A Role for Blood-brain Barrier Dysfunction in Delirium following Non-Cardiac Surgery in Older adults

Abstract

Objective: Although animal models suggest a role for blood-brain barrier dysfunction in postoperative delirium-like behavior, the role of postoperative blood-brain barrier dysfunction in postoperative delirium and overall recovery is unclear. Thus, we evaluated the role of blood-brain barrier dysfunction in postoperative delirium and hospital length of stay among older surgery patients. Methods: Cognitive testing, delirium assessment, and cerebrospinal fluid and blood sampling was prospectively performed before and after non-cardiac, non-neurologic surgery in older adults. Blood-brain barrier dysfunction was assessed using the cerebrospinal fluid-to-plasma albumin ratio (CPAR). Results: Of 207 patients with complete CPAR and delirium data, 26 (12.6%) developed postoperative delirium. Overall, CPAR increased from before to 24 hours after surgery (median postoperative change 0.28, [IQR] [-0.48- 1.24]; Wilcoxon p=0.001). Preoperative to 24-hour postoperative change in CPAR was greater among patients who developed delirium vs those who did not (median [IQR] 1.31 [0.004, 2.34] vs 0.19 [-0.55, 1.08]; p=0.003). In a multivariable model adjusting for age, baseline cognition, and surgery type, preoperative to 24-hour postoperative change in CPAR was independently associated with delirium incidence (OR, 1.30, [95% CI 1.03-1.63]; p=0.026) and increased hospital length of stay (incidence rate ratio, 1.15 [95% CI 1.09-1.22]; p<0.001) Interpretation: These data demonstrate that postoperative increases in blood-brain barrier permeability are associated with increased delirium risk and increased postoperative hospital length of stay. Although these findings do not establish causality, they suggest studies are warranted to determine whether interventions to reduce postoperative blood-brain barrier dysfunction would reduce postoperative delirium risk and hospital length of stay.