Postoperative delirium is a type of acute cognitive dysfunction characterized by inattention, disorganized thinking, and altered levels of consciousness that commonly develops after major surgery. Efforts to reduce the incidence of delirium have focused primarily on optimizing perioperative care, however the development of prophylactic interventions have been hindered by a limited understanding of the underlying mechanisms involved in delirium. In this secondary analysis of the Minimizing ICU Neurological Dysfunction with Dexmedetomidine-induced Sleep (MINDDS) trial, a nested case-control study (n = 51) was conducted using total RNA-sequencing analysis of whole-blood to investigate genes associated with delirium risk and development. Transcriptomic analysis revealed significantly lower expression of a key complement pathway inhibitor, C4BPA, in participants who experienced postoperative delirium. This finding was confirmed by quantitative PCR in the MINDDS cohort (n = 319) in adjusted logistic models. Furthermore, complement inhibitor CD55 was also found to be under-expressed in participants who developed delirium. Dexmedetomidine treatment modified associations between C4BPA and CD55 expression and the incidence of postoperative delirium by decreasing incidence in participants with low C4BPA and CD55 expression. This study revealed key complement regulators as risk biomarkers of postoperative delirium. Importantly, our findings suggest postoperative delirium risk is modifiable. Unlike previous research that has mainly focused on proteomics, this study underscores the effectiveness of whole-blood transcriptomics in identifying biomarkers and underlying biological mechanisms of postoperative delirium.
© 2025. The Author(s), under exclusive licence to Springer Nature Limited.