Ignite Creation Date:
2024-05-05 @ 12:01 PM
Last Modification Date:
2024-10-26 @ 9:18 AM
Study NCT ID:
NCT00212147
Status:
COMPLETED
Last Update Posted:
2022-08-08
First Post:
2005-09-13
Brief Title:
Interaction of Cobalamin Status With Nitrous Oxide in Relation to Postoperative Cognitive Changes in the Elderly
Sponsor:
National Institute of Diabetes and Digestive and Kidney Diseases NIDDK
Organization:
National Institute of Diabetes and Digestive and Kidney Diseases NIDDK
Study Overview
Official Title:
Subtle Disturbances of Cobalamin Status
Status:
COMPLETED
Status Verified Date:
2012-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Low cobalamin vitamin B12 levels are frequent in the elderly Most often they reflect a mild metabolic abnormality without clinical symptoms subclinical cobalamin deficiency It is unclear if these elderly people require medical intervention unlike that small minority with clinical symptoms which can progress and create severe blood or nervous system problems The study aims to determine if nitrous oxide N2O a common anesthetic agent worsens cobalamin status in elderly patients with unrecognized subclinical cobalamin deficiency The reason for concern is that N2O inactivates cobalamin and can aggravate the clinical picture of patients who already have clinical manifestations of cobalamin deficiency The elderly are known to have an increased risk of developing mental changes after surgery and it may be that sometimes these result from aggravation of subclinical cobalamin deficiency
The study recruits people over the age of 60 years who are undergoing clinically indicated elective surgery requiring general anesthesia for more than 1 hour Patients meeting exclusion and inclusion criteria are randomized to receive either a standard anesthetic regimen that includes N2O or a nearly identical one without N2O Before surgery and 2 weeks and 4 weeks after surgery each patient undergoes 1 a broad battery of tests of cognition and mood and 2 blood tests measuring cobalamin folate and homocysteine-methionine metabolism to determine whether they have any subtle biochemical impairment of cobalamin status DNA from blood cells is also tested for the presence of common mutations that affect key enzymes in those metabolic pathways A brief testing for postoperative delirium is also done 2 hours after surgery
The patient subgroups are analyzed for neuropsychologic changes over time using the preoperative test as the baseline for all comparisons and associations of those changes with metabolic genetic demographic and clinical data
The primary question is what effect routine N2O exposure has on the latter compared with non-N2O anesthesia in elderly people who either have or do not have subclinical cobalamin deficiency It will help answer whether or not the combination can help explain the increased risk of cognitive problems after surgery in elderly patients and by extension whether preoperative cobalamin testing and treatment may be indicated in the elderly It will also test whether genetic predisposition affects the described problems
The study recruits people over the age of 60 years who are undergoing clinically indicated elective surgery requiring general anesthesia for more than 1 hour Patients meeting exclusion and inclusion criteria are randomized to receive either a standard anesthetic regimen that includes N2O or a nearly identical one without N2O Before surgery and 2 weeks and 4 weeks after surgery each patient undergoes 1 a broad battery of tests of cognition and mood and 2 blood tests measuring cobalamin folate and homocysteine-methionine metabolism to determine whether they have any subtle biochemical impairment of cobalamin status DNA from blood cells is also tested for the presence of common mutations that affect key enzymes in those metabolic pathways A brief testing for postoperative delirium is also done 2 hours after surgery
The patient subgroups are analyzed for neuropsychologic changes over time using the preoperative test as the baseline for all comparisons and associations of those changes with metabolic genetic demographic and clinical data
The primary question is what effect routine N2O exposure has on the latter compared with non-N2O anesthesia in elderly people who either have or do not have subclinical cobalamin deficiency It will help answer whether or not the combination can help explain the increased risk of cognitive problems after surgery in elderly patients and by extension whether preoperative cobalamin testing and treatment may be indicated in the elderly It will also test whether genetic predisposition affects the described problems
Detailed Description:
Study Design
Double-blind randomized study of elderly patients scheduled for elective surgery under general anesthesia
Medical cobalamin-related and demographic information
Blood tests of cobalamin-related metabolic status and genotyping for 4 relevant mutations
Psychoneurologic evaluation before surgery
Randomization to receive a standard anesthetic regimen with nitrous oxide N2O or the same regimen without N2O
Intraoperative and perioperative data are collected
Testing for delirium 2-3 hours after surgery
All preoperative studies are repeated after 2 weeks and 4 weeks
Patients with abnormal cognitive status persisting at 4 weeks receive cobalamin and are retested at 3 months
