Vitamins in Nitrous Oxide Study (VINO)

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 Overview

• Status: Completed
• Conditions: Coronary Artery Disease; Major Surgery
• Intervention / Treatment: Drug: Vitamin B12 and folic acid; Drug: Nitrous oxide and placebo; Other: standard of care

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

• Study Type: Interventional
• Enrollment (Actual): 687
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Barnes-Jewish Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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]

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment; Vitamin B12 and folic acid	Drug: Vitamin B12 and folic acid; 1 mg vitamin B12 IV 5 mg folic acid IV in 100 ml NS infusion
Placebo Comparator: Comparator; Nitrous oxide and placebo	Drug: Nitrous oxide and placebo
Other: Standard of care; standard of care	Other: standard of care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Myocardial Ischemia	Measured by serial troponin and ECG	first 3 postoperative days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-fatal MI	Myocardial Infarction per Third Definition of MI	30 day postoperative

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: National Institute of General Medical Sciences (NIGMS); Foundation for Anesthesia Education and Research

Study record dates

Study Major Dates

• Study Start: February 1, 2008
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: April 4, 2008
• First Submitted That Met QC Criteria: April 4, 2008
• First Posted (Estimate): April 10, 2008

Study Record Updates

• Last Update Posted (Actual): October 1, 2020
• Last Update Submitted That Met QC Criteria: September 8, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Coronary Artery Disease; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, General; Anesthetics; Analgesics, Non-Narcotic; Micronutrients; Vitamins; Anesthetics, Inhalation; Vitamin B Complex; Hematinics; Nitrous Oxide; Folic Acid; Vitamin B 12; Hydroxocobalamin
• Other Study ID Numbers: HSC 07-0592

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No