Optimal oxygen targets in patients undergoing general anesthesia for major non‐cardiac surgery—How to handle the conflict between observational and randomized trials?

Supplemental oxygen is used for all patients undergoing general anesthesia, and the amount administered can easily be changed by adjusting the fraction of inspired oxygen (FiO2) during mechanical ventilation. In case of sudden apnea, for example, related to an airway problem, hypoxia will be delayed in patients with high levels of oxygen in the lungs and blood. In addition, some data suggest a decrease in postoperative infections in patients receiving an FiO2 of 0.80. Liberal perioperative oxygen administration will, in most cases, result in arterial hyperoxia, which may also have some harmful effects. These include an increase in the formation of reactive oxygen species, inflammation, and arterial vasoconstriction. Vasoconstriction of the coronary arteries has been documented following hyperoxia and could potentially result in worsening postoperative myocardial injury, which is a recognized contributor to poor outcome in patients undergoing major non-cardiac surgery. In the end, how can we use the information obtained from small physiological studies to tailor patient management? For the clinician, patient outcome is, of course, most important. Any possible effects of oxygen targets can be ascertained from both observational and randomized controlled trials (RCTs). Here, we discuss remarkable discrepancies between recent findings in the two types of trials with regards to hyperoxia and cardiac injury. Evidence regarding the effect of hyperoxia on the development of myocardial injury in general surgery patients is mixed, and defining the optimal and safe intraoperative oxygen target is not straightforward. In the VitamIn and oXygen Interventions and cardiovascular Events (VIXIE) study published in 2022, a total of 600 patients aged more than 45 years with risk factors for coronary artery disease were randomized to receive an FiO2 of either 0.80 or 0.30 during noncardiac surgery. The study employed a factorial 2 2 design, where allocation in the two oxygen arms was combined with allocation to either the two antioxidants vitamin C and N-acetylcysteine or to matching placebo. The primary outcome was myocardial injury assessed with serial troponin levels measured on the first 3 days after surgery. The study found no difference in troponin levels between the two oxygen groups. The study also included a number of secondary endpoints without significant differences: mortality, postoperative infections, clinically diagnosed myocardial infarction, and acute kidney injury (AKI). As these endpoints were rare due to the study's limited sample size, these analyses should be seen as exploratory. Interestingly, mortality in the 80% oxygen group was 2% and 1% in the 30% group. Such relative difference would be highly clinically relevant, but a study to confirm or refute this would need to randomize more than 6000 patients. The conclusion of the VIXIE study is that higher oxygen fractions do not result in a higher level of troponin, which is a well-documented marker of myocardial injury. Also published in 2022, a RCT of 191 patients allocated to an FiO2 of either 0.21 or ≥0.50 during vascular surgery found no significant difference in myocardial injury and other postoperative complications. These results are in line with other RCTs conducted on critically ill patients with acute myocardial infarction and cardiac arrest, where moderate hyperoxia compared with normoxia did not worsen myocardial injury. A recent observational cohort study of more than 350,000 patients across 42 US hospitals evaluated supraphysiological oxygen administration during general anesthesia for major surgical procedures. The primary exposure was the area under the curve for an FiO2 above 0.21 when peripheral oxygen saturation (SpO2) was above 92%, and the main outcomes were AKI, myocardial injury and lung injury. Even after adjusting for relevant confounders, all these organ injuries were significantly and linearly associated with increased time with excess oxygen supplementation. The odds ratios were 1.26 for AKI, 1.12 for myocardial injury and 1.14 for lung injury when comparing the 75th and 25th percentiles. Such a difference—if true—is highly clinically relevant, but almost impossible to recognize in daily anaesthesiological practices, since the increased risks are equivalent to numbers needed to harm of 64 for AKI, 307 for myocardial injury and 171 for lung injury. This is why observational studies are excellent for detecting rare complications. Excess lung injury was previously found to a higher extent in a large observational study. Another important cohort study, also published in 2022, detected an increase in myocardial injury with a higher FiO2. 11 This study utilized routine postoperative troponin screening of 6588 patients across six hospitals in four continents included in the Vascular events In non-cardiac Surgery patIents cOhort evaluatioN (VISION) study, finding that each 0.10 increase in median intraoperative FiO2 was associated with a confounder-adjusted odds ratio of 1.17 for myocardial injury. Interestingly, the observational study also found that increasing FiO2 was associated with lower odds of surgical wound infection—a finding that supports the first RCT in this field but contrasts with the largest RCT to date that documented no significant benefit of high oxygen Received: 3 March 2023 Accepted: 21 March 2023