Intraoperative Oxidative Damage and Delirium after Cardiac Surgery

Abstract

Background: Mechanisms of postoperative delirium remain poorly understood, limiting development of effective treatments. We tested the hypothesis that intraoperative oxidative damage is associated with delirium and neuronal injury and that disruption of the blood-brain barrier modifies these associations.

Methods: In a prespecified cohort study of 400 cardiac surgery patients enrolled in a clinical trial of atorvastatin to reduce kidney injury and delirium, we measured plasma concentrations of F2-isoprostanes and isofurans using gas chromatography-mass spectrometry to quantify oxidative damage, ubiquitin carboxyl-terminal hydrolase isozyme L1 to quantify neuronal injury, and S100 calcium-binding protein B using enzyme-linked immunosorbent assays to quantify blood-brain barrier disruption before, during, and after surgery. We performed the Confusion Assessment Method for the Intensive Care Unit twice daily to diagnose delirium. We measured the independent associations between intraoperative F2-isoprostanes and isofurans and delirium (primary outcome) and postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 (secondary outcome), and we assessed if S100 calcium-binding protein B modified these associations.

Results: Delirium occurred in 109 of 400 (27.3%) patients for a median (10th, 90th percentile) of 1.0 (0.5, 3.0) days. In the total cohort, plasma ubiquitin carboxyl-terminal hydrolase isozyme L1 concentration was 6.3 ng/ml (2.7, 14.9) at baseline and 12.4 ng/ml (7.9, 31.2) on postoperative day 1. F2-isoprostanes and isofurans increased throughout surgery, and the log-transformed sum of intraoperative F2-isoprostanes and isofurans was independently associated with increased odds of postoperative delirium (odds ratio, 3.70 [95% CI, 1.41 to 9.70]; P = 0.008) and with increased postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 (ratio of geometric means, 1.42 [1.11 to 1.81]; P = 0.005). The association between increased intraoperative F2-isoprostanes and isofurans and increased postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 was amplified in patients with elevated S100 calcium-binding protein B (P = 0.049).

Conclusions: Intraoperative oxidative damage was associated with increased postoperative delirium and neuronal injury, and the association between oxidative damage and neuronal injury was stronger among patients with increased blood-brain barrier disruption.

Figure 1.. Perioperative plasma expression of F₂-isoprostanes, isofurans, ubiquitin carboxyl-terminal hydrolase isozyme L1, and S100 calcium binding protein B

Plasma concentrations of markers of oxidative damage (F₂-isoprostanes, Panel A and isofurans, Panel B), neuronal injury (ubiquitin carboxyl-terminal hydrolase isozyme L1, Panel C), and blood-brain barrier disruption (S100 calcium binding protein B, Panel D) during the perioperative period in patients who developed delirium and those who did not develop delirium.

Figure 2.. Intraoperative oxidative damage versus postoperative delirium and neuronal injury

Intraoperative oxidative damage, quantified as the plasma concentration of F₂-isoprostanes and isofurans, was independently associated with increased probability of postoperative delirium (Panel A) and plasma concentration of ubiquitin carboxyl-terminal hydrolase isozyme L1 on postoperative day 1 (Panel B) after adjusting for potential confounders. This association with ubiquitin carboxyl-terminal hydrolase isozyme L1 concentration was differentially modified by the extent of blood-brain barrier disruption (measured as plasma S100 calcium binding protein B concentration at the time of intensive care unit admission). The association with delirium was not modified by S100 calcium binding protein B. Shaded areas represent the 95% CI of the probability of delirium (Panel A) and ubiquitin carboxyl-terminal hydrolase isozyme L1 concentration (Panel B). Tick marks at the bottom of the figure indicate the observed values among the study cohort.