Inclusion criteria
Age 60 years
Anticipated duration of general anesthesia 1 hour
Good English comprehension
Exclusion criteria
Surgery involving the brain blood supply to head and neck or heart
Dementia psychosis or brain disease
Contraindication to N2O use
Clinical status other than ASA class 1 or 2
Bronchospastic or obstructive pulmonary disease
N2O exposure in past 6 months
Cobalamin injection in past 6 months
RBC mean corpuscular volume 95 fl
Creatinine 18 mgdl
History or evidence of paresthesias numbness of feet or hands gait and balance problems memory and thinking problems
If the preoperative cognitive test produces a suspicious result two or more unrelated test results 15 x standard deviation below the normal mean immediate review is done to decide about exclusion of the patient from the study
All investigators and testers are blinded to the N2O exposure except the anesthesiologist and cobalamin status
Subject Numbers Statistical power analysis by our statistician projected the need for 386 subjects to achieve a power of 80 with type I error of 005 Based on a possible 15 subject loss rate 444 subjects are planned
Patient Information questionnaire includes
Demographic information
Relevant medical history
Cobalamin-related history
Exclusion factors
Randomization
Computer-generated numbers system
Made known just before surgery to the anesthesiologist only
Anesthetic protocol
One of two effective commonly used anesthetic regimens protocols
Standard ASA monitors an oxygen analyzer and carbon dioxide capnograph are applied
General anesthesia is induced in both the N2O and non-N2O groups with fentanyl 2-5 µgkg and propofol 1-3 mgkg which allows for appropriate titration to the desired end point without adverse reactions Cisatracurium 015 mgkg is given for muscle relaxation
Anesthesia is then maintained with either 40 oxygen60 N2O N2O study arm or 40 oxygen in air non-N2O arm with desflurane for both study groups titrated to depth of anesthesia Fentanyl is used in both groups 1 µgkghr as the primary narcotic until just before the end of surgery
Following intubation monitored ventilation maintains normocapnea and adequate oxygenation Temperature blood pressure and heart rate are maintained by prescribed standard methods
At the end of surgery desflurane and N2O or in the other study arm desflurane and O2room air are stopped residual neuromuscular block is pharmacologically antagonized dolasetron is given as prophylaxis against nausea and vomiting and postoperative analgesia is provided with opioids as needed
The protocols allow for clinically indicated modifications at any time
All the above assures that anesthetic management is not compromised allows the inclusion of N2O vs room air to be the only difference between the two arms and uses no agents known to affect cobalamin other than N2O
Intraoperative data collection
Duration of N2O exposure
Doses of all anesthetics
Surgery actually performed
Oxygen saturation as monitored continuously
End-tidal CO2
End-tidal desflurane
Blood loss and transfusions
Temperature on emergence from anesthesia and minimal temperature
Range of perioperative blood pressures
Presence of emergence delirium
Adverse postoperative events
Medications required postoperatively
Blood Tests of Cobalamin Status and related tests
Serum cobalamin and folate levels
Homocysteine by immunoassay of EDTA-anticoagulated plasma separated within 1 hour in the PIs laboratory
Serum methylmalonic acid MMA by gas chromatography-mass spectrometry
Plasma metabolites methionine glutathione S-adenosylmethionine S-adenosylhomocysteine cysteine and cysteinylglycine see later
Serum creatinine complete blood count and blood smear
The diagnosis of subclinical cobalamin deficiency is made if BOTH of the following criteria are met
Two or more of the following 3 abnormalities low cobalamin high homocysteine or high MMA levels All investigators remain blinded to these findings which require no action
Clinically apparent cobalamin deficiency is ruled out This is always known by the investigators before surgery permitting immediate exclusion of the patient from the study if positive
Assay of Metabolites of Homocysteine and Methionine
Plasma is separated within 15 minutes of venipuncture kept on ice until centrifugation and stored in aliquots at -80C
Unthawed aliquots are shipped on dry ice to the University of Arkansas for assay using HPLC with coulometric detection
Because some metabolites are affected by renal status adjustment for creatinine is made
Analyses focus on metabolite results in relation to a each other b original cobalamin status c folate levels d N2O exposure both in relation to original cobalamin status and gene polymorphisms e presence of gene polymorphisms including combinations and f appearance of cognitive dysfunction vs none Longitudinal metabolic changes over the entire follow-up period are examined
Gene Polymorphism Analyses
DNA is extracted from preoperative blood samples and purified DNA is stored at -80C
The 677C-T and 1298A-C mutations of MTHFR are determined by standard techniques
The methionine synthase 2756A-G D919G mutation is identified using HaeIII and the MTRR 66A-G I22M mutation using NdeI
Analysis will consider homozygous mutation states and combined heterozygosity that produces impaired enzyme activity combined mutations of the different enzymes as well as allele frequencies
