Preliminary Study of Serum Biomarkers Associated With Delirium After Major Cardiac Surgery

Abstract

Objectives: The objective of this study was to identify novel serum biomarkers specific to postoperative delirium after major cardiac surgery to provide insight into the pathologic processes involved in delirium and its sequelae.

Design: Nested, case-control study.

Setting: Cardiac surgical intensive care unit in a single-site hospital setting.

Participants: The study comprised 24 older adults (aged >60 years) undergoing major cardiac surgery with cardiopulmonary bypass.

Interventions: None.

Measurements and main results: The primary outcome was a positive screen for delirium from postoperative days one through three based on criteria included in the long form of the Confusion Assessment Method. A multiplexed proteomic approach was applied using proximity extension assays to identify and quantify proteins found in serum collected on the day of surgery and postoperative day one in delirious and nondelirious patient cohorts. An increase in serum fibroblast growth factor (FGF)-21 levels was identified in the delirious cohort from a presurgery baseline of (mean ± standard deviation) 5.0 ± 1.1 log2 abundance (95% confidence interval [CI], 4.3-5.7) to 6.7 ± 1.6 log2 abundance (95% CI, 5.7-7.7; p = 0.01) postsurgery. A similar increase was identified in FGF-23 from a presurgery baseline of 1.7 ± 1.3 log2 abundance (95% CI, 0.8-2.5) to 3.4 ± 2.2 log2 abundance (95% CI, 2.0-4.8; p = 0.06) postsurgery. An increase in interleukin-6 serum levels also was identified in the delirious cohort from a presurgery baseline of 3.8 ± 1.1 log2 abundance (95% CI, 3.1-4.5) to 8.7 ± 1.9 log2 abundance (95% CI, 7.5-9.9; p < 0.0001) postsurgery. However, the increase in interleukin-6 serum levels of the nondelirious cohort also met the study's threshold for statistical significance (p < 0.0001). Finally, an increase in monocyte chemotactic protein-3 serum levels was identified in the delirious cohort from a presurgery baseline of 4.1 ± 0.9 log2 abundance (95% CI, 3.6-4.7) to 6.1 ± 2.0 log2 abundance (95% CI, 4.8-7; p = 0.009) postsurgery.

Conclusions: FGF-21, FGF-23, interleukin-6, and monocyte chemotactic protein-3 serum levels were increased postoperatively in patients who developed delirium after major cardiac surgery. This study identified two members of the FGF family as potential putative systemic biomarkers for postoperative delirium after cardiac surgery, suggesting a possible role for metabolic recovery in the pathophysiologic mechanisms underlying neurocognitive dysfunction.

Keywords: FGF; cardiac surgery; cardiopulmonary bypass; cognition; delirium; fibroblast growth factor; inflammation; metabolism; neurodegeneration.

Figure 1.

Clinical characteristics and physical and cognitive assessments of patients enrolled in a substudy to evaluate serum biomarkers detected at pre- and postoperative states in control and delirium cohorts. (A) Study design and data collection; (B) Age, body mass index (BMI), and total cardiopulmonary bypass (CPB) time; (C) Patient-Reported Outcomes Measurement Information System (PROMIS) scores of the patients’ overall physical health, and mental and physical function reported at pre-op; (D) PROMIS cognitive score, sleep disturbance, and pain interference scores reported at pre-op; and (E) temporal evaluation of overall cognitive abilities and applied cognition from pre- to postoperative day (POD) 30, 90, and 180. Bars show mean ± standard deviation. Statistical significance was evaluated using a Mann-Whitney U test.

Figure 2.

Select proteins detected in serum from patients with delirium compared to age- and sex-matched control patients. (A) FGF-21, FGF-23, IL-6, MCP-3, CCL19, and CCL20 expression in control and delirium cohorts at preoperative day 0 and postoperative day (POD) 1; (B) The individual patient response of FGF-21, FGF-23, IL-6, MCP-3, CCL19, and CCL20 from preoperative day 0 to POD1. *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001 based on an ordinary two-way ANOVA with Šídák’s multiple comparisons test.