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Vitamins in Nitrous Oxide Study (VINO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT00655980
Recruitment Status : Completed
First Posted : April 10, 2008
Last Update Posted : December 18, 2017
Information provided by (Responsible Party):

Study Description
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.

Condition or disease Intervention/treatment
Major Surgery Coronary Artery Disease 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 Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 625 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Diagnostic
Official Title: Pharmacogenetics of Adverse Outcomes After Nitrous Oxide Anesthesia
Study Start Date : February 2008
Primary Completion Date : December 2016
Study Completion Date : December 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Folic Acid
U.S. FDA Resources

Arms and Interventions

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
Standard of care
standard of care
Other: standard of care

Outcome Measures

Primary Outcome Measures :
  1. Myocardial ischemia [ Time Frame: first 3 postoperative days ]
    Measured by serial troponin and ECG

Secondary Outcome Measures :
  1. Composite endpoint of 30-day mortality and major cardiac morbidity (non-fatal MI) [ Time Frame: 30 day postoperative ]

Eligibility Criteria

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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]
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00655980

United States, Missouri
Barnes-Jewish Hospital
Saint Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
National Institute of General Medical Sciences (NIGMS)
Foundation for Anesthesia Education and Research
Principal Investigator: Peter Nagele, MD Washington University School of Medicine
More Information

Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT00655980     History of Changes
Other Study ID Numbers: HSC 07-0592
First Posted: April 10, 2008    Key Record Dates
Last Update Posted: December 18, 2017
Last Verified: December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Heart Diseases
Cardiovascular Diseases
Arterial Occlusive Diseases
Vascular Diseases
Folic Acid
Vitamin B 12
Vitamin B Complex
Nitrous Oxide
Growth Substances
Physiological Effects of Drugs
Anesthetics, Inhalation
Anesthetics, General
Central Nervous System Depressants
Analgesics, Non-Narcotic
Sensory System Agents
Peripheral Nervous System Agents