Clinical trial NCT00655980: Vitamins in Nitrous Oxide Study
Official title: Pharmacogenetics of Adverse Outcomes After Nitrous Oxide Anesthesia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Major Surgery
Coronary Artery Disease
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: National Institute of General Medical Sciences (NIGMS)
name: Foundation for Anesthesia Education and Research
First posted: 2008-04-10
Enrollment: 687
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: DIAGNOSTIC

Brief 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.

Detailed description: 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 \[folate interference\]

Primary outcomes:
measure: Myocardial Ischemia
timeFrame: first 3 postoperative days
Secondary outcomes:
measure: Non-fatal MI
timeFrame: 30 day postoperative
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Barnes-Jewish Hospital
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Peter Nagele, MD
role: PRINCIPAL_INVESTIGATOR
References: