Clinical Summary | Cardiovascular Disease

Intraoperative Oxygen Treatment, Oxidative Stress, and Organ Injury Following Cardiac Surgery

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Originally Published: JAMA Surgery, 5 August 2024. This is a summary of the clinical study and in no way represents the original research. Unless otherwise indicated, all work contained here is implicitly referenced to the original author and trial. Links to all original material can be found at the end of this summary.

 

Key Take Aways

1. Among adults receiving elective cardiac surgery, intraoperative hyperoxia increased intraoperative oxidative stress when compared to normoxia

2. Hyperoxia did not impact the risk of kidney injury or other indicators of organ injury and function when compared to a strategy aimed at maintaining intraoperative normoxia

3. Continuing oxygen treatment into the early postoperative period could mitigate the susceptibility to oxidative stress and organ injury, as many patients remain hemodynamically unstable after surgery

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Overview | Objectives | Study Design | Findings | Discussion| Limitations | Conclusion | Original Research | Funding | References

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Overview

 

Each year, approximately 2 million people worldwide undergo cardiac surgery, but the risks are significant. Up to 35% develop new-onset atrial fibrillation, 25% experience postoperative delirium, and 22% suffer from acute kidney injury. ^2,3 These complications, driven by ischemia-reperfusion and oxidative damage, often lead to extended hospital stays, long-term issues like chronic kidney disease and cognitive decline, and a 500% increase in 30-day mortality risk.^4,5 6

In response to these alarming trends, researchers led by Lopes et al. documented the findings of the Risk of Oxygen during Cardiac Surgery (ROCS) trial (NCT02361944), which offers valuable insights.⁷  We summarize their key findings.
 

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Study Purpose

The study aimed to "…test the hypothesis that intraoperative physiologic oxygenation decreases the generation of reactive oxygen species, oxidative damage, and postoperative organ injury compared to hyper-oxygenation." ⁷


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Findings 

The median duration of the surgeries was 5.22 hours, with 167 participants (83.5%) undergoing cardiopulmonary bypass (CPB).  Baseline and procedural factors were comparable between the hyperoxia and normoxia groups.
 

All participants initially received 1.00 fraction of inspired oxygen (FiO2) during anaesthesia induction and intubation.

 

• In the hyperoxia group, the anaesthesiologist continued to administer 1.00 FiO2 during mechanical ventilation, and the perfusionist gave 0.80 fraction of delivered oxygen (FdO2) during cardiopulmonary bypass.

• In the normoxia group, the anaesthesiologist reduced the FiO2 to 0.21 after intubation and adjusted it as needed to keep arterial oxygen saturation (SpO2) between 95% and 97%, but not below 0.21.

During the transfer from surgery to the ICU, 1.00 FiO2 was continued, and at least 0.40 FiO2 was given in the ICU to maintain SpO2 >95%. Post-operative oxygenation and extubation were at the intensivist's discretion. 


The researchers recorded the following:

Oxidative stress, measured by the combined levels of plasma F2-isoprostanes and isofurans, rose from a baseline median of 73.3 pg/mL to a peak of 85.5 pg/mL when patients were admitted to the ICU. Researchers linked this rise to a higher likelihood of organ injury, including a 68.3% increased risk of acute kidney injury (AKI) and an 89.3% increased risk of delirium.
 

Patients in the hyperoxia group had greater levels of oxidative stress compared to those in the normoxia group, though these effects did not last into the recovery period after oxygen treatment stopped. Importantly, oxygen treatment during surgery did not significantly affect kidney injury outcomes.
 

Delirium occurred in 22% of patients in the hyperoxia group, compared to 16% in the normoxia group. Despite this, the severity and duration of delirium over the first three postoperative days were similar between both groups.
 

Postoperative atrial fibrillation was reported in 46% of hyperoxia patients versus 37% of those in the normoxia group. In addition, some patients in the hyperoxia group experienced cerebral hypoxia during surgery, defined by cerebral oximetry readings below 80% of their baseline levels.
 

There were no significant differences between the two groups in terms of the length of mechanical ventilation, rates of pneumonia, surgical site infections, ICU stays, or a combined measure of organ injury and death. Rates of myocardial infarction, stroke, transient ischemic attacks, reintubation, and death remained low across both groups, although some evidence suggested hyperoxia might be linked to increased postoperative leukocytosis.
 

At the one-year follow-up, six of the participants had died. Of the remaining participants, three participants from the normoxia group were receiving kidney replacement therapy one-year follow-up. Of the 119  follow-up participants who were able to complete cognitive assessments, 109 (91.6%) had normal to minimal impairment, and the remainder had minimal to moderate impairment. There was no difference in activities of daily living in one year between the two groups.

 

 

 

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 Discussion

In summary, the study found that oxidative stress, as indicated by increased levels of F2-isoprostanes and isofurans, was associated with a higher likelihood of developing postoperative organ injury, particularly acute kidney injury (AKI) and delirium. However, intraoperative hyperoxia did not influence postoperative kidney injury despite higher oxidative stress levels during surgery.

