A doubling of plasma Ang-2 (p < 0.001) and Ang-2/1 ratio (p = 0.01) was associated with significantly fewer delirium- and coma-free days at 14 days in critically ill adults.
Cohort (n=264)
Yes
Does elevated Ang-2 and Ang-2/1 ratio reduce delirium- and coma-free days in critically ill patients?
Elevated markers of endothelial dysfunction, specifically Ang-2 and the Ang-2/1 ratio, are associated with fewer delirium- and coma-free days in critically ill patients.
p-value: p=<0.001 for Ang-2, 0.01 for Ang-2/1
Abstract Rationale Delirium is a complex syndrome with emerging evidence suggesting that systemic inflammation, vasculature destabilization and endothelial dysfunction contribute to its development through disruption of the blood brain barrier. Specific biological mechanisms driving these pathways remain poorly understood. We analyzed associations between Angiopoietin-2 (Ang-2), a vascular destabilizing protein, and Angioprotein-1 (Ang-1), a vascular stabilizing protein and delirium-and coma-free days (DCFDs) in critically ill patients. Methods We prospectively enrolled adults admitted to a medical or surgical ICU from University of Washington and Vanderbilt University Medical Center from 2020 to 2024. We measured Ang-1, - 2 and defined the Ang-2/1 ratio in plasma collected within 48 hours of ICU admission. Delirium and coma were assessed daily in the ICU via the Confusion Assessment Method-ICU (CAM-ICU) and Richmond Agitation-Sedation Scale (RASS) and the primary outcome was the number of DCFDs at 7 and 14 days. We used linear regression to examine associations between endothelial markers and DCFDs at 7 and 14 days, adjusting for age, sex, SOFA, cardiovascular disease, chronic kidney disease, and diabetes. Regression coefficients are interpreted as the adjusted difference of DCFDs per doubling of biomarker concentration. We completed analyses overall and stratified by acute respiratory failure (ARF) and acute kidney injury (AKI) on enrollment. These subgroups were selected due to known secretion of angiopoietins from the lungs and kidneys and subsequent hypothesized effect modification. Results Among 264 patients the average age was 55 years, 160 (61%) were male, 228 (86%) were Caucasian, the average SOFA score was 5 (IQR 1.0-10.0), 97 (37%) had ARF and 83 (31%) had AKI. 96 (36%) patients experienced delirium within the first 14 days and the median time to developing delirium was 1 day (IQR 1-2). In multivariable models, a doubling of Ang-2 (p 0.001) and Ang-2/1 (p = 0.01) was associated with significantly fewer DCFDs at 14 days (Figure 1A), exhibiting a linear relationship (Figure 1B). In a sensitivity analysis, we found consistent results at 7 days. In stratified analyses, we found no effect modification by baseline ARF or AKI status for the association of Ang-2 and Ang-2/1 ratio with DCFDs. Conclusions Elevated markers of endothelial dysfunction, Ang-2 and Ang-2/1 ratio, demonstrated fewer DCFDs in critically ill patients and the association was consistent across sub-groups of ARF or AKI. These results highlight the need to assess the predictive value of these biomarkers for delirium and whether modulation of the endothelium can improve delirium outcomes. This abstract is funded by: T32HL007287, R01DK124063, R01DK133177
McDonald et al. (2026) conducted a cohort in Critically ill patients (n=264). Plasma Angiopoietin-2 (Ang-2) and Ang-2/1 ratio was evaluated on Number of delirium- and coma-free days (DCFDs) at 7 and 14 days (p=<0.001 for Ang-2, 0.01 for Ang-2/1). A doubling of plasma Ang-2 (p < 0.001) and Ang-2/1 ratio (p = 0.01) was associated with significantly fewer delirium- and coma-free days at 14 days in critically ill adults.