Hyperoxia and Antioxidants for Myocardial Injury in Noncardiac Surgery: A 2 × 2 Factorial, Blinded, Randomized Clinical Trial

Abstract

Background Hyperoxia and oxidative stress may be associated with increased risk of myocardial injury. The authors hypothesized that a perioperative inspiratory oxygen fraction of 0.80 versus 0.30 would increase the degree of myocardial injury within the first 3 days of surgery, and that an antioxidant intervention would reduce degree of myocardial injury versus placebo. Methods A 2 × 2 factorial, randomized, blinded, multicenter trial enrolled patients older than 45 yr who had cardiovascular risk factors undergoing major noncardiac surgery. Factorial randomization allocated patients to one of two oxygen interventions from intubation and at 2 h after surgery, as well as antioxidant intervention or matching placebo. Antioxidants were 3 g IV vitamin C and 100 mg/kg N-acetylcysteine. The primary outcome was the degree of myocardial injury assessed by the area under the curve for high-sensitive troponin within the first 3 postoperative days. Results The authors randomized 600 participants from April 2018 to January 2020 and analyzed 576 patients for the primary outcome. Baseline and intraoperative characteristics did not differ between groups. The primary outcome was 35 ng · day/l (19 to 58) in the 80% oxygen group; 35 ng · day/l (17 to 56) in the 30% oxygen group; 35 ng · day/l (19 to 54) in the antioxidants group; and 33 ng · day/l (18 to 57) in the placebo group. The median difference between oxygen groups was 1.5 ng · day/l (95% CI, −2.5 to 5.3; P = 0.202) and −0.5 ng · day/l (95% CI, −4.5 to 3.0; P = 0.228) between antioxidant groups. Mortality at 30 days occurred in 9 of 576 patients (1.6%; odds ratio, 2.01 [95% CI, 0.50 to 8.1]; P = 0.329 for the 80% vs. 30% oxygen groups; and odds ratio, 0.79 [95% CI, 0.214 to 2.99]; P = 0.732 for the antioxidants vs. placebo groups). Conclusions Perioperative interventions with high inspiratory oxygen fraction and antioxidants did not change the degree of myocardial injury within the first 3 days of surgery. This implies safety with 80% oxygen and no cardiovascular benefits of vitamin C and N-acetylcysteine in major noncardiac surgery. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Fraction of inspired oxygen during general anesthesia for non‐cardiac surgery: Systematic review and meta‐analysis

“…The included trials were generally small with only eight trials including 500 patients or more 9,27,35,36,39,40,48,58 and only three trials including more than 1000 patients. 39,40,48 A noticeable proportion of the trials did not report patient and surgical characteristics deemed crucial for determining potential clinical heterogeneity (e.g., ASA score, length of surgery).…”

“…5,6 Thus, some uncertainty remains regarding this balance of beneficial versus deleterious effects, and it might depend on certain patient and surgical characteristics. Although there are recent systematic reviews on this topic, 7,8 there are new trials to consider, 9,10 and these previous reviews have not extensively explored the potential effect heterogeneity between trials.…”

Intraoperative Inspiratory Oxygen Fraction and Myocardial Injury After Noncardiac Surgery: Results From an International Observational Study in Relation to Recent Controlled Trials

“…Outcomes in the highest and lowest quintile of intraoperative F io 2 were presented with descriptive statistics in relation to the 2 recent controlled trials of oxygen therapy 9,10,13 for contextual analysis of MINS, as well as the most commonly reported outcomes in hyperoxia trials: surgical wound infection and mortality.…”

“…7,8 Current intraoperative F io 2 is variable, and myocardial injury has recently been prospectively evaluated in 2240 patients in 2 controlled trials with nonsignificant results. 9,10…”

The Importance of Definitive Trials: The VIXIE Trial

“…The VIXIE trial (Vitamin and Oxygen Interventions and Cardiovascular Events), whose results are reported in this issue of Anesthesiology , 1 aimed to answer two important questions: First, does a high inspiratory oxygen concentration increase the risk of perioperative myocardial injury attributable to oxidative stress; and second, does the coadministration of antioxidants mitigate such risk? Accordingly, the investigators compared 80% with 30% inspiratory oxygen concentration as first intervention and intravenous vitamin C and N-acetylcysteine versus placebo as second intervention in their trial.…”