ANESTHESIA WITH AND WITHOUT NITROUS OXIDE AND LONG-TERM COGNITIVE TRAJECTORIES IN OLDER ADULTS

Juraj Sprung; Arnoley S (Arney) Abcejo; David S Knopman; Ronald C Petersen; Michelle M Mielke; Andrew C Hanson; Darrell R Schroeder; Phillip J Schulte; David P Martin; Toby N Weingarten; Jeffrey J Pasternak; David O Warner

doi:10.1213/ANE.0000000000004490

. Author manuscript; available in PMC: 2021 Aug 1.

Published in final edited form as: Anesth Analg. 2020 Aug;131(2):594–604. doi: 10.1213/ANE.0000000000004490

ANESTHESIA WITH AND WITHOUT NITROUS OXIDE AND LONG-TERM COGNITIVE TRAJECTORIES IN OLDER ADULTS

Juraj Sprung ^*, Arnoley S (Arney) Abcejo ^*, David S Knopman ^†,^‡, Ronald C Petersen ^†,^‡, Michelle M Mielke ^†,^‡, Andrew C Hanson ^§, Darrell R Schroeder ^§, Phillip J Schulte ^§, David P Martin ^*, Toby N Weingarten ^*, Jeffrey J Pasternak ^*, David O Warner ^*

^*Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA

^†Department of Neurology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA

^‡Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA

^§Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA

Author’s individual contributions:

Name: Juraj Sprung, MD, PhD

Contribution: This author designed the study, analyzed and interpreted the data, and helped to write the manuscript.

Name: Arnoley S. (Arney) Abcejo MD

Contribution: This author helped design the study, analyze the data, and write the manuscript.

Name: David S. Knopman, MD

Contribution: This author helped design the study, and conducted revision for important intellectual content.

Name: Ronald C. Petersen, MD, PhD

Contribution: This author helped design the study, and conducted revision for important intellectual content.

Name: Michelle M. Mielke, PhD

Contribution: This author helped design the study, analyze and interpret the data, and revision for important intellectual content.

Name: Andrew C. Hanson, BS

Contribution: This author helped analyze the data, and revision for important intellectual content.

Name: Darrell R. Schroeder, MS

Contribution: This author helped design the study, analyze the data, and revision for important intellectual content.

Name: Phillip J. Schulte, PhD

Contribution: This author was instrumental in statistical modeling, and helped to analyze the data and revise the manuscript.

Name: David P. Martin, MD, PhD

Contribution: This author helped design the study, interpretation of data, and write the manuscript.

Name: Toby N. Weingarten, MD

Contribution: This author helped design the study, interpretation of data, and write the manuscript.

Name: Jeffrey Pasternak, MD

Contribution: This author helped design the study, interpretation of data, and write the manuscript.

Name: David O. Warner, MD

Contribution: This author helped design the study, revision for important intellectual content and write the manuscript

^✉

Corresponding author: Juraj Sprung, MD, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine and Science, 200 First St SW, Rochester, MN 55905 (sprung.juraj@mayo.edu; Phone: 507-255-3298 Fax: 507-255-6463)

PMCID: PMC7165021 NIHMSID: NIHMS1066097 PMID: 31651458

Abstract

BACKGROUND:

We evaluated the hypothesis that the rate of postoperative decline in global cognition is greater in older adults exposed to general anesthesia with nitrous oxide (N₂O) compared to general anesthesia without N₂O.

METHODS:

Longitudinal measures of cognitive function were analyzed in non-demented adults, aged 70–91, enrolled in the Mayo Clinic Study of Aging. Linear mixed-effects models with time-varying covariates assessed the relationship between exposure to surgery with general anesthesia (surgery/GA) with or without N₂O and the rate of long-term cognitive changes. Global cognition and domain-specific cognitive outcomes were defined using z-scores, which measure how far an observation is, in standard deviations, from the unimpaired population mean.

RESULTS:

The analysis included 1,819 participants: 280 exposed to GA without N₂O following enrollment and prior to censoring during follow-up (median [IQR] follow-up of 5.4 [3.9, 7.9] years), 256 exposed to GA with N₂O (follow-up 5.6 [4.0, 7.9] years), and 1,283 not exposed to surgery/GA (follow-up 4.1 [2.5, 6.4] years). The slope of the global cognitive z-score was significantly more negative following exposure to surgery/GA after enrollment [change in slope of −0.062 (95%CI −0.085, −0.039) for GA without N₂O, and −0.058 (95%CI −0.080, −0.035) for GA with N₂O, both P<0.001]. The change in slope following exposure to surgery/GA did not differ between those exposed to anesthesia without vs. with N₂O (estimated difference −0.004 (95% CI −0.035 to 0.026), P=0.783).

CONCLUSIONS:

Exposure to surgery/GA is associated with a small, but statistically significant decline in cognitive z-scores. Cognitive decline did not differ between anesthetics with and without N₂O. This finding provides evidence that the use of N₂O in older adults does not need to be avoided because of concerns related to decline in cognition.

Keywords: cognitive aging, cognitive global z-scores, cognitive domains, memory, attention/executive function, language, visuospatial skills, general anesthesia, Mayo Clinic Study of Aging, older adults, surgery, nitrous oxide, volatile anesthetic agents

INTRODUCTION

Exposure of animals to inhalational anesthetics can cause brain neuropathology consistent with Alzheimer disease (AD), including increased amyloid-β (Aβ) peptide production, and oligomerization, abnormal Tau (τ) levels and phosphorylation, and neuroapoptosis.¹ The potential clinical significance of these preclinical findings is uncertain. Some studies suggested that exposure of the elderly to surgery with general anesthesia (surgery/GA) is not associated with an increased risk of AD dementia or mild cognitive impairment (MCI),^2–5,6 although there are reports that suggest a positive association.⁷ The use of longitudinal cognitive assessments, rather than binary outcomes (dementia, MCI), may be a more sensitive indicator of potential effects. Indeed, we recently found that exposure to surgery/GA for up to 20 years before study assessment was associated with a modest acceleration of cognitive trajectories in population-based cohort of older adults enrolled in the Mayo Clinic Study of Aging (MCSA).^8,9

