Vitamins in Nitrous Oxide Study

Coronary Artery Disease Clinical Trial

— VINO  

Official title:

Pharmacogenetics of Adverse Outcomes After Nitrous Oxide Anesthesia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00655980
• Other study ID #: HSC 07-0592
• Status: Completed
• Phase: N/A
• Start date: February 2008
• Est. completion date: December 2016

Study information

• Verified date: September 2020
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 687
• Est. completion date: December 2016
• Est. primary completion date: December 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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]

Related Conditions & MeSH terms

• Coronary Artery Disease
• Major Surgery

Intervention

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

Other:
• standard of care

Locations

Country	Name	City	State
United States	Barnes-Jewish Hospital	Saint Louis	Missouri

Sponsors (3)

Lead Sponsor	Collaborator
Washington University School of Medicine	Foundation for Anesthesia Education and Research, National Institute of General Medical Sciences (NIGMS)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Myocardial Ischemia	Measured by serial troponin and ECG	first 3 postoperative days
Secondary	Non-fatal MI	Myocardial Infarction per Third Definition of MI	30 day postoperative