Major SurgeryVINONCT00655980
Vitamins in Nitrous Oxide Study
A study testing Vitamin B12 and folic acid in people with Major Surgery and Coronary Artery Disease, run by Washington University School of Medicine at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Major Surgery, Coronary Artery Disease
- What is being tested?
- Vitamin B12 and folic acid
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 687 participants
- Where
- 1 siteUnited States
- Study dates
- Feb 2008to Dec 2016
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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)
Who cannot join
- 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]
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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.
Read the 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
- Being tested
- Vitamin B12 and folic acid, Nitrous oxide and placebo, standard of care
- Medical subject headings
- Coronary Artery Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Vitamin B12 and folic acidDrug
1 mg vitamin B12 IV 5 mg folic acid IV in 100 ml NS infusion
Nitrous oxide and placeboDrug
standard of careOther
| Study group | Role | What they receive |
|---|---|---|
| Treatment | Experimental | Vitamin B12 and folic acid Receives: Drug: Vitamin B12 and folic acid |
| Comparator | Placebo comparator | Nitrous oxide and placebo Receives: Drug: Nitrous oxide and placebo |
| Standard of care | Other | standard of care Receives: Other: standard of care |
What is being measured
The primary outcome is the main question the study is designed to answer.
Myocardial Ischemia
Measured by serial troponin and ECG
Measured: first 3 postoperative days
Secondary outcomes (1)
Non-fatal MI
Myocardial Infarction per Third Definition of MI
Measured: 30 day postoperative
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Apr 2008 (estimated)
- Study startFeb 2008
- Primary completionDec 2016
- Study completionDec 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Major SurgeryStudies of the same condition, open and under way.
- More trials run by Washington University School of MedicineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 687 participants (actual)
Sponsor and investigators
- Lead sponsor
- Washington University School of Medicine
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of General Medical Sciences (NIGMS), Foundation for Anesthesia Education and Research
- Responsible party
- Sponsor
- Investigators
- Peter Nagele, MD, Principal investigator, Washington University School of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00655980
- Sponsor's protocol ID
- HSC 07-0592
- Acronym
- VINO
- Status last verified
- Sep 2020
- First submitted
- 4 Apr 2008
- Last updated
- 1 Oct 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 1 Oct 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacogenetics of Adverse Outcomes After Nitrous Oxide Anesthesia
- ClinicalTrials.gov ID
- NCT00655980
- Acronym / sponsor ID
- VINO / HSC 07-0592
- Conditions
- Major Surgery, Coronary Artery Disease
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 687 participants (actual)
- Lead sponsor
- Washington University School of MedicineUniversity, hospital or other
- Collaborators
- National Institute of General Medical Sciences (NIGMS), Foundation for Anesthesia Education and Research
- Study start
- Feb 2008
- Primary completion
- Dec 2016 (actual)
- Study completion
- Dec 2016 (actual)
- First posted
- 10 Apr 2008 (estimated)
- Results
- Posted 1 Oct 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Treatment | Experimental | Drug: Vitamin B12 and folic acidVitamin B12 and folic acid |
| Comparator | Placebo comparator | Drug: Nitrous oxide and placeboNitrous oxide and placebo |
| Standard of care | Other | Other: standard of carestandard of care |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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)
Key exclusion criteria (7 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Vitamin B12 and folic acid1 mg vitamin B12 IV 5 mg folic acid IV in 100 ml NS infusion | Drug | Treatment |
| Nitrous oxide and placebo | Drug | Comparator |
| standard of care | Other | Standard of care |
Primary outcome
Myocardial Ischemia
Time frame: first 3 postoperative days
Measured by serial troponin and ECG
1 secondary outcome
Non-fatal MI
Time frame: 30 day postoperative
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Oct 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Peter Nagele, MD principal investigator
Washington University School of Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Vitamin B12 and folic acid in people with Major Surgery and Coronary Artery Disease, run by Washington University School of Medicine at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Oct 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 1 Oct 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Myocardial Ischemia (time frame: first 3 postoperative days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Oct 2020.