Cardiovascular Abnormalities
Conditions
Keywords
Nitrous oxide, cobalamin, homocysteine, vitamin B12, folate, No specific diseases targeted
Brief summary
The goal of this study is to find out if giving intravenous B-vitamins before general anesthesia with nitrous oxide prevents the increase in homocysteine, a metabolite that has been linked to cardiovascular complications.
Detailed description
Patients will be randomized into the following arms: * Arm A: patients will receive N2O (60% N2O/40% O2) in an open-label fashion during surgery and vitamin supplementation (vitamin B12, 1 mg, and folate, 5 mg) before surgery. * Arm B: patients will receive N2O 60% N2O/40% O2) in an open-label fashion during surgery and placebo before and after surgery. * Arm C: patients will not receive N2O, vitamin supplementation, or placebo during/before surgery. Patients in this arm will not be randomized. Patients will have blood drawn (total of 1-2 teaspoons over 3 days). We will take these samples before their surgery, when their surgery is completed, and in the morning of post-operative day 1. We will be checking their troponin I and troponin T, homocysteine, Vitamin B12, and folate levels. We will also perform a 12-lead EKG. Before and after surgery for patients in Arm A or B, will receive either vitamin B12 (1 mg) and folic acid (5 mg) (or placebo) added to their IV infusion. We also plan to use a non-invasive test known as a nerve conduction study to measure the function of their nerve system. Briefly, 2 small electrodes are attached to their skin over a nerve and, like an EKG, faint electrical pulses are generated and recorded. A typical nerve conduction measurement lasts about 10 minutes. After the patients surgery we will do genetic testing of MTHFR genotype. All study samples have been collected. Of note: there were no secondary outcomes.
Interventions
DRUGB12-Folic Acid, nitrous oxide
IV vitamin B12 (cyanocobalamin) 1 mg, single administration over 30 min. IV folic acid, 5 mg, single administration over 30 min. Both diluted in 250 ml normal saline.
DRUGNitrous oxide (NO) and placebo
60% nitrous oxide anesthesia plus saline
OTHERPlacebo
Saline
OTHERoxygen nitrogen
60% air and oxygen mix.
Sponsors
Foundation for Anesthesia Education and Research
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult patients scheduled for elective surgery with expected duration \> 2 hours * Healthy patients undergoing moderate surgery where the use of N2O is unproblematic
Exclusion criteria
* Contraindication against N2O (pneumothorax, mechanical bowel obstruction, middle ear occlusion, laparoscopic surgery, raised intracranial pressure) * Patients requiring supplemental oxygen * Urgent or emergent surgery * Patients with vitamin B12 or folate deficiency or megaloblastic anemia * Patients with seizure disorder (epilepsy) * Allergy or hypersensitivity against IV cobalamin or folate * Patients with Leber's disease (hereditary optic nerve atrophy) * Patients taking supplemental vitamin B12 or folate
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Plasma Total Homocysteine Concentration (tHcy) | Immediately postoperatively and on postoperative day 1 | Difference between baseline (pre-operative) and peak postoperative (i.e., maximum of postoperative value obtained within 30 minutes after anesthesia end time and morning of post-operative day 1) tHcy concentration . Of note: there were no secondary outcomes. |
Countries
United States
Participant flow
Recruitment details
63 patients were consented however only 59 were analyzed.
Participants by arm
| Arm | Count |
|---|---|
| B-vitamins Plus Nitrous Oxide | 20 |
| Nitrous Oxide Plus Placebo | 19 |
| Nitrous Oxide-free Group Plus Placebo | 20 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Physician Decision | 1 | 1 | 2 |
Baseline characteristics
| Characteristic | B-vitamins Plus Nitrous Oxide | Nitrous Oxide Plus Placebo | Nitrous Oxide-free Group Plus Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 40 years STANDARD_DEVIATION 13 | 40 years STANDARD_DEVIATION 14 | 42 years STANDARD_DEVIATION 15 | 41 years STANDARD_DEVIATION 14 |
| Region of Enrollment United States | 20 participants | 19 participants | 20 participants | 59 participants |
| Sex: Female, Male Female | 11 Participants | 10 Participants | 12 Participants | 33 Participants |
| Sex: Female, Male Male | 9 Participants | 9 Participants | 8 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 19 | 0 / 20 |
| other Total, other adverse events | 0 / 20 | 2 / 19 | 1 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 19 | 0 / 20 |
Outcome results
Primary
Change in Plasma Total Homocysteine Concentration (tHcy)
Difference between baseline (pre-operative) and peak postoperative (i.e., maximum of postoperative value obtained within 30 minutes after anesthesia end time and morning of post-operative day 1) tHcy concentration . Of note: there were no secondary outcomes.
Time frame: Immediately postoperatively and on postoperative day 1
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment 1 | Change in Plasma Total Homocysteine Concentration (tHcy) | 1.9 mcmol/L |
| Treatment 2 | Change in Plasma Total Homocysteine Concentration (tHcy) | 2.7 mcmol/L |
| Control Group | Change in Plasma Total Homocysteine Concentration (tHcy) | 0.5 mcmol/L |
Comparison: For baseline comparisons among the three groups, one-way ANOVA was used for normally distributed variables and χ2 goodness-of-fit for categorical variables. To model the effects of B-vitamin treatment on nitrous-oxide-induced total homocysteine increase at the three different timepoints within individual patients and between the three groups, a linear mixed model with was used and we included a group × time interaction in the model.p-value: <0.05Mixed Models Analysis