There have been long-standing concerns that the inhaled anesthetic nitrous oxide (N2O), an N-methyl-d-aspartate (NMDA)-antagonist, can cause toxicity by irreversibly inactivating vitamin B₁₂, an essential cofactor for methionine synthase.¹⁰ This enzyme converts homocysteine to methionine,¹⁰ which is important for synthesis and repair of DNA. Increased levels of homocysteine due to B₁₂ deficiency may contribute to AD.¹¹ Indeed, exposure of aged rats to N₂O causes lasting impairment in spatial working memory and learning.¹² Concerns regarding the potential neurotoxic effects of N₂O, and other putative adverse effects, have led to reductions in its clinical use.¹³ Although large trials have addressed several aspects related to the clinical safety of N₂O, its effects on cognitive function in older adults remain unknown.¹⁰

Our present retrospective observational study extends our prior analysis⁹ to determine whether the use of N₂O during GA is associated with accelerated cognitive decline in years following exposure. Cognitive decline was assessed from longitudinal global and domain-specific cognitive z-scores, calculated using the performance of a reference population of cognitively unimpaired individuals. We hypothesized that the rate of postoperative decline (i.e., trajectory) of global cognitive z-scores, the primary outcome of interest, is greater in those participants exposed to surgery/GA with N₂O compared with those exposed to surgery/GA without N₂O. Secondary outcomes included the trajectories of four domain-specific scores of cognitive function (memory, attention/executive function, language, and visuospatial skills).

METHODS

This study was approved by the Institutional Review Boards of Mayo Clinic and Olmsted Medical Center, Rochester, Minnesota. At enrollment in the MCSA, all participants provided written informed consent to participate in the study. This study conformed to the requirements of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement.

Participants

The present study included participants enrolled in the MCSA who were 1) aged 70 through 91 at the baseline assessment conducted from November 2004 through November 2009, 2) were not demented at baseline assessment (i.e., those without cognitive impairment or who had MCI), and; 3) who had at least two cognitive z-scores: baseline on enrollment and 1 follow-up MCSA visit assessment. To avoid the effects of an acute illness and/or surgery/GA on cognitive function, follow-up assessments were never performed in the temporal vicinity of an acute illness, surgery or major procedure.

Identification of anesthetic exposures

For each MCSA participant, procedures performed with GA which occurred during the time period starting 20 years prior to MSCA enrollment thru the date of their last MCSA visit prior to December 31, 2014 were identified using the Rochester Epidemiology Project (REP) medical record linkage system.¹⁴ Thus, for any participant who had surgery which was included in the study, there was at least one MCSA assessment after the surgery/GA. All anesthetic episodes were reviewed for agents used. The anesthetic was considered to utilize N₂O only if N₂O was used during anesthesia maintenance. Therefore, the exposure time in each participant was equal to the duration of anesthetic. Percent concentrations of N₂O were not abstracted, but typically are between 50% and 70%. Short exposure, such as use of N₂O only during anesthetic induction or emergence, were not considered exposure to N₂O and for the purpose of analysis were treated as exposure to GA without N₂O. For the present study the primary exposure of interest was receipt of GA with or without N₂O following MCSA enrollment. Exposure to surgery/GA within the 20 years prior to the MCSA entitlement was included as an adjustment covariate. A 20-year period (prior to enrollment) was selected because our earlier report suggested that when this exposure period was used there was some evidence suggesting that exposure to surgery/GA was associated with subsequent development of MCI.³ This is important because clinically detectable cognitive impairment often lags behind the neurodegenerative insult. For example, clinically normal individuals who are amyloid PET-positive have higher likelihood for progression to clinically diagnosed AD dementia 15–20 years later.^15,16 Therefore, studies that examine the association between exposure to anesthesia and development of AD must account for mid-life anesthetic exposures.

Demographic and clinical characteristics

Information on how demographic and clinical characteristics were obtained has been previously reported.⁸ Briefly, self-reported medical history obtained at the initial MCSA visit was corroborated using information abstracted from the medical records using the records-linkage system.⁸ Variables used as covariates for the present analyses included sex; age at enrollment; years of education; APOE ε4 status; midlife diabetes; midlife hypertension; midlife dyslipidemia (midlife is defined prior to age 65); atrial fibrillation; Charlson Comorbidity Index (updated at each MCSA visit); history of congestive heart failure; stroke; coronary artery disease; marital status; smoking status; and diagnosed alcohol problem. These covariates were chosen based on prior studies that reported they were associated with cognition.¹⁷

Cognitive Assessments

Details of the clinical evaluation at baseline and at each 15-month follow-up have been described previously and are summarized here.⁸ Initial and follow-up evaluations were performed by a physician and included the Short Test of Mental Status,¹⁸ a modified Hachinski Ischemic Scale,^19,20 a modified Unified Parkinson’s Disease Rating Scale,²¹ and a neurologic examination. The neuropsychological evaluation included assessment of 4 cognitive domains using nine tests: 1) attention/executive domain (Trail Making Test B and Digit Symbol Substitution Test);^22,23 2) language (Boston Naming Test²⁴ and Category Fluency);²⁵ 3) memory domain (Wechsler Memory Scale-Revised Logical Memory II [delayed recall], Wechsler Memory Scale-Revised Visual Reproduction- II [delayed recall],²⁶ and Auditory Verbal Learning Test [delayed recall],²⁷ and 4) visuospatial skills (Wechsler Adult Intelligence Scale-Revised Picture Completion test and Wechsler Adult Intelligence Scale-Revised Block Design test).²² To compute domain z-scores and overall global cognitive z-score, means and standard deviations of nine raw test scores for participants who were cognitively unimpaired in the MCSA 2004 enrollment cohort (n = 1,969) were used as the reference distribution. Participants were classified as cognitively unimpaired if they had Clinical Dementia Rating scale = 0, normal functional status, and neuropsychological testing within normal limits.⁸ Of note, the baseline scores for the 68.3% (1,243/1,819) of participants included in the present report were included in the reference population.⁸ Using this approach, a participant with a z-score of 0 has cognitive function equal what would be expected in a cognitively unimpaired individual from the reference population. An individual with z-score of −1 has cognitive function that is 1 SD below expected. In the present study, we assessed longitudinal cognitive trajectories after study enrollment. Cognitive trajectories are summarized by presenting the slope of cognitive z-scores over time (per year) and the change in slope following exposure to GA with and without N₂O.

Statistical Analyses

The analytic methods were similar to those previously described.⁹ Participant characteristics at MCSA enrollment were described as mean (standard deviation) or median [Q₁, Q₃] percentiles for continuous variables and percentage for categorical variables according to exposure status during follow-up. Because all participants start as ‘unexposed’ and some subjects later have exposures to GA with or without N₂O, P-values for comparison were estimated with cause-specific Cox proportional hazards models for time to general anesthesia with and without N₂O during follow-up, separately. In the current analysis, the first post-MCSA enrollment exposure to surgery/GA is considered as the primary exposure variable; anesthesia and surgical characteristics are described based on the first exposure following enrollment when participants had more than one exposure.

Prior research has suggested that surgery/GA is associated with accelerated decline in cognitive function;⁹ the aim of the current study is to assess whether the slope of global and domain-specific cognitive z-scores differs following GA with N₂O versus GA without N₂O. The rates of change of the global and domain specific z-scores over time (i.e., slopes) were estimated from longitudinal assessments using linear mixed effects models. For these analyses, time was modeled using a linear term. Prior longitudinal studies of other cohorts of older adults with moderate length of follow up (<10 years) have been mixed in their conclusions for quadratic trends of cognitive function over time and those that model quadratic terms did not demonstrate meaningfully different results compared to linear trends for time on study.^28–31 In the current study, we did not consider quadratic trends over time on the study since individuals had roughly 4–8 year follow up in our sample. Key fixed effects in the model included time following enrollment, time after post-enrollment GA exposure without N₂O, and time after post-enrollment GA with N₂O. These effects estimate an average slope among unexposed and the change in slope (compared to unexposed) following GA without and with N₂O, respectively. The difference in slope over time between GA without N₂O and GA with N₂O is also estimated. In brief, time after GA with N₂O is a time-dependent variables that is zero in participants prior to a post-enrollment GA with N₂O; the variable turns ‘on’ at the time of post-enrollment GA with N₂O and subsequently counts time following post-enrollment GA exposure with N₂O. Thus, the estimate provided assesses the change in slope of cognitive z-scores associated with a post-enrollment GA exposure with N₂O, as compared to no post-enrollment exposure. GA without N₂O was defined similarly. A detailed description of the statistical methods is provided in Supplemental Statistical Materials.

If participants first exposed to GA without N₂O later received GA with N₂O (or vice versa) follow-up was censored at the time of exposure to the other type but follow up was continued when exposed to the same type. Thus, if a participant had GA without N₂O at 1 year after enrollment and GA with N₂O at 4 years after enrollment, they would be summarized descriptively as a GA without N₂O participant, and in regression models their follow-up would be censored at 4 years. A sensitivity analysis was performed for the global z-score where all participants were censored at their second exposure to surgery/GA during follow up.

Sensitivity analysis was performed using the same approach as for primary analysis, but considered new exposures only in those without exposure to GA prior to MCSA enrollment (anesthesia naïve participants). By the same token, this analysis examined changes in the trajectory of cognitive z-scores after new exposures to surgery/GA (with and without N₂O) following enrollment where a post-enrollment exposure in participants who were exposed prior to enrollment is not considered a new exposure. All models were adjusted for participant covariates at the time of enrollment and their interactions with the slope (time) following enrollment. Covariates were chosen based on prior studies as associated with cognitive scores.³² Models included subject-specific random intercepts and random slopes; random terms were assessed with likelihood ratio tests, which suggested that the model including both fit the data better than a reduced model. Results are summarized by presenting 1) slope estimates for participants not exposed to surgery/GA after enrollment, 2) the estimated difference in slope associated with each type of exposure (compared with those not exposed), and 3) the estimated difference in slope between post-enrollment GA without N₂O versus GA with N₂O.

For all analyses, the significance level was set at P <0.05, with the 2-tailed test. Analyses were performed with SAS statistical software (Version 9.3; SAS Institute, Inc, Cary). A primary outcome and analysis approach was specified a priori and secondary outcomes were not adjusted for multiple comparisons.

RESULTS

Of the 2,563 MCSA participants who were enrolled during the study period, 744 were excluded (Figure 1), leaving 1,819 participants (1,564 who were cognitively unimpaired at enrollment and 255 who had MCI at enrollment) who had a cognitive z-score calculated on at least 2 study visits. A total of 536 participants were exposed to surgery/GA following enrollment. Of 280 participants whose initial surgery after enrollment included GA without N₂O the median [IQR] follow-up was 5.4 [3.9, 7.9] years, the median number of z-score assessments was 5 [4, 7], and the length of follow-up after first anesthetic exposure was 2.3 [1.1, 4.2] years. During follow-up, these 280 participants underwent 410 surgeries/GA without N₂O (participants in this group were censored at the time of receiving any GA with N₂O). Of 256 participants whose initial surgery after enrollment was performed using GA with N₂O the median follow-up was 5.6 [4.0, 7.9] years, the median number of z-score assessments was 5 [4, 7], and the length of follow-up after first anesthetic exposure was 3.1 [1.4, 5.1] years. During follow-up, these 256 patients underwent 326 surgeries/GA with N₂O (participants in this group were censored at the time of receiving any GA without N₂O). Finally, for the 1,283 patients not exposed to post-enrollment GA, the median follow-up was 4.1 [2.5, 6.4] years, and the median number of visits was 4 [3, 6] (Figure 1).

Demographic and clinical characteristics at enrollment among exposure categories are shown in Table 1. Participants who were of a younger age at enrollment or have APOE-ε4 genotype were more likely to have GA with N₂O after enrollment. Participants with MCI were less likely to undergo GA with or without N₂O. Male participants and those with higher Charlson comorbidity index score were more likely to have GA without N₂O after enrollment. Anesthetics that utilized N₂O were more likely to include isoflurane and propofol and less likely sodium thiopental (Table 2). The frequency of N₂O utilization differed across some procedure types; e.g., N₂O was more likely to be used in orthopedic surgery and less likely to be used in general/other surgeries.

