidence for beta (β) blockers in sepsis-associated encephalopathy (SAE) is limited, and the influence of blood-brain barrier penetration (BBBp) on their neuroprotective efficacy remains unclear. We analyzed 17,446 SAE patients from the Medical Information Mart in Intensive Care (MIMIC)-Ⅳ database, assessing the association between β-blocker use and mortality, comparing agents stratified by BBBp (low, medium, high), and developing a benefit-calculation tool to identify subgroups with distinct responses; findings were externally validated in 15,965 patients from the eICU Collaborative Research Database (eICU-CRD). In MIMIC-Ⅳ, 11,687 patients (67.0 %) received β blockers, which were associated with reduced mortality (HR 0.65, 95 % CI 0.62-0.69, E-value 2.45); high-BBBp agents conferred greater survival advantage (HR 0.72, 95 % CI 0.59-0.87) compared with low-BBBp agents, while medium-BBBp agents showed intermediate benefit (HR 0.87, 95 % CI 0.75-1.02); similar trends were confirmed in eICU-CRD (adjusted HR 0.63, 95 % CI 0.57-0.70 for ICU mortality). A preliminary benefit algorithm stratified patients into quartiles with progressively increasing benefit: Q1 (HR: 1.01 [95 % CI: 0.98-1.24]), Q2 (HR: 0.85 [95 % CI: 0.76-0.96]), Q3 (HR: 0.59 [95 % CI: 0.53-0.67]), and Q4 (HR: 0.38 [95 % CI: 0.34-0.43]). An online calculator (https://nkuwangkai.shinyapps.io/betablocker-in-sepsis-encephalopathy/) was deployed as a hypothesis-generating tool for potential clinical application, pending prospective validation. β-blocker therapy is associated with improved survival in SAE, particularly with high-BBBp agents, and precision tools could identify patients with maximal therapeutic gain; prospective trials are warranted to validate causality and refine targeted treatment strategies.