Mini-VINO: Vitamin B12 and Folate Administration on Homocysteine Concentrations After Nitrous Oxide Anesthesia

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Completed
• CT.gov ID: NCT00901394
• Collaborator: Foundation for Anesthesia Education and Research (Other)
• Enrollment: 63
• Location: 1
• Arms: 3
• Duration (Months): 10.1
• Patients Per Site Per Month: 6.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Cardiovascular Abnormalities	Drug: B12-Folic Acid, nitrous oxide; Drug: Nitrous oxide (NO) and placebo; Other: Placebo; Other: oxygen nitrogen	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 63 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Influence of Preoperative Vitamin B12 and Folate Administration on Homocysteine Concentrations After Nitrous Oxide Anesthesia
• Study Start Date: Mar 1, 2009
• Actual Primary Completion Date: Jan 1, 2010
• Actual Study Completion Date: Jan 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment 1 B12-Folic acid, nitrous oxide	Drug: B12-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.; Other Names: b supplements ; Drug: Nitrous oxide (NO) and placebo; 60% nitrous oxide anesthesia plus saline; Other Names: nitrous oxide
Active Comparator: Treatment 2 Nitrous oxide (NO) and placebo	Drug: Nitrous oxide (NO) and placebo; 60% nitrous oxide anesthesia plus saline; Other Names: nitrous oxide ; Other: Placebo; Saline; Other Names: saline
Placebo Comparator: Control group oxygen nitrogen	Other: Placebo; Saline; Other Names: saline ; Other: oxygen nitrogen; 60% air and oxygen mix.; Other Names: air

Outcome Measures

Primary Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Barnes Jewish Hospital	Saint 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

Study Documents (Full-Text)

None provided.

More Information

Publications

• Myles PS, Chan MT, Kaye DM, McIlroy DR, Lau CW, Symons JA, Chen S. Effect of nitrous oxide anesthesia on plasma homocysteine and endothelial function. Anesthesiology. 2008 Oct;109(4):657-63. doi: 10.1097/ALN.0b013e31818629db.
• Nagele P, Zeugswetter B, Eberle C, Hüpfl M, Mittlböck M, Födinger M. A common gene variant in methionine synthase reductase is not associated with peak homocysteine concentrations after nitrous oxide anesthesia. Pharmacogenet Genomics. 2009 May;19(5):325-9. doi: 10.1097/FPC.0b013e328328d54c.
• Nagele P, Zeugswetter B, Wiener C, Burger H, Hüpfl M, Mittlböck M, Födinger M. Influence of methylenetetrahydrofolate reductase gene polymorphisms on homocysteine concentrations after nitrous oxide anesthesia. Anesthesiology. 2008 Jul;109(1):36-43. doi: 10.1097/ALN.0b013e318178820b.

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT00901394
• Other Study ID Numbers: 09-0074
• First Posted: May 13, 2009
• Last Update Posted: Sep 16, 2020
• Last Verified: Aug 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Washington University School of Medicine: Nitrous oxide; cobalamin; homocysteine; vitamin B12; folate; No specific diseases targeted
• Additional relevant MeSH terms: Cardiovascular Abnormalities; Folic Acid; Nitrous Oxide

Study Results

Participant Flow

Recruitment Details	63 patients were consented however only 59 were analyzed.

Arm/Group Title	B-vitamins Plus Nitrous Oxide	Nitrous Oxide Plus Placebo	Nitrous Oxide-free Group Plus Placebo
Arm/Group Description	IV vitamin B12 (cyanocobalamin) 1 mg, IV folic acid, 5 mg, 60% nitrous oxide	60% nitrous oxide Placebo: normal saline (no vitamins)	No nitrous oxide during anesthesia (oxygen/nitrogen) Placebo: normal saline
Period Title: Overall Study
STARTED	21	20	22
COMPLETED	20	19	20
NOT COMPLETED	1	1	2

Baseline Characteristics

Arm/Group Title	B-vitamins Plus Nitrous Oxide	Nitrous Oxide Plus Placebo	Nitrous Oxide-free Group Plus Placebo	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	20	19	20	59
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40 (13)	40 (14)	42 (15)	41 (14)
Sex: Female, Male (Count of Participants)
Female	11 55%	10 52.6%	12 60%	33 55.9%
Male	9 45%	9 47.4%	8 40%	26 44.1%
Region of Enrollment (participants) [Number]
United States	20 100%	19 100%	20 100%	59 100%

Outcome Measures

1. Primary Outcome

Title	Change in Plasma Total Homocysteine Concentration (tHcy)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment 1	Treatment 2	Control Group
Arm/Group Description	B12-Folic acid, nitrous oxide B12-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. Nitrous oxide (NO) and placebo: 60% nitrous oxide anesthesia plus saline	Nitrous oxide (NO) and placebo Nitrous oxide (NO) and placebo: 60% nitrous oxide anesthesia plus saline Placebo: Saline	oxygen nitrogen Placebo: Saline oxygen nitrogen: 60% air and oxygen mix.
Measure Participants	20	19	20
Median (95% Confidence Interval) [mcmol/L]	1.9	2.7	0.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment 1, Treatment 2, Control Group
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Mixed Models Analysis
	Comments

Adverse Events

Time Frame	AEs were assessed only in the immediate study period (surgery to postoperative day 1)
Arm/Group Title	B-vitamins Plus Nitrous Oxide		Nitrous Oxide Plus Placebo		Nitrous Oxide-free Group Plus Placebo
Arm/Group Description
All Cause Mortality
	B-vitamins Plus Nitrous Oxide		Nitrous Oxide Plus Placebo		Nitrous Oxide-free Group Plus Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/19 (0%)		0/20 (0%)
Serious Adverse Events
	B-vitamins Plus Nitrous Oxide		Nitrous Oxide Plus Placebo		Nitrous Oxide-free Group Plus Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/19 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	B-vitamins Plus Nitrous Oxide		Nitrous Oxide Plus Placebo		Nitrous Oxide-free Group Plus Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		2/19 (10.5%)		1/20 (5%)
Cardiac disorders
Postop. cardiac troponin elevation	0/20 (0%)		0/19 (0%)		1/20 (5%)
Nervous system disorders
PONV	0/20 (0%)		2/19 (10.5%)		0/20 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.