Protein alterations in patients with delirium after cardiac surgery: An exploratory case-control sub-study of the VISION Cardiac Surgery Biobank

Jessica Spence; P J Devereaux; Shaheena Bashir; Katheryn Brady; Tao Sun; Matthew T V Chan; Chew Yin Wang; Andre Lamy; Richard P Whitlock; William F McIntyre; Emilie Belley-Côté; Guillaume Paré; Michael Chong

doi:10.1097/ALN.0000000000005368

Protein alterations in patients with delirium after cardiac surgery: An exploratory case-control sub-study of the VISION Cardiac Surgery Biobank

Anesthesiology. 2025 Jan 9. doi: 10.1097/ALN.0000000000005368. Online ahead of print.

Authors

Jessica Spence^{1

2

3

4}, P J Devereaux^{1

3

4

5}, Shaheena Bashir¹, Katheryn Brady¹, Tao Sun¹, Matthew T V Chan⁶, Chew Yin Wang⁷, Andre Lamy^{1

3

4

8}, Richard P Whitlock^{1

3

4

8}, William F McIntyre^{1

3

4

5}, Emilie Belley-Côté^{1

3

4

9}, Guillaume Paré^{1

4

10

11}, Michael Chong^{1

4

10}

Affiliations

¹ Population Health Research Institute, Hamilton, Canada.
² Department of Anesthesia and Critical Care, McMaster University, Hamilton, Canada.
³ Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada.
⁴ World Health Research Trust, Hamilton, Canada.
⁵ Department of Medicine (Cardiology), McMaster University, Hamilton, Canada.
⁶ Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Shatin, Hong Kong.
⁷ Department of Anaesthesiology, University of Malaya, Kuala Lumpur, Wilayah Persekutuan, Malaysia.
⁸ Department of Surgery (Cardiac Surgery), McMaster University, Hamilton, Canada.
⁹ Department of Medicine (Cardiology and Critical Care), McMaster University, Hamilton, Canada.
¹⁰ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada.
¹¹ Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Canada.

PMID: 39786937
DOI: 10.1097/ALN.0000000000005368

Abstract

Background: Delirium is an acute state of confusion associated with adverse postoperative outcomes. Delirium is diagnosed clinically using screening tools; most cases go undetected. Identifying a delirium biomarker would allow for accurate diagnosis, application of therapies, and insight into causal pathways. To agnostically discover novel biomarkers of delirium, we conducted a case-control sub-study using the VISION-Cardiac Surgery biobank. Our objective was to identify candidate biomarkers to investigate in future studies.

Methods: We obtained a convenience sample of 30 patients with delirium on postoperative day 1 matched to 30 matched controls by age, sex, ethnicity, center and cardiopulmonary bypass time. The Olink Explore 3K platform was used to identify blood protein alterations on postoperative day 3. Protein concentrations were expressed as normalized protein expression (NPx) units (log2 fold scale). We compared protein expression between cases and controls using a paired t-test and reported significantly different biomarkers based on a False Discovery Rate (FDR)-adjusted p-value<0.05.

Results: Of 2,865 unique serum proteins, 26 (0.9%) were significantly associated with delirium status; all were elevated in cases versus controls at an FDR<0.05. Pathway analysis identified "calcium-release channel activity" (Padj=0.02) and "Guanosine 5' triphosphate (GTP)-binding" (Padj=0.005) functions as characteristic of proteins associated with delirium. The top three differentially expressed biomarkers were FKBP1B (Padj=0.003), C2CD2L (Padj=0.004), and RAB6B (Padj=0.004). The inflammatory biomarker IL-8 (CXCL8) (mean difference = 2.36; P=3.6x10-4) was also associated with delirium.

Discussion: We identified 26 biomarkers significantly associated with delirium; all are novel except for IL-8. We did not identify an association between delirium and recognized neuro-inflammatory proteins and markers of brain injury, which supports using biomarkers to differentiate between delirium and other neurological conditions. While exploratory, our findings support using biomarkers to diagnose postoperative delirium and validate using agnostic screens to identify potential delirium biomarkers.