Table 1:

Demographic and clinical characteristics collected at enrollment according to new exposure category (GA exposure after enrollment)^*

Demographics and Comorbidities	No new exposure (N=1,283)		GA without N₂O (N=280)		GA with N₂O (N=256)
Age (y)^‡	79.3	(5.2)	78.4	(4.6)	77.3	(4.9)
Sex^†
Male	651	(51%)	160	(57%)	133	(52%)
Female	632	(49%)	120	(43%)	123	(48%)
Education
Less than 12 years	119	(9%)	20	(7%)	28	(11%)
12 years	438	(34%)	92	(33%)	81	(32%)
13–15 years	319	(25%)	71	(25%)	62	(24%)
16 years and above	407	(32%)	97	(35%)	85	(33%)
Smoking status
Never	692	(54%)	134	(48%)	132	(52%)
Former	543	(42%)	135	(48%)	119	(46%)
Current	48	(4%)	11	(4%)	5	(2%)
Marital status
Single	130	(10%)	23	(8%)	22	(9%)
Married	798	(62%)	195	(70%)	176	(69%)
Widowed	355	(28%)	62	(22%)	58	(23%)
APOE-ε4 genotype (n=1816)^‡	328	(26%)	72	(26%)	84	(33%)
Ever diagnosed alcohol problem (n=1,816)^‡	45	(4%)	9	(3%)	15	(6%)
Charlson Comorbidity Index^†	3	[2, 6]	4	[2, 6]	3	[1, 5]
Midlife diabetes	75	(6%)	8	(3%)	12	(5%)
Midlife hypertension	441	(34%)	110	(39%)	95	(37%)
Midlife dyslipidemia	544	(42%)	137	(49%)	120	(47%)
Atrial fibrillation	216	(17%)	48	(17%)	30	(12%)
Congestive heart failure	127	(10%)	31	(11%)	22	(9%)
Stroke^†	69	(5%)	18	(6%)	9	(4%)
Coronary artery disease	505	(39%)	119	(43%)	87	(34%)
Cognitive status^‡
Cognitively unimapired	1,075	(84%)	252	(90%)	237	(93%)
Mild cognitive impairment	208	(16%)	28	(10%)	19	(7%)

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Values are n (%) for categorical variables, mean (SD) for age, and median [Q1, Q3] for Charlson comorbidity index. Exposure category is determined by new exposure status prior to censoring or end of follow-up. When not all data is available numbers of rows with complete information are presented.

^†

Indicates a significant univariable association (P<0.05) between the given characteristic and cause-specific hazard for GA without N₂O

^‡

Indicates a significant univariable association (P<0.05) between the given characteristic and cause-specific hazard for GA with N₂O

Table 2 -.

Procedural and anesthetic characteristic for the first anesthetic after enrollment^s^*

Anesthetic Characteristics	General without N₂O (N=280)		General without N₂O (N=256)
Type of surgery (n=535)
General	72	(26%)	38	(15%)
Orthopedic	40	(14%)	97	(38%)
Obstetrics/gynecology/urology	31	(11%)	44	(17%)
Cardiac with bypass	33	(12%)	4	(2%)
Neurosurgery	10	(4%)	19	(7%)
Vascular	15	(5%)	6	(2%)
Thoracic	14	(5%)	1	(0%)
Breast/plastic	7	(3%)	17	(7%)
Ear, nose, and throat/oral surgery	18	(6%)	18	(7%)
Other^†	39	(14%)	12	(5%)
Duration of anesthesia (minutes)	163	[106, 240]	155	[112, 202]
Inhalational agents
Isoflurane	112	(40%)	141	(55%)
Sevoflurane	61	(22%)	50	(20%)
Desflurane	96	(34%)	76	(30%)
Intravenous agents
Propofol	223	(80%)	236	(92%)
Benzodiazepines	137	(49%)	139	(54%)
Sodium thiopental	56	(20%)	18	(7%)
Ketamine	12	(4%)	13	(5%)

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Only the first new exposure is summarized and exposures that are censored are not included. Censoring occurs at the first exposure to anesthesia of differing N₂O usage (e.g. participants who have already had a new exposure to anesthesia without N₂O would be censored at a new exposure to anesthesia with N₂O). Categorical variables are summarized as n (%) and compared with Chi-square test. Continuous variables are summarized as mean (SD) and compared with t-tests except duration of anesthesia which is summarized as median [Q1, Q3] and compared with a rank-sum test.

^†

Other includes cardioversion (n=14), ophthalmologic (n=12), magnetic resonance imaging (n=6), electroconvulsive therapy (n=6), interventional cardiology (n=3), wound irrigation and debridement (n=2), interventional radiology (n=2), dermatologic (n=1), endoscopy (n=1), bronchoscopy (n=1), RF/cryoablation (n=2), ureteral stent placement (n=1).

Effects of anesthesia exposure on long-term cognitive trajectories in all participants

Global z-score.

In adjusted linear mixed models, any exposure to GA after enrollment (with or without N₂O) was associated with an accelerated decline in global z-scores over time after exposure [change in slope vs unexposed −0.062 (95% CI −0.085 to −0.039), P<0.001, for GA without N₂O, and −0.058 (95% CI −0.080 to −0.035) for GA with N₂O, P<0.001] (Table 3). The rate of decline in global z-scores (i.e., change in slope) following GA exposure did not differ between those who had exposure to anesthesia without or with N₂O, estimated difference −0.004 (95% CI −0.035 to 0.026), P=0.783. From a sensitivity analysis which censored participants at the time of their second exposure to surgery/GA during follow-up, the direction of estimates and statistical significance remained unchanged: change in slope vs unexposed −0.044 (95% CI −0.068 to −0.019), P<0.001, for GA without N₂O, and −0.056 (95% CI −0.083 to −0.030) P<0.001, for GA with N₂O. The rate of decline in global z-scores following anesthetic exposure did not differ between those who had anesthesia with or without N₂O [0.013 (95% CI −0.021, 0.047) P=0.459].

Table 3:

Change in cognitive scores over time before and after post-enrollment exposure to general anesthesia (GA) with or without N₂O and estimated difference in change in slope for GA without and with N₂O

Cognitive Score		GA without N₂O^*		GA with N₂O^*		GA without N₂O – GA with N₂O^‡
Cognitive Score	Slope est.^†	Change in slope est. (95% CI)	P	Change in slope est. (95% CI)	P	Difference in change in slope est. (95% CI)	P
Global z-score	−0.075	−0.062 (−0.085, −0.039)	<0.001	−0.058 (−0.080, −0.035)	<0.001	−0.004 (−0.035 to 0.026)	0.783
Domain specific z-score
Memory	−0.016	−0.073 (−0.100, −0.045)	<0.001	−0.064 (−0.089, −0.038)	<0.001	−0.009 (−0.044 to 0.027)	0.621
Language	−0.080	−0.002 (−0.024, 0.020)	0.869	−0.029 (−0.050, −0.008)	0.007	0.027 (−0.001 to 0.055)	0.057
Visuospatial	−0.043	−0.003 (−0.023, 0.017)	0.756	−0.005 (−0.025, 0.015)	0.621	0.002 (−0.024 to 0.027)	0.887
Attention/executive	−0.096	−0.052 (−0.080, −0.024)	<0.001	−0.051 (−0.075, −0.027)	<0.001	−0.001 (−0.036 to 0.034)	0.953

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Analyses presented are from adjusted linear mixed effects models. Six participants were excluded from the analyses because of missing covariates. After exclusions there were 1,813 participants included in the analysis (1,278 had not had a subsequent or new exposure prior to censoring, 280 had a subsequent or new exposure to GA without N₂O, and 255 had a subsequent or new exposure to GA with N₂O). All models are adjusted for prior 20-year exposure to GA without N₂O, GA with N₂O, age, sex, cognitive status at enrollment, education, marital status, Charlson comorbidity index, presence of APOE-ε4 genotype, ever-diagnosed alcohol problem, smoking status, mid-life diagnosis of diabetes, hypertension, and dyslipidemia, and history of atrial fibrillation, congestive heart failure, stroke, and coronary artery disease.

^†

Slope estimate represents average annual change (slope) in z-score for participants prior to any post-enrollment exposure to surgery/GA.

Estimates, 95% confidence intervals, and P-values for the time-dependent change in slope following new exposure to GA without and with N₂O based on a post-enrollment exposure;

^‡

P-value for comparison of change in slope estimates between GA without and with N₂O.

Domain specific z-scores.

In analysis of domain specific z-scores, a significant change in slope was detected following exposure to GA with or without N₂O for the memory and attention/executive domains indicating accelerated decline, both P<0.001 (Table 3). Exposure to GA was not associated with changes in slopes for the language and visuospatial domains, with the exception of language in those who received GA with N₂O (P=0.007). Changes in slope for domain specific z-scores associated with GA did not differ between those who did and did not receive N₂O (Table 3).

Effects of anesthesia exposure on long-term cognitive trajectories in participants not receiving GA in the 20 years prior to MCSA enrollment

From a model including interaction effects to test whether the relationship between time after new exposures and global z-scores differed between those who did and did not receive GA in the 20 years prior to MCSA enrollment, we did not find compelling evidence to suggest a difference (P=0.373 for the interaction term). Nonetheless, we executed our a priori plan to perform a sensitivity analysis with exposures to surgery/GA following enrollment where post-enrollment exposure is examined for anesthesia naïve participants (no exposure prior to enrollment).

Global z-score.

A total of 601 participants were not exposed to surgery/GA in the 20 years prior to enrollment. After enrollment in MCSA and over a median follow-up of 5.0 (2.7, 7.5) years, 454 (76%) of these participants had no exposure to GA, 83 (14%) had GA without N₂O, and 64 (11%) had GA with N₂O. In adjusted linear mixed models, following a new post-enrollment exposure to surgery with GA without N₂O was associated with an acceleration in the rate of decline in global cognitive z-scores, −0.071 (95% CI −0.110 to −0.031), P<0.001 (Table 4). This association was not significant after exposure to GA with N₂O, −0.019 (95% CI −0.057 to 0.019), P=0.325, and the effect of anesthesia exposure on slope was greater after GA without N₂O compared with GA with N₂O (P=0.047) (Table 4).

Table 4:

Sensitivity analysis for change in cognitive scores over time before and after post-enrollment exposure to general anesthesia (GA) with or without N₂O and estimated difference in change in slope for GA without and with N₂O, where post-enrollment exposure is defined only for those without exposures in the 20 years before enrollment.

Cognitive Ssore		GA without N₂O^*		GA with N₂O^*		GA without N₂O – GA with N₂O^‡
Cognitive Ssore	Slope est. ^†	Change in slope est. (95% CI)	P	Change in slope est. (95% CI)	P	Difference in change in slope est. (95% CI)	P
Global z-score	−0.086	−0.071 (−0.110 to −0.031)	<0.001	−0.019 (−0.057 to 0.019)	0.325	−0.052 (−0.104 to −0.001)	0.047
Domain specific z-score
Memory	−0.027	−0.090 (−0.142 to −0.038)	<0.001	−0.040 (−0.077 to −0.004)	0.030	−0.049 (−0.109 to 0.011)	0.105
Language	−0.083	−0.035 (−0.072 to 0.003)	0.068	−0.008 (−0.042 to 0.026)	0.631	−0.027 (−0.073 to 0.019)	0.251
Visuospatial	−0.045	0.008 (−0.030 to 0.047)	0.660	−0.006 (−0.044 to 0.032)	0.749	0.015 (−0.036 to 0.065)	0.567
Attention/executive	−0.104	−0.055 (−0.101 to −0.008)	0.022	−0.028 (−0.079 to 0.024)	0.285	−0.027 (−0.093 to 0.039)	0.415

Open in a new tab

Analyses presented are from adjusted linear mixed effects models. Six participants were excluded from the analyses because of missing covariates. After exclusions there were 1,813 participants included in the analysis (1,217 had an exposure in the 20 years prior to MCSA enrollment; of 596 without a prior exposure, 83 had a new exposure to GA without N₂O, and 63 had a new exposure to GA with N₂O). All models are adjusted for prior 20-year exposure to GA without N₂O, GA with N₂O, age, sex, cognitive status at enrollment, education, marital status, Charlson comorbidity index, presence of APOE-ε4 genotype, ever-diagnosed alcohol problem, smoking status, mid-life diagnosis of diabetes, hypertension, and dyslipidemia, and history of atrial fibrillation, congestive heart failure, stroke, and coronary artery disease.

^†

Slope estimate represents average annual change (slope) in z-score for participants prior to any post-enrollment exposure to surgery/GA.

Estimates, 95% confidence intervals, and P-values for the time-dependent change in slope following new exposure to GA without and with N₂O based on a post-enrollment exposure;

^‡

P-value for comparison of change in slope estimates between GA without and with N₂O.

Domain specific z-scores.

In analysis of domain specific z-scores, exposure to GA without N₂O was associated with an accelerated decline (more negative slope) for memory (P<0.001) and attention/executive domains (P=0.022), but not language and visuospatial domains. Exposure to GA with N₂O was associated with significant acceleration in decline for memory (P=0.030), but not for the other three domain specific z-scores (Table 4). Changes in slopes before and after exposure to surgery/GA for domain specific z-scores did not differ between those who did and did not receive N₂O (Table 4).

DISCUSSION

The main finding of this study was that the inclusion of N₂O with GA was not associated with an increased rate of cognitive decline compared with GA without N₂O. While both GA without N₂O and GA with N₂O were consistently associated with accelerated decline in global z-scores and memory and attention/executive domain-specific z-scores, there was insufficient evidence to suggest the effects of GA with N₂O is different from GA without N₂O for any of our cognitive outcomes. However, in a sensitivity analysis focused on participants who were GA naïve at enrollment, GA without N₂O, but not GA with N₂O, was associated with accelerated decline in global z-scores.

The current analysis extends our prior report in this population⁹ and thus recapitulates several features observed and discussed in this work, including the association between GA and accelerated declines in global cognition and predominantly in the domains of memory and attention/executive function, associations that largely did not depend on a history of GA exposure prior to MCSA enrollment. Of note, these are the typical cognitive changes first encountered with normative aging and development of Alzheimer’s dementia.^33–36 While the language domain showed accelerated decline in GA with N₂O participants, when differences in change is slope for this domain were compared between GA with and without N₂O there was no statistically significant difference. As we previously discussed, there are many factors associated with surgery and GA (e.g., participants with significant comorbid conditions being more likely to require surgery, potential effects of the perioperative inflammatory response or other perioperative factors on cognition, events such a postoperative delirium, etc.) that preclude interpreting any association as indicating a causal effect of GA.

Although magnitude of the acceleration in cognitive decline after exposure to surgery/GA is statistically significant, however, the clinical implications are unclear. For example, on average the global cognitive z-score is expected to decline −0.075 SD per year, and we have found that participants exposed to surgery/GA with or without N₂O have an acceleration of cognitive decline of approximately an additional −0.06 SD per year. Thus, surgery/GA in older age nearly doubles the rate of cognitive decline compared to what would be expected without exposure. The clinical relevance of this acceleration of cognitive decline depends upon an individual’s expected survival and their cognitive function at the time of exposure (Figure 2). For example, an individual with serious comorbidities and poor life expectancy, but with above average cognitive function at the time of exposure, may not survive to experience noticeable implications of surgery/GA on cognition. However, for an individual with longer expected survival the accelerated cognitive decline after surgery/GA may result in earlier onset of cognitive impairment than would be expected without such exposure. Therefore, exposure to surgery/GA may be considered one of many potentially deleterious events (e.g., head trauma, inflammatory conditions, cardiovascular disease, and neurodegenerative disease) that may cumulatively degrade cognition ever so slightly over a lifetime.

Figure 2. — Simulated trajectories for four hypothetical individuals under three scenarios (no post-enrollment exposure to anesthesia; a post-enrollment exposure to anesthesia with N₂O and without N₂O). The four hypothetical individuals were chosen to represent varying degrees of cognitive function at enrollment. The plot demonstrates statistically significant acceleration in decline of cognitive trajectories after exposure to surgery with general anesthesia. This acceleration was similar after anesthesia with vs. without N₂O. The clinical significance of the change of the acceleration decline of cognitive z-scores is relative to the level of cognitive reserve at the time of exposure. For individuals with above average cognitive function at the time of exposure (*Individuals 1 and 2*) there may be no clinical implications (i.e., development of mild impairment) until years following exposure, whereas individuals whose cognitive function is already below average (*Individuals 3 and 4*) clinical implications would be experienced sooner.

As recently reviewed,¹⁰ some animal studies suggest that N₂O causes neurotoxicity in both young and aged rats. For example, administration of N₂O either alone or in combination with volatile anesthetics is associated with impaired learning and memory in aged rats.^12,37,38 Proposed mechanisms of toxicity include NMDA antagonism, the generation of reactive oxygen species and mitochondrial dysfunction, and increases in homocysteine levels secondary to reduced activity of methionine synthase (although elevated serum homocysteine after N₂O anesthesia reverts back to the normal levels after 24 hours).³⁹ The potential for N₂O toxicity depends on B₁₂/folate level deficiencies and genetic factors.³⁹ Up to 20% of population have reduced activity of enzyme 5,10-methylenetetrahydrofolate reductase; these individuals, may be more likely to develop perioperative hyperhomocysteinemia.^39,40 Although hyperhomocysteinemia is a modifiable risk factor for vascular dementia and AD¹¹ increase in plasma homocysteine after anesthesia is transient and elevated levels revert into the normal range within 24 postoperative hours, irrespective of the magnitude of the increase caused by N₂O.³⁹ While we do not have the information regarding methylenetetrahydrofolate reductase activity in our participants, our study does not provide evidence that the use of N₂O for the duration of anesthesia is associated with clinically-evident neurotoxicity.

Limitations.

The most important limitation of our study is the possibility for unmeasured confounding inherent in an observational study: factors responsible for the decision to include N₂O, or associated with its use, may also be associated with postoperative changes in cognitive function. Although the analysis did control for several factors known to be important determinants of cognition, there were differences between those who did and did not receive N₂O in the type of surgery received and the other anesthetic agents utilized. To the extent that these variables might affect cognitive function, such differences could bias against finding associations of cognition with N₂O. Also, although we did not measure anesthetic dose, it is likely that those receiving N₂O also received lower concentrations of other anesthetic agents. Our modelling of cognitive trajectories assumes that within a given participant cognitive changes are linear over the interval of follow-up in our study. We specified a primary analysis approach and outcome and did not adjust for multiple comparisons among domain-specific outcomes or for our sensitivity analyses which may inflate the overall error rate among all analyses. There is partial overlap between the current sample and the reference cohort used to standardize cognitive outcomes. As a result, the distribution of z-scores in the current sample may not have mean 0 or standard deviation of 1 and inference should be considered relative to the reference population. In some ways, this is a strength as the reference population is clearly defined by the original MCSA sampling scheme as cognitively unimpaired individuals >70 years of age residing in Olmsted County, Minnesota. Finally, due to the limited number of participants who had multiple exposures to surgery/GA during follow-up, we could not examine the role of multiple anesthetic exposures on z-score slope estimates.