Patients in the hyperoxia group had a greater incidence of postoperative atrial fibrillation, cerebral hypoxia during surgery, and possibly increased postoperative leukocytosis. These findings suggest that intraoperative hyperoxia could be linked to certain negative outcomes, although the effects were not uniformly significant across all measured variables.

The study reported no significant differences between hyperoxia and normoxia groups concerning major outcomes like myocardial infarction, stroke, reintubation, death, or mechanical ventilation duration. This suggests that hyperoxia may not provide benefits for these endpoints and could introduce some risks without improving overall recovery. 

Future research opportunities exist to investigate whether extending hyperoxia and normoxia treatments into the postoperative period, particularly when patients are often mechanically ventilated and hemodynamically unstable, would improve potential patient outcomes.

 

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Limitations

This trial has notable limitations, including a limited cohort size, which restricted the power to detect small yet clinically significant differences in secondary endpoints and subgroups, potentially increasing the risk of type II error. Conducting the trial at a single centre may affect generalisability and external validity. Importantly, oxygen treatment was not continued into the early postoperative period when the risk of oxidative stress and organ injury remained high, which may have influenced the outcomes.


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Conclusion

In conclusion, while hyperoxia during surgery was linked to higher oxidative stress and some negative effects (e.g., atrial fibrillation and cerebral hypoxia), it did not significantly alter most major postoperative outcomes. These findings may support a cautious approach to using high oxygen levels during surgery.


ClinicalTrials.gov Identifier: NCT02361944

 

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Conflict of Interest, Funding and Support

Role of the Funder/Sponsor
The study's funder had no role in the design, data collection, data analysis, data interpretation, or writing of the report.

Conflict of Interest Disclosures
Dr Brown reported serving as a science advisory board member for Alnylam Pharmaceuticals and eStar Biotech outside the submitted work.
Dr Billings reported grants from the National Institutes of Health outside the submitted work. No other disclosures were reported.

Funding/Support
Dr Lopez received funding from the National Institutes of Health (NIH; K23GM129662). 
Dr Mace received funding from the NIH (T32GM108554). 
Dr Billings received funding from the NIH (R01GM112871 and R35GM145375). 
NIH grant UL1TR000445 and the Vanderbilt University Medical Center Department of Anaesthesiology also supported this study.

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References
 

1. Hu  J, Chen  R, Liu  S, Yu  X, Zou  J, Ding  X.  Global incidence and outcomes of adult patients with acute kidney injury after cardiac surgery: a systematic review and meta-analysis.   J Cardiothorac Vasc Anesth. 2016;30(1):82-89. doi:10.1053/j.jvca.2015.06.017
 

2. Brown, C. H., 4th, Probert, J., Healy, R., Parish, M., Nomura, Y., Yamaguchi, A., Tian, J., Zehr, K., Mandal, K., Kamath, V., Neufeld, K. J., & Hogue, C. W. (2018). Cognitive Decline after Delirium in Patients Undergoing Cardiac Surgery. Anesthesiology, 129(3), 406–416. https://doi.org/10.1097/ALN.0000000000002253
 

3. Yadava, M., Hughey, A. B., & Crawford, T. C. (2016). Postoperative Atrial Fibrillation: Incidence, Mechanisms, and Clinical Correlates. Heart failure clinics, 12(2), 299–308. https://doi.org/10.1016/j.hfc.2015.08.023
 

4. Pandharipande, P. P., Girard, T. D., Jackson, J. C., Morandi, A., Thompson, J. L., Pun, B. T., Brummel, N. E., Hughes, C. G., Vasilevskis, E. E., Shintani, A. K., Moons, K. G., Geevarghese, S. K., Canonico, A., Hopkins, R. O., Bernard, G. R., Dittus, R. S., Ely, E. W., & BRAIN-ICU Study Investigators (2013). Long-term cognitive impairment after critical illness. The New England journal of medicine, 369(14), 1306–1316. https://doi.org/10.1056/NEJMoa1301372
 

5. LaPar, D. J., Speir, A. M., Crosby, I. K., Fonner, E., Jr, Brown, M., Rich, J. B., Quader, M., Kern, J. A., Kron, I. L., Ailawadi, G., & Investigators for the Virginia Cardiac Surgery Quality Initiative (2014). Postoperative atrial fibrillation significantly increases mortality, hospital readmission, and hospital costs. The Annals of thoracic surgery, 98(2), 527–533. https://doi.org/10.1016/j.athoracsur.2014.03.039

6. Loef, B. G., Epema, A. H., Smilde, T. D., Henning, R. H., Ebels, T., Navis, G., & Stegeman, C. A. (2005). Immediate postoperative renal function deterioration in cardiac surgical patients predicts in-hospital mortality and long-term survival. Journal of the American Society of Nephrology : JASN, 16(1), 195–200. https://doi.org/10.1681/ASN.2003100875
 

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