Perioperative Hyperoxia and Delirium after On-pump Cardiac Surgery: A Mediation Analysis

Background Neurologic and neurobehavioural complications are common after cardiac surgery with cardiopulmonary bypass (CPB). Exposure to the artificial bypass surface, conversion to laminar flow and hypothermia likely contribute to systemic inflammation observed after CPB. To ensure adequate systemic oxygenation, the CPB patient is often exposed to supraphysiologic levels of oxygen. Relative to normoxia, perioperative hyperoxia during CPB has not been shown to impact neurocognition in the long-term. Whether this holds true for the immediate post-operative neurocognitive function is the question of this nested case-control study. Methods 46 age-and sex-matched subjects, aged ≥65 years, selected for this study were randomized to receive normoxia or hyperoxia during CABG with CPB in the parent trial. Levels of four neuroinflammatory biomarkers (S100B, ENO2, CHI3L1, UCHL1) were measured at baseline and at post-bypass. Baseline neurocognition was established with the Montreal Cognitive Assessment tool and patients were assessed on each post-operative day for delirium using the confusion assessment method. Mediation analyses was conducted for the conditional effect of perioperative oxygen treatment on the occurrence of delirium, assuming mediation effect from change in biomarker levels. Results 26 subjects ( n = 12) demonstrated delirium. Of the four biomarkers, only S100B levels were differentially abundant post-bypass regardless of treatment (8.18 versus 10.15pg/mL, p value < 0.001). We found significant direct effects of treatment on the occurrence of delirium (effect size = -2.477, p = 0.004). There was no statistically significant mediating effect by S100B. Conclusion While perioperative hyperoxia may not be associated with neurocognitive dysfunction in the long-term, its immediate effects may contribute significantly to the occurrence of post-operative delirium. Taken together, our findings suggest a dose-response-time relationship between hyperoxia and neurocognitive function. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT02591589 ### Clinical Protocols ### Funding Statement Funding for this work was supplied by the Burroughs Wellcome training grant to KW, the National Institutes of Health (R01 GM122846) to SAG, and K08 GM134220 and R03 AG060179 to SS. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional review board (IRB) approval 2014P000398/33 was amended for the purposes of this current study on 09/17/2021 by the Committee on Clinical Investigations (CCI) at the Beth Israel Deaconess Medical Center, Boston MA I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors