Influence of Nitrous Oxide Anesthesia, B-Vitamins, and MTHFR Gene Polymorphisms on Perioperative Cardiac Events: The Vitamins in Nitrous Oxide (VINO) Randomized Trial

Nagele P, Brown F, Francis A, Scott MG, Gage BF, Miller JP, VINO Study Team. Influence of Nitrous Oxide Anesthesia, B-Vitamins, and MTHFR Gene Polymorphisms on Perioperative Cardiac Events: The Vitamins in Nitrous Oxide (VINO) Randomized Trial. Anesthesiology 2013;119:19-28.

Nitrous oxide is the oldest and most widely used general anaesthetic. Some studies have reported an increased risk for perioperative myocardial ischaemia and infarction with its use during general anaesthesia in patients with cardiac risk factors. Nitrous oxide causes an acute increase in plasma homocysteine by irreversible inactivation of vitamin B12, which has been proposed as the cause for the increased perioperative myocardial infarction risk. The present authors have earlier reported that patients homozygous for the C677T or A1298C variant in the methylenetetrahydrofolate reductase (MTHFR) gene, which is the most important genetic determinant of plasma homocysteine, developed higher plasma homocysteine concentrations after nitrous oxide anaesthesia. The purpose of this double-blind, randomised, placebo-controlled trial was to determine whether patients who were homozygous for the MTHFR C677T or A1298C variant had an increased risk for perioperative cardiac events after nitrous oxide anaesthesia, and whether this risk could be mitigated by B-vitamins, which reliably lowers plasma homocysteine.[1]

Adult patients diagnosed with or at risk for coronary artery disease, who were scheduled for elective non-cardiac surgery under general anaesthesia lasting more than 2 hours, were included. The total sample size was 500 patients. All patients received nitrous oxide throughout surgery at a concentration of 60% and were randomised to receive either, 1 mg vitamin B12 and 5 mg folic acid in 100 ml of normal saline before and after surgery (nitrous oxide/B vitamin group; n = 250), or a placebo infusion of 100 ml normal saline (nitrous oxide/placebo group; n = 250). A nitrous oxide-free non-randomised reference group (n = 125) was added to determine if nitrous oxide had an effect on perioperative cardiac events independent of homocysteine increase. For outcome assessments, patients had five serial blood collections and electrocardiograms at the following time points: Preoperative (baseline), end of surgery, and postoperative days 1, 2 and 3. Plasma total homocysteine, serum troponin I and high-sensitivity troponin T were measured at all the time points; serum folate and vitamin B12 were measured at baseline and on postoperative day 1. MTHFR genotypes (rs1801131, rs1801133) were determined by the Sequenom MassARRAY. The study endpoints were the incidence of myocardial injury, defined by cardiac troponin I increase (peak concentration >0.07 μg/l) within the first 72 hours after surgery, the incidence of myocardial infarction within the first 72 hours after surgery, and a composite of 30-day mortality and nonfatal myocardial infarction. Patients were grouped according to their MTHFR genotype in homozygotes and wild type or heterozygotes.

Patients in the nitrous oxide/B-vitamin group had significantly higher postoperative vitamin B12 and folate concentrations compared to baseline and both the other groups. Plasma total homocysteine concentrations rose in all patients who received nitrous oxide, regardless of MTHFR genotype. The increase was significantly blunted in patients receiving B-vitamins. The MTHFR C677T and A1298C allele status did not influence the extent of plasma total homocysteine increase. Neither the MTHFR genotype, nor the B-vitamin treatment, had an effect on cardiac study outcomes. Patients who were homozygous for either MTHFR C677T, or A1298C gene variant (n = 98; 19.6%) had no increased rate of postoperative cardiac troponin I increase compared with wild type and heterozygous patients (11.2 vs. 14.0%; relative risk 0.96; 95% CI, 0.85-1.07; P = 0.48). B-vitamins blunted the rise in homocysteine, but had no effect on cardiac troponin I increase compared with patients receiving placebo (13.2 vs. 13.6%; relative risk 1.02; 95% CI 0.78–1.32; P = 0.91). No adverse events were related to the administration of intravenous B-vitamins.

The authors concluded that prophylactic use of vitamin B12 and folic acid successfully blunted the nitrous oxide-induced increase in plasma homocysteine but had no effect on perioperative cardiac outcomes. Patients who are homozygous for the MTHFR C677T and A1298C gene variants had no increased risk for perioperative cardiac events after nitrous oxide anaesthesia and the acute increase in plasma homocysteine caused by nitrous oxide was not associated with perioperative cardiac troponin increases. The authors have questioned the prevailing notion that acute nitrous oxide induced hyperhomocysteinaemia has a causal effect on perioperative myocardial ischaemia and infarction and believe that homocysteine may be a marker, rather than a cause of atherosclerotic disease and increased cardiovascular risk. The ENIGMA trial, the only large clinical trial investigating nitrous oxide and cardiovascular outcomes, has reported an inconclusive, statistically non-significant increase in the incidence of myocardial infarction in patients receiving nitrous oxide. The on-going ENIGMA-II trial, a large-scale multicentre clinical trial, will provide robust and definitive evidence to the question of the association between nitrous oxide and perioperative myocardial infarction. Though many practitioners have abandoned the use of nitrous oxide for patients with cardiac risk factors, the authors believe that, as yet, there is no proven increased cardiac risk from acute nitrous oxide-induced hyperhomocysteinaemia.

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• REFERENCE

• 1 Nagele P, Brown F, Francis A, Scott MG, Gage BF, Miller JP. VINO Study Team. Influence of Nitrous Oxide Anesthesia, B-Vitamins, and MTHFR Gene Polymorphisms on Perioperative Cardiac Events: The Vitamins in Nitrous Oxide (VINO) Randomized Trial. Anesthesiology 2013; 119: 19-28