Official Title: “Pharmacogenetics of Adverse Outcomes After Nitrous Oxide Anesthesia”

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.

Study Type: Interventional

Study Design: Prevention, Randomized, Double Blind (Subject, Caregiver, Outcomes Assessor), Placebo Control, Factorial Assignment

Study Primary Completion Date: January 2010

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

Outcome definition: Peak serum troponin I concentration during the first 3 postoperative days

Secondary outcome: Composite endpoint of 30-day mortality and major cardiac morbidity (non-fatal MI)

Design: Randomized controlled trial. Patients will be randomized to receive vitamin supplementation or placebo before surgery. All patients will receive N2O during surgery.

Mendelian randomization of MTHFR genotype.

Intervention: IV vitamin B12 (1 mg) and folate (5 mg) preoperatively

Study setting: Barnes-Jewish-Hospital, St. Louis, MO

Patients: Patients scheduled for major vascular surgery with previously diagnosed coronary artery disease

Statistical Approach: Comparison of two groups: MTHFR homozygous vs. heterozygous/wild-type patients. General linear model will be fit to the data after normalizing transformation (e.g.

log troponin).

Anticipated result: Patients carrying a homozygous MTHFR 677C>T or 1298 A>C variant allele will have a 50% increased peak TnI due to elevated homocysteine compared to non-carriers.

Secondly, treatment with vitamin B12/folate will prevent the homocysteine increase as well as the increase in peak troponin and myocardial ischemia.

Intervention(s) in this Clinical Trial

• Drug: Vitamin B12 and folic acid
  • 1 mg vitamin B12 IV 5 mg folic acid IV in 100 ml NS infusion

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Patients homozygous for MTHFR 677 C>T and 1298 A>G + receiving vitamins before and after surgery
• Placebo Comparator: 2
  • Patients homozygous for MTHFR 677 C>T and 1298 A>G receiving placebo infusion (plain normal saline 100ml)
• Experimental: 3
  • Patients wildtype for MTHFR 677 C>T and 1298 A>G + receiving vitamin B12 and folic acid before and after surgery
• Placebo Comparator: 4
  • Patients wild-type for MTHFR 677 C>T and 1298 A>G + receiving placebo (100 ml NS infusion)

Primary Measures

• Myocardial ischemia assessed by peak serum troponin I concentration
  • Time Frame: first 3 postoperative days
    Safety Issue?: No

Secondary Measures

• Composite endpoint of 30-day mortality and major cardiac morbidity (non-fatal MI)
  • Time Frame: 30 day postoperative
    Safety Issue?: No

Inclusion Criteria:

• Adult patients; age >18 yrs, ASA III-IV
• Previously diagnosed coronary artery disease
• Scheduled for major vascular or ENT surgery (>2 hrs)

Exclusion Criteria:

• Patients not expected to live past 30 days (ASA 5)
• Patients with significant pulmonary disease or 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]

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Washington University School of Medicine

Overall Clinical Trial Officials and Contacts

Peter Nagele, MD Principal Investigator Washington University School of Medicine  

Overall Contact: Peter Nagele, MD 314-362-5129 nagelep@wustl.edu

Information obtained from ClinicalTrials.gov on September 05, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00655980

Study ID Number: HSC 07-0592

ClinicalTrials.gov Identifier: NCT00655980

Health Authority: United States: Institutional Review Board