Study analyses focus on these questions a Does metabolic or clinical N2O effect vary with genotype b Do the polymorphisms influence the appearance of subclinical cobalamin deficiency c How are metabolite changes affected by each mutation
Cognitive Function and Depression Testing
Done by a trained tester in a quiet office free of distractions
A focused battery of neuropsychological tests that requires 15 hours is administered
The tests assess
AttentionConcentration a Paced Serial Addition Test which requires active attention and rapid information processing b California Computerized Assessment Package measures perfomance sensitive to attention and decision making
Cognitive flexibility is tested by Letter-Number Sequencing a subtest from the Wechsler Adult Intelligence Scale-III
Memory and learning are tested with the California Verbal Learning Test-2
Depression is assessed with the Beck Depression Inventory
All tests are scored within 48 hours and reviewed with the neuropsychologist both of whom are blinded to the patients status All measures are expected to show some practice familiarization effect over the 3 administrations and appropriate adjustments and analyses are made
If results in any test in two of the four test categories are 15 SD below normal mean in the preoperative assessment immediate review for possible exclusion from the study is done A decline in postoperative test results by the 15 x SD of the normal mean from the previous result in 2 individual tests is also brought to the attention of the PI and the safety monitor for a decision concerning cobalamin treatment
Assessment for delirium is done 2-3 hours postoperatively with the Mini-Mental State Examination and the CAM-ICU test Potential confounders such as drugs hypoxia and infection are taken into account in the analysis
Long-term follow-up beyond 4 weeks is done in those patients with any cognitive function including depression testing significantly worse at the 4 week test than preoperatively A decline in any test equivalent to 1 SD of the normal mean for that test is used as the decision benchmark
Data Analysis
The primary question is whether patients with subclinical deficiency show neuropsychologic impairment after N2O exposure that is greater than in patients without deficiency Analysis of these differences include comparison between deficient and non-deficient patients assigned to the non-N2O arm Confounders are addressed by adjusting for relevant variables
The statistician conducts all analyses and consult on an ongoing basis throughout the study Before analysis continuous variables are subjected to logarithmic transformation Univariate analyses followed by selected multivariate analyses include duration of anesthetic exposure level of preoperative and postoperative metabolic deficits as well as coexisting disorders Bonferroni adjustment is used for multiple comparisons where appropriate Multiple logitic regression is used to evaluate significant independent predictors of abnormal results
An interim analysis will be done after 35 years using an alpha of 0005
Analyses of metabolic and genetic findings will be done by univariate analyses followed by multivariate analyses to determine the mutations effects
Risks to Subjects
All subjects are undergoing clinically indicated elective surgery under general anesthesia No aspect of their surgical management will be affected by their participation The only study-related change in their clinical management will be the random assignment to omission or inclusion of N2O from near identical standard anesthesia regimens
The only other manipulations are blood sampling and undergoing neuropsychologic testing several days before surgery and on 3-4 occasions postoperatively except genetic tests which are done only once
Medical information collection relevant to the study is subject to confidentiality protection in all HIPAA-mandated respects
CobalaminN2O related risks are actually smaller in participants than in nonparticipants Several layers of protection against the small risks associated with the study include the cobalamin-related evaluation that is not otherwise done routinely before N2O anesthesia to identify patients who are at known risk from N2O continued postoperative monitoring for changes in cobalamin status and significant cognitive decline intervention with cobalamin therapy in possibly affected patients institution of a Data Safety Monitoring plan with an independent safety monitor and interim analysis of study findings
Safety monitoring
Preoperative discovery of cognitive test dysfunction excludes patients from the study before any exposure to risk
A postoperative decline exceeding the equivalent of 15 x SD of the normal mean in two unrelated measures of cognitive function are brought to the immediate attention of the PI the collaborating neuropsychologist and an independent scientist-clinician who is not a part of our study
Double-blind randomized study of elderly patients scheduled for elective surgery under general anesthesia
Medical cobalamin-related and demographic information
Blood tests of cobalamin-related metabolic status and genotyping for 4 relevant mutations
Psychoneurologic evaluation before surgery
Randomization to receive a standard anesthetic regimen with nitrous oxide N2O or the same regimen without N2O
