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.

Intraoperative Oxidative Damage and Delirium after Cardiac Surgery
Marcos G. Lopez, M.D., M.S.; Christopher G. Hughes, M.D., M.S.; Anthony DeMatteo, B.S.; Jason B. O’Neal, M.D.; J. Brennan McNeil, B.S.; et alMatthew S. Shotwell, Ph.D.; Jennifer Morse, M.S.; Michael R. Petracek, M.D.; Ashish S. Shah, M.D.; Nancy J. Brown, M.D.; Frederic T. Billings, IV, M.D., M.Sc.
 Author Notes
From the Divisions of Anesthesiology Critical Care Medicine (M.G.L., C.G.H., F.T.B.) and Cardiothoracic Anesthesiology (J.B.O., F.T.B.), Department of Anesthesiology; Department of Biostatistics (M.S.S., J.M.); Department of Cardiac Surgery (M.R.P., A.S.S.); Divisions of Allergy, Pulmonary, and Critical Care Medicine (J.B.M.) and Clinical Pharmacology (A.D., N.J.B., F.T.B.), Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Submitted for publication January 18, 2019. Accepted for publication September 16, 2019.
Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
Part of the work presented in this article has been presented as an abstract at the Society of Critical Care Medicine 2017 Congress on January 21 to 25, 2017 in Honolulu, Hawaii.
Correspondence: Address correspondence to Dr. Lopez: 1211 21st Avenue South, Medical Arts Building 422, Nashville, Tennessee 37212. marcos.g.lopez@vumc.org, Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Anesthesiology Newly Published on November 18, 2019. doi:https://doi.org/10.1097/ALN.0000000000003016

Postoperative delirium occurs in approximately 25% of cardiac surgery patients.

Hyperoxic cerebral perfusion during cardiac surgery has been associated with increased postoperative delirium, and oxidative damage may mediate this association.

What This Article Tells Us That Is New:

In a cohort of 400 cardiac surgery patients, intraoperative plasma concentrations of F2-isoprostanes and isofurans (markers of oxidative damage) were independently associated with both increased postoperative delirium and increased plasma concentrations of ubiquitin carboxyl-terminal hydrolase isozyme L1, a marker of neuronal injury.

The association between increased systemic markers of oxidative damage and increased neuronal injury was stronger in patients with elevated plasma S100 calcium-binding protein B, a marker of blood–brain barrier disruption. This suggests that blood–brain barrier disruption may increase susceptibility to neuronal injury associated with systemic oxidative stress.

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.