Acute kidney injury-associated delirium after cardiac surgery

About This Grant

Our mechanistic understanding of delirium after cardiac surgery (CS-Delirium) is limited and few pharmacologic treatments exist. Acute kidney injury (AKI) is a strong risk factor for delirium. However, in the cardiac surgery patient population, the incidence of AKI-associated delirium (CS-AKI-Delirium) and the risk factors for CS-AKI-Delirium are unknown. Our preliminary data suggest that the CS-AKI-Delirium subgroup accounts for 55% of CS-Delirium patients, develops a unique intraoperative cytokine and chemokine profile, and develops higher intraoperative endothelial activation than the non-AKI CS-Delirium subgroup. Further, our data suggest that an association between higher intraoperative endothelial activation and a greater odds of delirium exists only in the CS-AKI-Delirium subgroup. We hypothesize that CS-AKI and CS-Delirium are mechanistically linked by systemic inflammation and endothelial activation in the CS-AKI-Delirium subgroup. If data supporting a linked mechanism were generated, these data would rapidly advance the study of CS- Delirium by facilitating the translations of a portion of CS-AKI mechanistic knowledge and therapeutic targets to CS-AKI-Delirium. We propose the first prospective study of CS-AKI-Delirium, involving 300 adults undergoing on-pump coronary artery bypass surgery. This study will determine the incidence and clinical phenotype of CS- AKI-Delirium (Aim 1), delineate signaling pathways composed of intracellular and extracellular mediators of inflammation and endothelial activation associated with CS-Delirium and CS-AKI-Delirium specifically (Aim 2), and test the hypothesis that higher endogenous high-density lipoprotein capacity to suppress endothelial activation is associated with less CS-AKI and less CS-AKI-Delirium (Aim 3). During this study, inflammatory signaling pathways will be characterized using comprehensive and complementary methods including high throughput biomarker analysis of plasma collected before and after surgery, and total RNA sequencing, RNA in situ hybridization, and immunohistochemical staining of ascending aortic tissue collected during surgery. Our research team has over 70 years of combined experience identifying and deeply characterizing such pathways. The innovation of this proposed study is the recognition that CS-AKI and CS-Delirium may not be independent postoperative co-morbidities, but instead may be mechanistically linked disease states in a large subset of CS-Delirium patients. Data generated in this study about the incidence of CS-AKI-Delirium and the statistical tool developed during this study to identify this patient subgroup will facilitate designing and powering future CS-AKI therapeutics trials to add CS-AKI-Delirium as a secondary endpoint if scientifically justified. This single change in scientific thinking and addition of our clinical study data to the field of CS-Delirium could increase the number of CS-Delirium therapeutic trials many-fold in a highly-cost effective manner. Our research team has over 25 years of combined experience performing prospective observational studies of AKI and delirium at the proposed study site and is highly qualified to complete this proposed study.