CONCLUSIONS

Exposure to surgery with GA is associated with a small increase in the rate of cognitive decline, but the inclusion of N₂O with GA does not affect increase decline. This finding provides evidence that the use of N₂O in older adults does not need to be avoided because of concerns related to accelerated decline in cognition.

Supplementary Material

NIHMS1066097-supplement-1.docx^{(23.7KB, docx)}

KEY POINTS:

Question: Does the association between exposure to surgery with general anesthesia (surgery/GA) and cognitive decline depend upon the use of nitrous oxide (N₂O) which some reported to have neurotoxic effects?
Findings: Compared to unexposed participants, exposure to surgery/GA was associated with accelerated cognitive decline; the magnitude of this association did not depend upon whether or not N₂O was used as a part of anesthesia.
Meaning: N₂O, included as part of anesthetic management, was not associated with long-term cognitive function decline beyond that seen after exposure to surgery/GA without N₂O.

Acknowledgments:

The authors thank Mr. Jeremiah Aakre, statistician for the MCSA.

Role of the funding source: This study was supported by the NIH grants P50 AG016574 and U01 AG006786 (Petersen), by the Robert H. and Clarice Smith and Abigail van Buren Alzheimer’s Disease Research Program, the Rochester Epidemiology Project (R01 AG034676, Principal Investigators: Walter A. Rocca, MD, and Jennifer St. Sauver, PhD) and the Mayo Clinic Center for Translational Sciences Activities (CTSA), grant number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Financial support for statistical analyses was provided by the Department of Anesthesiology Mayo Clinic.

Disclosures: D.S.K. previously served as deputy editor for the journal Neurology, and he serves on a Data Safety Monitoring Board for Lundbeck and for the Dominantly Inherited Alzheimer Network Trials Unit. He is an investigator in clinical trials sponsored by Biogen, Eli Lilly and Co, and TauRx Therapeutics Limited and receives research support from the NIH. M.M.M. has served as a consultant for Eli Lilly and has received unrestricted research grants from Biogen and Lundbeck. R.C.P. is the chair of Data Monitoring Committees for Pfizer Inc and Janssen Alzheimer Immunotherapy, LLC, and has served as a consultant for F. Hoffmann-La Roche Ltd; Merck and Co, Inc; and Genentech Inc. He receives royalties from sales of the book Mild Cognitive Impairment (Oxford University Press). J.S., T.N.W., P.J.S., A.C.H., D.P.M., J.J.P., A.A.S., and D.O.W. have nothing to disclose.

Alphabetical List of Abbreviations:

APOE ε4 allele: apolipoprotein E genotype
MCSA: Mayo Clinic Study of Aging
N₂O: nitrous oxide
REP: Rochester Epidemiology Project
GA: general anesthesia
Surgery/GA: surgery with general anesthesia

Footnotes

Conflicts of Interest: None.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

NIHMS1066097-supplement-1.docx^{(23.7KB, docx)}

[R1] 1.Xie Z, Culley DJ, Dong Y, et al. The common inhalation anesthetic isoflurane induces caspase activation and increases amyloid beta-protein level in vivo. Ann Neurol 2008; 64(6): 618–27. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R2] 2.Avidan MS, Searleman AC, Storandt M, et al. Long-term cognitive decline in older subjects was not attributable to noncardiac surgery or major illness. Anesthesiology 2009; 111(5): 964–70. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R3] 3.Sprung J, Roberts RO, Knopman DS, et al. Mild cognitive impairment and exposure to general anesthesia for surgeries and procedures: a population-based case-control study. Anesth Analg 2017; 124(4): 1277–90. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R4] 4.Sprung J, Jankowski CJ, Roberts RO, et al. Anesthesia and incident dementia: a population-based, nested, case-control study. Mayo Clin Proc 2013; 88(6): 552–61. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R5] 5.Dokkedal U, Hansen TG, Rasmussen LS, Mengel-From J, Christensen K. Cognitive Functioning after surgery in middle-aged and elderly Danish twins. Anesthesiology 2016; 124(2): 312–21. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R6] 6.Hughes CG, Patel MB, Jackson JC, et al. Surgery and anesthesia exposure is not a risk factor for cognitive impairment after major noncardiac surgery and critical Illness. Ann Surg 2017; 265(6): 1126–33. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R7] 7.Chen PL, Yang CW, Tseng YK, et al. Risk of dementia after anaesthesia and surgery. Br J Psychiatry 2014; 204(3): 188–93. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R8] 8.Roberts RO, Geda YE, Knopman DS, et al. The Mayo Clinic Study of Aging: design and sampling, participation, baseline measures and sample characteristics. Neuroepidemiology 2008; 30(1): 58–69. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R9] 9.Schulte PJ, Roberts RO, Knopman DS, et al. Association between exposure to anaesthesia and surgery and long-term cognitive trajectories in older adults: report from the Mayo Clinic Study of Aging. Br J Anaesth 2018; 121(2): 398–405. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R10] 10.Savage S, Ma D. The neurotoxicity of nitrous oxide: the facts and “putative” mechanisms. Brain Sci 2014; 4(1): 73–90. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R11] 11.Smith AD, Refsum H. Homocysteine, B vitamins, and cognitive impairment. Annu Rev Nutr 2016; 36: 211–39. [DOI] [PubMed] [Google Scholar]

[R12] 12.Culley DJ, Raghavan SV, Waly M, et al. Nitrous oxide decreases cortical methionine synthase transiently but produces lasting memory impairment in aged rats. Anesth Analg 2007; 105(1): 83–8. [DOI] [PubMed] [Google Scholar]