Intraoperative and perioperative data are collected
Testing for delirium 2-3 hours after surgery
All preoperative studies are repeated after 2 weeks and 4 weeks
Patients with abnormal cognitive status persisting at 4 weeks receive cobalamin and are retested at 3 months
Inclusion criteria
Age 60 years
Anticipated duration of general anesthesia 1 hour
Good English comprehension
Exclusion criteria
Surgery involving the brain blood supply to head and neck or heart
Dementia psychosis or brain disease
Contraindication to N2O use
Clinical status other than ASA class 1 or 2
Bronchospastic or obstructive pulmonary disease
N2O exposure in past 6 months
Cobalamin injection in past 6 months
RBC mean corpuscular volume 95 fl
Creatinine 18 mgdl
History or evidence of paresthesias numbness of feet or hands gait and balance problems memory and thinking problems
If the preoperative cognitive test produces a suspicious result two or more unrelated test results 15 x standard deviation below the normal mean immediate review is done to decide about exclusion of the patient from the study
All investigators and testers are blinded to the N2O exposure except the anesthesiologist and cobalamin status
Subject Numbers Statistical power analysis by our statistician projected the need for 386 subjects to achieve a power of 80 with type I error of 005 Based on a possible 15 subject loss rate 444 subjects are planned
Patient Information questionnaire includes
Demographic information
Relevant medical history
Cobalamin-related history
Exclusion factors
Randomization
Computer-generated numbers system
Made known just before surgery to the anesthesiologist only
Anesthetic protocol
One of two effective commonly used anesthetic regimens protocols
Standard ASA monitors an oxygen analyzer and carbon dioxide capnograph are applied
General anesthesia is induced in both the N2O and non-N2O groups with fentanyl 2-5 µgkg and propofol 1-3 mgkg which allows for appropriate titration to the desired end point without adverse reactions Cisatracurium 015 mgkg is given for muscle relaxation
Anesthesia is then maintained with either 40 oxygen60 N2O N2O study arm or 40 oxygen in air non-N2O arm with desflurane for both study groups titrated to depth of anesthesia Fentanyl is used in both groups 1 µgkghr as the primary narcotic until just before the end of surgery
Following intubation monitored ventilation maintains normocapnea and adequate oxygenation Temperature blood pressure and heart rate are maintained by prescribed standard methods
At the end of surgery desflurane and N2O or in the other study arm desflurane and O2room air are stopped residual neuromuscular block is pharmacologically antagonized dolasetron is given as prophylaxis against nausea and vomiting and postoperative analgesia is provided with opioids as needed
The protocols allow for clinically indicated modifications at any time
All the above assures that anesthetic management is not compromised allows the inclusion of N2O vs room air to be the only difference between the two arms and uses no agents known to affect cobalamin other than N2O
Intraoperative data collection
Duration of N2O exposure
Doses of all anesthetics
Surgery actually performed
Oxygen saturation as monitored continuously
End-tidal CO2
End-tidal desflurane
Blood loss and transfusions
Temperature on emergence from anesthesia and minimal temperature
Range of perioperative blood pressures
Presence of emergence delirium
Adverse postoperative events
Medications required postoperatively
Blood Tests of Cobalamin Status and related tests
Serum cobalamin and folate levels
Homocysteine by immunoassay of EDTA-anticoagulated plasma separated within 1 hour in the PIs laboratory
Serum methylmalonic acid MMA by gas chromatography-mass spectrometry
Plasma metabolites methionine glutathione S-adenosylmethionine S-adenosylhomocysteine cysteine and cysteinylglycine see later
Serum creatinine complete blood count and blood smear
The diagnosis of subclinical cobalamin deficiency is made if BOTH of the following criteria are met
Two or more of the following 3 abnormalities low cobalamin high homocysteine or high MMA levels All investigators remain blinded to these findings which require no action
Clinically apparent cobalamin deficiency is ruled out This is always known by the investigators before surgery permitting immediate exclusion of the patient from the study if positive
Assay of Metabolites of Homocysteine and Methionine
Plasma is separated within 15 minutes of venipuncture kept on ice until centrifugation and stored in aliquots at -80C
Unthawed aliquots are shipped on dry ice to the University of Arkansas for assay using HPLC with coulometric detection
Because some metabolites are affected by renal status adjustment for creatinine is made
Analyses focus on metabolite results in relation to a each other b original cobalamin status c folate levels d N2O exposure both in relation to original cobalamin status and gene polymorphisms e presence of gene polymorphisms including combinations and f appearance of cognitive dysfunction vs none Longitudinal metabolic changes over the entire follow-up period are examined
Gene Polymorphism Analyses
DNA is extracted from preoperative blood samples and purified DNA is stored at -80C
The 677C-T and 1298A-C mutations of MTHFR are determined by standard techniques
