Intraoperative Oxygen Treatment, Oxidative Stress, and Organ Injury Following Cardiac Surgery: A Randomized Clinical Trial

Abstract

Importance: Liberal oxygen (hyperoxia) is commonly administered to patients during surgery, and oxygenation is known to impact mechanisms of perioperative organ injury.

Objective: To evaluate the effect of intraoperative hyperoxia compared to maintaining normoxia on oxidative stress, kidney injury, and other organ dysfunctions after cardiac surgery.

Design, setting, and participants: This was a participant- and assessor-blinded, randomized clinical trial conducted from April 2016 to October 2020 with 1 year of follow-up at a single tertiary care medical center. Adult patients (>18 years) presenting for elective open cardiac surgery without preoperative oxygen requirement, acute coronary syndrome, carotid stenosis, or dialysis were included. Of 3919 patients assessed, 2501 were considered eligible and 213 provided consent. Of these, 12 were excluded prior to randomization and 1 following randomization whose surgery was cancelled, leaving 100 participants in each group.

Interventions: Participants were randomly assigned to hyperoxia (1.00 fraction of inspired oxygen [FiO2]) or normoxia (minimum FiO2 to maintain oxygen saturation 95%-97%) throughout surgery.

Main outcomes and measures: Participants were assessed for oxidative stress by measuring F2-isoprostanes and isofurans, for acute kidney injury (AKI), and for delirium, myocardial injury, atrial fibrillation, and additional secondary outcomes. Participants were monitored for 1 year following surgery.

Results: Two hundred participants were studied (median [IQR] age, 66 [59-72] years; 140 male and 60 female; 82 [41.0%] with diabetes). F2-isoprostanes and isofurans (primary mechanistic end point) increased on average throughout surgery, from a median (IQR) of 73.3 (53.1-101.1) pg/mL at baseline to a peak of 85.5 (64.0-109.8) pg/mL at admission to the intensive care unit and were 9.2 pg/mL (95% CI, 1.0-17.4; P = .03) higher during surgery in patients assigned to hyperoxia. Median (IQR) change in serum creatinine (primary clinical end point) from baseline to postoperative day 2 was 0.01 mg/dL (-0.12 to 0.19) in participants assigned hyperoxia and -0.01 mg/dL (-0.16 to 0.19) in those assigned normoxia (median difference, 0.03; 95% CI, -0.04 to 0.10; P = .45). AKI occurred in 21 participants (21%) in each group. Intraoperative oxygen treatment did not affect additional acute organ injuries, safety events, or kidney, neuropsychological, and functional outcomes at 1 year.

Conclusions: Among adults receiving cardiac surgery, intraoperative hyperoxia increased intraoperative oxidative stress compared to normoxia but did not affect kidney injury or additional measurements of organ injury including delirium, myocardial injury, and atrial fibrillation.

Trial registration: ClinicalTrials.gov Identifier: NCT02361944.

Figure 1.. CONSORT Diagram

Figure 2.. Intraoperative Oxygenation Metrics in Participants Assigned to Hyperoxia and Normoxia

A, Fraction of inspired oxygen (FiO₂) and delivered oxygen (FdO₂) during mechanical ventilation and cardiopulmonary bypass (CPB). B, Arterial oxygen saturation (SpO₂) and mixed venous oxygen saturation (SvO₂). C, Arterial partial pressure of oxygen (PaO₂). D, Cerebral oximetry. Dark lines reflect the median values and shading the IQRs. Median (IQR) durations of time from entering the operating room to induction of anesthesia were 16 (14-21) minutes; starting CPB or off-pump coronary grafting, 121 (106-147) minutes; stopping CPB or off-pump coronary grafting, 245 (203-290) minutes; and leaving the operating room, 313 (267-369) minutes.

Figure 3.. Clinical Outcomes and Safety Events

Data are presented as medians (IQRs) and absolute median differences (95% CIs) for continuous variables and as counts (percentages) and absolute risk differences (95% CIs) for categorical variables. P values were calculated using the Wald and Agresti-Coull methods for median differences and risk differences, respectively. In the Forest plot, we standardized the median difference for continuous variables such that 0.2 units on the risk difference scale represent the difference between the 75th and 25th centiles of the continuous variable. CK-MB indicates creatine kinase–myocardial band, measured the morning of postoperative day 1. ^aStage 2 or 3 acute kidney injury (AKI) based on Kidney Disease: Improving Global Outcomes consensus criteria. ^bAmong 38 participants who developed delirium. ^cMean confusion assessment method for the Confusion Assessment Method for the Intensive Care Unit 7 (CAM-ICU-7) score over the first 3 postoperative days. ^dAny of AKI, delirium, atrial fibrillation, myocardial infarction, stroke, transient ischemic attack, pneumonia, surgical site infection, or death.