Vitamins in Nitrous Oxide Study

NCT ID: NCT00655980

Last Updated: 2020-10-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 687 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-02-29
• Study Completion Date: 2016-12-31

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

Conditions

Major Surgery; Coronary Artery Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: QUADRUPLE

Study Groups

Treatment

Vitamin B12 and folic acid

Group Type: EXPERIMENTAL

Vitamin B12 and folic acid

Intervention Type: DRUG

1 mg vitamin B12 IV 5 mg folic acid IV in 100 ml NS infusion

Comparator

Nitrous oxide and placebo

Group Type: PLACEBO_COMPARATOR

Nitrous oxide and placebo

Intervention Type: DRUG

Standard of care

standard of care

Group Type: OTHER

standard of care

Intervention Type: OTHER

Interventions

Vitamin B12 and folic acid

1 mg vitamin B12 IV 5 mg folic acid IV in 100 ml NS infusion

Intervention Type: DRUG

Nitrous oxide and placebo

Intervention Type: DRUG

standard of care

Intervention Type: OTHER

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]

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of General Medical Sciences (NIGMS)

NIH

Sponsor Role: collaborator

Foundation for Anesthesia Education and Research

OTHER

Sponsor Role: collaborator

Washington University School of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Peter Nagele, MD

Role: PRINCIPAL_INVESTIGATOR

Washington University School of Medicine

Locations

Barnes-Jewish Hospital

St Louis, Missouri, United States

Countries

United States

Other Identifiers

HSC 07-0592

Identifier Type: -

Identifier Source: org_study_id