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Vitamins in Nitrous Oxide Study (VINO)
This study is currently recruiting participants.
Verified by Washington University School of Medicine, April 2008
Sponsors and Collaborators: Washington University School of Medicine
Foundation for Anesthesia Education and Research
Information provided by: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT00655980
  Purpose

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 Intervention
Major Vascular Surgery
Coronary Artery Disease
Drug: Vitamin B12 and folic acid

MedlinePlus related topics: Anesthesia Coronary Artery Disease
Drug Information available for: Folic acid Vitamin B 12 Hydroxocobalamin Nitrous oxide
U.S. FDA Resources
Study Type: Interventional
Study Design: Prevention, Randomized, Double Blind (Subject, Caregiver, Outcomes Assessor), Placebo Control, Factorial Assignment
Official Title: Pharmacogenetics of Adverse Outcomes After Nitrous Oxide Anesthesia

Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • Myocardial ischemia assessed by peak serum troponin I concentration [ Time Frame: first 3 postoperative days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Composite endpoint of 30-day mortality and major cardiac morbidity (non-fatal MI) [ Time Frame: 30 day postoperative ] [ Designated as safety issue: No ]

Estimated Enrollment: 500
Study Start Date: February 2008
Estimated Study Completion Date: March 2010
Estimated Primary Completion Date: January 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
1: Experimental

Patients homozygous for MTHFR 677 C>T and 1298 A>G

+ receiving vitamins before and after surgery

Drug: Vitamin B12 and folic acid
1 mg vitamin B12 IV 5 mg folic acid IV in 100 ml NS infusion
2: Placebo Comparator
Patients homozygous for MTHFR 677 C>T and 1298 A>G receiving placebo infusion (plain normal saline 100ml)
Drug: Vitamin B12 and folic acid
1 mg vitamin B12 IV 5 mg folic acid IV in 100 ml NS infusion
3: Experimental

Patients wildtype for MTHFR 677 C>T and 1298 A>G

+ receiving vitamin B12 and folic acid before and after surgery

Drug: Vitamin B12 and folic acid
1 mg vitamin B12 IV 5 mg folic acid IV in 100 ml NS infusion
4: Placebo Comparator

Patients wild-type for MTHFR 677 C>T and 1298 A>G

+ receiving placebo (100 ml NS infusion)

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

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

Outcome definition: Peak serum troponin I concentration during the first 3 postoperative days

Secondary outcome: Composite endpoint of 30-day mortality and major cardiac morbidity (non-fatal MI)

Design: Randomized controlled trial. Patients will be randomized to receive vitamin supplementation or placebo before surgery. All patients will receive N2O during surgery. Mendelian randomization of MTHFR genotype.

Intervention: IV vitamin B12 (1 mg) and folate (5 mg) preoperatively

Study setting: Barnes-Jewish-Hospital, St. Louis, MO

Patients: Patients scheduled for major vascular surgery with previously diagnosed coronary artery disease

Statistical Approach: Comparison of two groups: MTHFR homozygous vs. heterozygous/wild-type patients. General linear model will be fit to the data after normalizing transformation (e.g. log troponin).

Anticipated result: Patients carrying a homozygous MTHFR 677C>T or 1298 A>C variant allele will have a 50% increased peak TnI due to elevated homocysteine compared to non-carriers. Secondly, treatment with vitamin B12/folate will prevent the homocysteine increase as well as the increase in peak troponin and myocardial ischemia.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult patients; age >18 yrs, ASA III-IV
  • Previously diagnosed coronary artery disease
  • Scheduled for major vascular or ENT surgery (>2 hrs)

Exclusion Criteria:

  • Patients not expected to live past 30 days (ASA 5)
  • Patients with significant pulmonary disease or 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
Please refer to this study by its ClinicalTrials.gov identifier: NCT00655980

Contacts
Contact: Peter Nagele, MD 314-362-5129 nagelep@wustl.edu
Contact: Teresa Bieg, RN 314-747-5531 biegt@WUSTL.EDU

Locations
United States, Missouri
Barnes-Jewish Hospital Recruiting
St. Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
Foundation for Anesthesia Education and Research
Investigators
Principal Investigator: Peter Nagele, MD Washington University School of Medicine
  More Information

Responsible Party: Dept of Anesthesiology, Washington University School of Medicine ( Peter Nagele, M.D. )
Study ID Numbers: HSC 07-0592
Study First Received: April 4, 2008
Last Updated: April 4, 2008
ClinicalTrials.gov Identifier: NCT00655980  
Health Authority: United States: Institutional Review Board

Study placed in the following topic categories:
Folic Acid
Arterial Occlusive Diseases
Coronary Disease
Heart Diseases
Nitrous Oxide
Myocardial Ischemia
Hydroxocobalamin
Vascular Diseases
Vitamin B 12
Arteriosclerosis
Ischemia
Coronary Artery Disease

Additional relevant MeSH terms:
Vitamin B Complex
Hematinics
Growth Substances
Physiological Effects of Drugs
Hematologic Agents
Central Nervous System Depressants
Anesthetics
Pharmacologic Actions
Anesthetics, Inhalation
Anesthetics, General
Analgesics, Non-Narcotic
Sensory System Agents
Vitamins
Therapeutic Uses
Cardiovascular Diseases
Peripheral Nervous System Agents
Micronutrients
Analgesics
Central Nervous System Agents

ClinicalTrials.gov processed this record on January 16, 2009