The methionine synthase 2756A-G D919G mutation is identified using HaeIII and the MTRR 66A-G I22M mutation using NdeI
Analysis will consider homozygous mutation states and combined heterozygosity that produces impaired enzyme activity combined mutations of the different enzymes as well as allele frequencies
Study analyses focus on these questions a Does metabolic or clinical N2O effect vary with genotype b Do the polymorphisms influence the appearance of subclinical cobalamin deficiency c How are metabolite changes affected by each mutation
Cognitive Function and Depression Testing
Done by a trained tester in a quiet office free of distractions
A focused battery of neuropsychological tests that requires 15 hours is administered
The tests assess
AttentionConcentration a Paced Serial Addition Test which requires active attention and rapid information processing b California Computerized Assessment Package measures perfomance sensitive to attention and decision making
Cognitive flexibility is tested by Letter-Number Sequencing a subtest from the Wechsler Adult Intelligence Scale-III
Memory and learning are tested with the California Verbal Learning Test-2
Depression is assessed with the Beck Depression Inventory
All tests are scored within 48 hours and reviewed with the neuropsychologist both of whom are blinded to the patients status All measures are expected to show some practice familiarization effect over the 3 administrations and appropriate adjustments and analyses are made
If results in any test in two of the four test categories are 15 SD below normal mean in the preoperative assessment immediate review for possible exclusion from the study is done A decline in postoperative test results by the 15 x SD of the normal mean from the previous result in 2 individual tests is also brought to the attention of the PI and the safety monitor for a decision concerning cobalamin treatment
Assessment for delirium is done 2-3 hours postoperatively with the Mini-Mental State Examination and the CAM-ICU test Potential confounders such as drugs hypoxia and infection are taken into account in the analysis
Long-term follow-up beyond 4 weeks is done in those patients with any cognitive function including depression testing significantly worse at the 4 week test than preoperatively A decline in any test equivalent to 1 SD of the normal mean for that test is used as the decision benchmark
Data Analysis
The primary question is whether patients with subclinical deficiency show neuropsychologic impairment after N2O exposure that is greater than in patients without deficiency Analysis of these differences include comparison between deficient and non-deficient patients assigned to the non-N2O arm Confounders are addressed by adjusting for relevant variables
The statistician conducts all analyses and consult on an ongoing basis throughout the study Before analysis continuous variables are subjected to logarithmic transformation Univariate analyses followed by selected multivariate analyses include duration of anesthetic exposure level of preoperative and postoperative metabolic deficits as well as coexisting disorders Bonferroni adjustment is used for multiple comparisons where appropriate Multiple logitic regression is used to evaluate significant independent predictors of abnormal results
An interim analysis will be done after 35 years using an alpha of 0005
Analyses of metabolic and genetic findings will be done by univariate analyses followed by multivariate analyses to determine the mutations effects
Risks to Subjects
All subjects are undergoing clinically indicated elective surgery under general anesthesia No aspect of their surgical management will be affected by their participation The only study-related change in their clinical management will be the random assignment to omission or inclusion of N2O from near identical standard anesthesia regimens
The only other manipulations are blood sampling and undergoing neuropsychologic testing several days before surgery and on 3-4 occasions postoperatively except genetic tests which are done only once
Medical information collection relevant to the study is subject to confidentiality protection in all HIPAA-mandated respects
CobalaminN2O related risks are actually smaller in participants than in nonparticipants Several layers of protection against the small risks associated with the study include the cobalamin-related evaluation that is not otherwise done routinely before N2O anesthesia to identify patients who are at known risk from N2O continued postoperative monitoring for changes in cobalamin status and significant cognitive decline intervention with cobalamin therapy in possibly affected patients institution of a Data Safety Monitoring plan with an independent safety monitor and interim analysis of study findings
Safety monitoring
Preoperative discovery of cognitive test dysfunction excludes patients from the study before any exposure to risk
A postoperative decline exceeding the equivalent of 15 x SD of the normal mean in two unrelated measures of cognitive function are brought to the immediate attention of the PI the collaborating neuropsychologist and an independent scientist-clinician who is not a part of our study
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| R01DK032640 | NIH | None | httpsreporternihgovquickSearchR01DK032640 |