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
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
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
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
- 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)
- 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]