vitamins in nitrous oxide study

Conditions: Major Surgery; Coronary Artery Disease

Summary: in this study, we want to find out if laughing gas (nitrous oxide) leads to a higher rate of cardiac complications after surgery in patients with a specific genetic profile (mutations in the mthfr gene) and if this risk can be prevented by giving patients vitamin b12 and folate during surgery.

background and significance: recent studies have shown that nitrous oxide (n2o) anesthesia may be associated with an increased risk of adverse cardiovascular outcomes. it is well-known that n2o inhibits vitamin b12-dependent enzymes and as a result increases plasma homocysteine concentrations. homocysteine has been identified as risk factor for cardiovascular disease. therefore elevations in homocysteine after n2o may be a causative factor in n2o toxicity. in a previous investigation, we found that patients who carry a homozygous mutation in the mthfr gene develop higher homocysteine levels after n2o anesthesia than non-carriers. these patients might be at higher risk for adverse cardiac outcomes from n2o. thus, there may be a pharmacogenetic mechanism to account for the adverse cardiac outcomes from n2o. moreover, prevention of n2o-increased homocysteine concentrations in these high risk patients by perioperative vitamin b12 and folate supplementation might decrease the incidence of adverse cardiac outcomes. hypothesis: patients carrying a homozygous mthfr 677c\>t or 1298 a\>c variant allele will have a higher incidence rate of postoperative myocardial ischemia after n2o anesthesia \[detected by serial tni measurements\] due to elevated homocysteine levels than normal "wild-type" non-carriers, and that the incidence rate will be reduced if they receive perioperative vitamin b12/folate supplementation. primary outcome: myocardial ischemia in the first 72 hours after surgery (measured by serial troponin and ecgs). secondary outcome: composite endpoint of 30-day mortality and major cardiac morbidity (non-fatal mi) design: randomized controlled trial. 500 patients will receive n2o during surgery and will be randomized to receive b-vitamins or placebo. 125 patients will receive no n2o and no b-vitamins (control arm). mendelian randomization of mthfr genotype. intervention: iv vitamin b12 (1 mg) and folate (5 mg) pre- and postoperatively study setting: barnes-jewish-hospital, st. louis, mo patients: patients scheduled for major surgery with or at risk for coronary artery disease

Eligibility criteria:
inclusion criteria: * adult patients; age \>18 yrs, asa iii-iv * previously diagnosed coronary artery disease or at risk for coronary artery disease * scheduled for major surgery (\>2 hrs) exclusion criteria: * patients not expected to live past 24 hours (asa 5) * patients with significant pulmonary disease requiring supplemental oxygen * patients taking supplemental vitamin b12 or folate * contraindication against n2o (pneumothorax, mechanical bowel obstruction, middle ear occlusion, laparoscopic surgery, raised intracranial pressure) * hypersensitivity to cobalamins * leber's disease (hereditary optic nerve atrophy) \[vitamin b12 interaction\] * seizure disorder \[folate interference\]