[R13] 13.Sessler DI. Nitrous oxide is an effective and safe anesthetic. Turk J Anaesthesiol Reanim 2017; 45(1): 1–2. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R14] 14.Rocca WA, Yawn BP, St Sauver JL, Grossardt BR, Melton LJ. History of the Rochester Epidemiology Project: Half a century of medical records linkage in a US population. Mayo Clin Proc 2012; 87(12): 1202–13. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R15] 15.Rowe CC, Ellis KA, Rimajova M, et al. Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiol Aging 2010; 31(8): 1275–83. [DOI] [PubMed] [Google Scholar]

[R16] 16.Jack CR Jr., Bennett DA, Blennow K, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement 2018; 14(4): 535–62. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R17] 17.Vemuri P, Knopman DS, Lesnick TG, et al. Evaluation of amyloid protective factors and Alzheimer Disease neurodegeneration protective factors in elderly individuals. JAMA Neurol 2017; 74(6): 718–26. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R18] 18.Kokmen E, Smith GE, Petersen RC, Tangalos E, Ivnik RC. The short test of mental status. Correlations with standardized psychometric testing. Arch Neurol 1991; 48(7): 725–8. [DOI] [PubMed] [Google Scholar]

[R19] 19.Hachinski VC, Iliff LD, Zilhka E, et al. Cerebral blood flow in dementia. Arch Neurol 1975; 32(9): 632–7. [DOI] [PubMed] [Google Scholar]

[R20] 20.Rosen WG, Terry RD, Fuld PA, Katzman R, Peck A. Pathological verification of ischemic score in differentiation of dementias. Ann Neurol 1980; 7(5): 486–8. [DOI] [PubMed] [Google Scholar]

[R21] 21.Fahn S, Elton RL, Committee UD. Unified Parkinson’s Disease Rating Scale In: Fahn S, Marsden CD, Calne DB, Goldstein M, eds. Recent Developments in Parkinson’s Disease Florham Park. MacMillan Healthcare Information; 1987. 153–63. [Google Scholar]

[R22] 22.Wechsler DA. Wechsler Adult Intelligence Scale-Revised New York: Psychological Corporation; 1987.

[R23] 23.Reitan RM. Validity of the Trail Making Test as an indicator of organic brain damage. Percept Motor Skills 1958; 8: 271–6. [Google Scholar]

[R24] 24.Kaplan EF, Goodglass H, Weintraub S. The Boston Naming Test. 2nd ed. Philadelphia: Lea & Febiger; 1982. [Google Scholar]

[R25] 25.Lucas JA, Ivnik RJ, Smith GE, et al. Mayo’s Older Americans Normative Studies: category fluency norms. J Clin Exp Neuropsychol 1998. 20 194–200. [DOI] [PubMed] [Google Scholar]

[R26] 26.Wechsler DA. Wechsler Memory Scale-Revised. New York: Psychological Corporation; 1987. [Google Scholar]

[R27] 27.Ivnik RJ, Malec JF, Smith GE. WAISR, WMS-R and AVLT norms for ages 56 through 97. Clin Neuropsychol 1992. 6: 83–104. [Google Scholar]

[R28] 28.Salthouse TA. When does age-related cognitive decline begin? Neurobiol Aging 2009; 30(4): 507–14. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R29] 29.Buchman AS, Tanne D, Boyle PA, Shah RC, Leurgans SE, Bennett DA. Kidney function is associated with the rate of cognitive decline in the elderly. Neurology 2009; 73(12): 920–7. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R30] 30.Wilson RS, Hebert LE, Scherr PA, Barnes LL, Mendes de Leon CF, Evans DA. Educational attainment and cognitive decline in old age. Neurology 2009; 72(5): 460–5. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R31] 31.Yaffe K, Falvey C, Hamilton N, et al. Diabetes, glucose control, and 9-year cognitive decline among older adults without dementia. Arch Neurol 2012; 69(9): 1170–5. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R32] 32.Vemuri P, Lesnick TG, Przybelski SA, et al. Association of lifetime intellectual enrichment with cognitive decline in the older population. JAMA Neurol 2014; 71(8): 1017–24. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R33] 33.Harada CN, Natelson Love MC, Triebel KL. Normal cognitive aging. Clin Geriatr Med 2013; 29(4): 737–52. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R34] 34.Hayden KM, Welsh-Bohmer KA. Epidemiology of cognitive aging and Alzheimer’s disease: contributions of the cache county utah study of memory, health and aging. Curr Top Behav Neurosci 2012; 10: 3–31. [DOI] [PubMed] [Google Scholar]

[R35] 35.Knopman DS, Beiser A, Machulda MM, et al. Spectrum of cognition short of dementia: Framingham Heart Study and Mayo Clinic Study of Aging. Neurology 2015; 85(19): 1712–21. [DOI] [PMC free article] [PubMed] [Google Scholar]

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ANESTHESIA WITH AND WITHOUT NITROUS OXIDE AND LONG-TERM COGNITIVE TRAJECTORIES IN OLDER ADULTS

Juraj Sprung, MD, PhD

Arnoley S (Arney) Abcejo, MD

David S Knopman, MD

Ronald C Petersen, MD, PhD

Michelle M Mielke, PhD

Andrew C Hanson, BS

Darrell R Schroeder, MS

Phillip J Schulte, PhD

David P Martin, MD, PhD

Toby N Weingarten, MD

Jeffrey J Pasternak, MD

David O Warner, MD

Abstract

BACKGROUND:

METHODS:

RESULTS:

CONCLUSIONS:

INTRODUCTION

METHODS

Participants

Identification of anesthetic exposures

Demographic and clinical characteristics

Cognitive Assessments

Statistical Analyses

RESULTS

Figure 1.

Table 1:

Table 2 -.

Effects of anesthesia exposure on long-term cognitive trajectories in all participants

Global z-score.

Table 3:

Domain specific z-scores.

Effects of anesthesia exposure on long-term cognitive trajectories in participants not receiving GA in the 20 years prior to MCSA enrollment

Global z-score.

Table 4:

Domain specific z-scores.

DISCUSSION

Figure 2.

Limitations.

CONCLUSIONS

Supplementary Material

KEY POINTS:

Acknowledgments:

Alphabetical List of Abbreviations:

Footnotes

REFERENCES

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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