Elsevier

Free Radical Biology and Medicine

Volume 103, February 2017, Pages 192-198
Free Radical Biology and Medicine

Original article
Intraoperative cerebral oxygenation, oxidative injury, and delirium following cardiac surgery

https://doi.org/10.1016/j.freeradbiomed.2016.12.039Get rights and content

Highlights

  • Cerebral oxygenation fluctuates considerably during cardiac surgery.

  • Cerebral hyperoxia after hypoxia was strongly associated with delirium.

  • Hyperoxia independent of hypoxia was also associated with postoperative delirium.

  • Hypoxia was not associated with delirium.

  • Intraoperative oxidative injury may partially mediate these effects.

Abstract

Background

Delirium affects 20–30% of patients after cardiac surgery and is associated with increased mortality and persistent cognitive decline. Hyperoxic reperfusion of ischemic tissues increases oxidative injury, but oxygen administration remains high during cardiac surgery. We tested the hypothesis that intraoperative hyperoxic cerebral reperfusion is associated with increased postoperative delirium and that oxidative injury mediates this association.

Methods

We prospectively measured cerebral oxygenation with bilateral oximetry monitors in 310 cardiac surgery patients, quantified intraoperative hyperoxic cerebral reperfusion by measuring the magnitude of cerebral oxygenation above baseline after any ischemic event, and assessed patients for delirium twice daily in the ICU following surgery using the confusion assessment method for ICU (CAM-ICU). We examined the association between hyperoxic cerebral reperfusion and postoperative delirium, adjusted for the extent of cerebral hypoxia, the extent of cerebral hyperoxia prior to any ischemia, and additional potential confounders and risk factors for delirium. To assess oxidative injury mediation, we examined the association between hyperoxic cerebral reperfusion and delirium after further adjusting for plasma levels of F2-isoprostanes and isofurans at baseline and ICU admission, the association between hyperoxic cerebral reperfusion and these markers of oxidative injury, and the association between these markers and delirium.

Results

Ninety of the 310 patients developed delirium following surgery. Every 10%·hour of intraoperative hyperoxic cerebral reperfusion was independently associated with a 65% increase in the odds of delirium (OR, 1.65 [95% CI, 1.12–2.44]; P=0.01). Hyperoxia prior to ischemia was also independently associated with delirium (1.10 [1.01–1.19]; P=0.02), but hypoxia was not (1.12 [0.97–1.29]; P=0.11). Increased hyperoxic cerebral reperfusion was associated with increased concentrations of F2-isoprostanes and isofurans at ICU admission, increased concentrations of these markers were associated with increased delirium, and the association between hyperoxic cerebral reperfusion and delirium was weaker after adjusting for these markers of oxidative injury.

Conclusions

Intraoperative hyperoxic cerebral reperfusion was associated with increased postoperative delirium, and increased oxidative injury following hyperoxic cerebral reperfusion may partially mediate this association. Further research is needed to assess the potential deleterious role of cerebral hyper-oxygenation during surgery.

Introduction

Delirium is a manifestation of acute brain dysfunction and affects 20–30% of patients following cardiac surgery [1], [2]. Delirium is associated with increased mortality, pulmonary dysfunction, and duration of hospitalization following cardiac surgery, and is an independent predictor of long-term cognitive decline in other medical and surgical patient populations [3], [4], [5], [6].

During cardiac surgery impaired heart function, exposure to cardiopulmonary bypass, and rapid changes in temperature, intravascular pH, and arterial pressure lead to abrupt changes in cerebral perfusion, oxygen extraction, and oxygen consumption. These changes in brain oxygenation, along with exposure to anesthetics, systemic and cerebral inflammation, and microemboli may precipitate delirium following cardiac surgery, although precise mechanisms are poorly understood.

In preclinical studies tissue hypoxia, hyperoxia, ischemia, and hyperoxic reperfusion – all common in patients undergoing cardiac surgery – increase the production of reactive oxygen species and induce oxidative injury [7], [8], [9], [10]. Intraoperative oxidative injury may contribute to postoperative brain injury, as it has been demonstrated that intraoperative oxidative injury contributes to postoperative kidney injury, another organ susceptible to ischemia reperfusion injury [11]. Hyperoxia may contribute to this phenomenon. Indeed, in other clinical scenarios of cerebral ischemia and reperfusion injury, including cardiac arrest and stroke, hyperoxia during reperfusion is a strong predictor of neurologic damage [12], [13]. Hyperoxia during surgery remains standard clinical practice despite these potential deleterious effects.

We conducted this study to test the hypothesis that hyperoxic cerebral reperfusion is associated with the development of delirium following cardiac surgery and that increased oxidative injury may mediate this association.

Section snippets

Patients

We performed a cohort study using participants from the Statin AKI Cardiac Surgery RCT, a randomized clinical trial conducted to test the hypothesis that perioperative atorvastatin treatment compared to placebo reduces acute kidney injury, intensive care unit (ICU) delirium, and additional organ dysfunctions following cardiac surgery [14]. We used the Statin trial cohort because study participants were assessed for delirium by research personnel twice daily while in the ICU, had detailed

Results

The cohort included 310 patients. Demographic and intraoperative data are shown in Table 1. The median (10th percentile, 90th percentile) age of the cohort was 67 (47, 81) years, 30.6% of patients were diabetic, and 79.7% had surgery with the use of cardiopulmonary bypass. Ninety patients (29.0%) developed delirium after surgery for a median of 1.0 (1.0, 4.0) days. Treatment assignment of the parent trial (atorvastatin vs. placebo) did not affect oxygenation or delirium outcomes in this study.

Discussion

Reperfusion injury is frequently blamed for postoperative organ injury [22], [34], but clinicians do not limit hyper-oxygenation following intraoperative ischemia. In a well-phenotyped cohort of cardiac surgery patients intraoperative cerebral hyper-oxygenation following ischemia correlated strongly with an increased incidence of postoperative delirium, and we found some evidence that increased oxidative injury may partially mediate this association. Intraoperative cerebral hyper-oxygenation

Sources of funding

This work was supported by K23GM102676, R01GM112871, and UL1TR000445 from the National Institutes of Health, the Foundation for Anesthesia Education and Research, and the Vanderbilt University Medical Center Department of Anesthesiology.

Disclosures

None.

Acknowledgments

We acknowledge cardiopulmonary bypass perfusionists Matthew Warhoover, MS, MMHC, and Dane A. Fornero, BS, CCP, from the Vanderbilt Heart and Vascular Institute for assistance in obtaining cerebral oximetry data; Patty Hendricks, R.N., for nursing support; Will Hardeman, B.A., Cleo Carter, B.A., Kiersten Card, and Damon Michaels, B.S., of the Vanderbilt Department of Anesthesiology Perioperative Clinical Research Institute, for assisting us in data collection; Anthony DeMatteo, B.S., Stephanie

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