Intraoperative Oxidative Stress Associated With Postoperative Delirium

Intraoperative oxidative stress is associated with postoperative delirium in ICU patients after cardiac surgery, a study has found.

Researchers from Vanderbilt University Medical Center, in Nashville, Tenn., came to this conclusion after they found plasma concentrations of F₂-isoprostanes and isofurans, markers of oxidative damage, are associated with delirium. They measured plasma concentrations of F₂-isoprostanes and isofurans throughout the surgical period in 385 patients undergoing cardiac surgery.

The researchers noted that 106 patients (27.5%) developed delirium. In an analysis that accounted for other possible contributors to delirium, a 10-pg/mL increase in F₂-isoprostanes during surgery was associated with a 15% increase in the odds for developing delirium after surgery (P=0.02), whereas a 10-pg/mL increase in isofurans was associated with a 6% increase (P=0.04).

“We found that plasma markers of oxidative damage increase during cardiac surgery, and that increased concentrations of these markers are associated with increased postoperative delirium,” said Marcos Lopez, MD, MS, assistant professor and B.H. Robbins Scholar in the Division of Anesthesiology Critical Care Medicine at Vanderbilt, who presented the findings at the 2017 annual meeting of the Society for Critical Care Management (abstract 26).

“Delirium is a common problem after cardiac surgery, and is associated with long-term cognitive decline and increased mortality,” Dr. Lopez said.

Causality Not Established

“Our findings are consistent with the hypothesis that more oxidative damage during surgery is associated with organ dysfunction, in this case brain dysfunction.” Dr. Lopez noted that the study does not establish causality between oxidative stress and delirium.

Robert D. Stevens, MD, associate professor in the Department of Anesthesiology and Critical Care Medicine at Johns Hopkins University School of Medicine, in Baltimore, was asked to comment on the study. He said although the size of the markers found in the blood associated with oxidative stress and delirium was small, reducing oxidative stress as a way of diminishing perioperative or postoperative delirium was a valid target.

The study’s data do not establish causality, Dr. Stevens said. “We’re left with the question of the chicken and egg. Is oxidative stress in any way responsible for triggering delirium, or is it just a marker of underlying brain dysfunction?”

In addition to reducing oxidative stress, Dr. Stevens said other valid strategies include adapting blood pressure targets and inflammation of the brain. He noted that his team at Johns Hopkins is adapting blood pressure targets to reduce oxidative stress and delirium. “Oxidative stress is a valid target, but not the only one.”

The study was performed in the lab of Frederic T. Billings IV, MD, MSc, assistant professor in the Division of Anesthesiology Critical Care Medicine at Vanderbilt, who recently demonstrated that intraoperative oxidative damage was associated with kidney injury, Dr. Lopez noted. “But to our knowledge, this is the first time oxidative damage during cardiac surgery has been associated with brain dysfunction. This suggests that therapies aimed at decreasing intraoperative oxidative damage may reduce postoperative delirium.”

Although the study did not address whether intraoperative oxidative damage occurs as a result of anesthesia, Dr. Lopez said in vitro studies suggest that some gas anesthetics, local anesthetics and propofol may reduce oxidative damage. “It is possible that sedatives and anesthetics may have differing effects or no effect on oxidative damage,” he said. “Oxidative damage increases with surgery. This could be related to surgical procedure, use of cardiopulmonary bypass, ischemia and reperfusion of tissues, or even excess oxygen administration.”

Dr. Lopez said the next step is to better characterize stimuli of intraoperative oxidative damage during cardiac surgery and to develop treatments to decrease it. “There are many potential therapeutic interventions, including the administration of antioxidants before or during surgery or by decreasing exposure to excess oxygen during cardiac surgery,” he said. “We have chosen the latter approach, and are currently testing the hypothesis that maintenance of normoxia during cardiac surgery decreases oxidative damage and organ injury compared to the hyperoxia that patients typically experience.”