Vitamins in Nitrous Oxide Study
| Status: | Completed |
|---|---|
| Conditions: | Peripheral Vascular Disease, Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 12/20/2017 |
| Start Date: | February 2008 |
| End Date: | December 2016 |
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.
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.
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
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
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]
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