With the development of medical technology and healthcare systems, life expectancy has increased worldwide. Accordingly, the number of surgeries performed in elderly patients has also been increasing [
Dementia is a progressive neurodegenerative disease characterized by multiple cognitive impairments that represent a decline from one’s previous level of functioning. The global prevalence rate of dementia in people over the age of 60 ranges from 5–7%, and increases rapidly with age, to 20% in people over the age of 85 years [
Alzheimer’s disease (AD) is the most common cause of dementia, accounting for approximately 60–80% of dementia cases [
Previous studies have suggested advanced age, female sex, family history of AD, cardiovascular disease, head trauma, depression, and lower educational level as potential risk factors [
There have been several attempts to integrate the evidence from various epidemiological studies, such as the reanalysis of eight case-control studies [
The protocol for this review has been registered in the PROSPERO network (registration number:
A search was performed by two different investigators independently in MEDLINE, EMBASE, and Google Scholar for articles up to April 2018 using search terms related to AD, dementia, and general anesthesia and updated in February 2020. The search terms used in MEDLINE and EMBASE are presented in Appendix
Our selection criteria are as follows.
Peer-reviewed cohort and case-control studies including nested case-control studies were eligible for inclusion. We excluded data from proceedings, letters to the editor, posters, commentaries, laboratory science studies, and any other nonrelevant studies.
Inclusion criteria for study populations were as follows: (1) the elderly (defined as more than 60 or 65 years old) from all countries and (2) those who had not been diagnosed with dementia or AD before the beginning of the study period. If the study’s definition of the elderly was other than being older than 60 or 65 years of age, an attempt was made to contact the study authors to obtain the relevant information. When unsuccessful, we performed a pooled analysis including the data of that study first, and then, we performed a sensitivity analysis excluding the data. No restrictions were applied in terms of sex, race/ethnicity, or socioeconomic status.
Exposure to general anesthesia for surgery, usually using inhalation anesthetics, was included. Intravenous anesthesia, spinal anesthesia, epidural anesthesia, and regional anesthesia were excluded. If an article reported on general anesthesia including intravenous, spinal, epidural, or regional anesthesia along with inhalation anesthesia, we tried to contact the study authors to obtain information on general anesthesia using inhalation anesthetics. When unsuccessful, we first analyzed the data on general anesthesia, including intravenous, spinal, epidural, or regional anesthesia, and then we performed sensitivity analysis excluding the data. The source of exposure assessment was also collected.
Comparison groups included individuals with no history of general anesthesia. If a study only reported previous anesthesia history during the study period, we tried to contact the study authors for further information about previous anesthesia history prior to the study period. When unsuccessful, the reported information was used for our analysis. If a study investigated the associations of AD and general anesthesia using two or more comparison groups and reported each outcome separately, pooled estimates of associations for these groups were calculated and used for analysis.
To cover as many AD cases as possible, we included not only AD cases but also dementia cases, of which AD cases comprise the largest portion, diagnosed by standard criteria such as the DSM or clinically diagnosed by a professional physician. Studies reporting effect size (ES) as odds ratio (OR), relative risk (RR), or hazard ratio (HR) of dementia/AD to general anesthesia exposure were included. In some studies, which reported only the number of individuals with and without AD instead of ES, we obtained the ES by calculation from the data provided. When the study reported only dementia cases without distinguishing AD [
Reference lists obtained as described above were imported into Endnote software (Thompson Reuters, CA, USA), and duplicate articles were removed. The titles and abstracts identified through the search strategy were scanned independently by two investigators. To minimize data duplication as a result of multiple reporting, papers from the same author were compared. For reports determined to be eligible based on the title or abstract, the full paper was retrieved. Potentially relevant studies chosen by at least one investigator were retrieved and evaluated in full-text versions. Articles meeting the inclusion criteria were assessed separately by two investigators, and any discrepancies were resolved through discussion. In cases where agreement could not be reached, the disputes were resolved with the help of a third investigator.
Using a standardized extraction form, the following data were extracted independently by two reviewers: study name (along with the name of the first author and year of publication); region where the study was conducted; study design; source from which subjects were selected; age of subjects; exposure definition; method of data collection (self-reported vs. medical records); outcome definition; ES such as OR, RR, and HR with 95% confidence intervals (CIs); methods for controlling covariates and the confounding variables controlled for; number of cases/controls or cohort groups; and total number of participants. If information was missing, an attempt was made to contact the study authors to obtain the relevant information. When unsuccessful, missing information was calculated if possible from the relevant data in the study. As the ES was not reported or needed to be integrated because of the multiple groups, it was calculated in six studies [
The quality of the studies was independently assessed by two investigators using the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS) [
All statistical analyses were performed using Stata SE version 15.0 (StataCorp, College Station, TX).
Overall pooled ES and its corresponding 95% CI and 95% prediction interval were computed. Between-study heterogeneity was assessed using the Cochran’s
Subgroup analysis was carried out based on study design (case-control vs. cohort study), region of the study population, exposure assessment (self-reported vs. medical record), outcome definition (AD vs. dementia), and method of case ascertainment (standard criteria vs. clinical diagnosis).
We conducted sensitivity analyses to evaluate the influence of individual studies on the overall effect estimate by excluding one study at a time from the analysis.
Publication bias was assessed by using contour-enhanced funnel plots and Egger’s test [
A total of 2784 articles were obtained after searching the databases and references and through the manual search (Figure
PRISMA flow diagram of literature search and selection.
Of the 46 studies selected for review of their whole content, 23 were excluded for the following reasons: One was a conference proceeding [
The study characteristics are summarized in Table
Study characteristics.
Study (1st author, year) |
Study design | Study population | Source of data extraction | Method of exposure assessment | Outcome definition | Lag time; adjusted or matched covariates | Group definition | Statistics | |
---|---|---|---|---|---|---|---|---|---|
Cohort study | |||||||||
Kim, 2018 [ |
PC | From the South Korean NHIS-NSC database. |
Patient records on NHIS-NSC database files between 2002 and 2013 | GA operation codes in the NHIS-NSCdatabase | Dementia (clinical diagnosis using ICD-10 codes and history of dementia medication) | Did not included lag time; adjusted for gender, age group, health security system, health care visit frequency, and Charlson comorbidity index | HR | ||
GA group | 44954 | 1.285 (1.214–1.361) | |||||||
Age 60–69 | 17387 | 1.216 (1.118–1.322) | |||||||
5655 | 1.162 (1.059–1.276) | ||||||||
Unexposed group | 174469 | 1.000 | |||||||
Age 60–69 | 57867 | 1.000 | |||||||
Age> 69 | 41461 | 1.000 | |||||||
Teipel, 2018 [ |
RC | From the German statutory health insurance database. |
Medical records from AOK | History of joint replacement surgery | Dementia (clinical diagnosis using ICD-10 codes) | Included lag time; adjusted for cerebrovascular risk factors, age, sex, the presence of delirium, and regular prescription of sedative or analgesic drugs (SAD) | No surgery | 154604 | Calculated HR |
Quarter 0 | 10563 | ||||||||
1-3 quarter | 0.95 (0.82–1.11) | ||||||||
4-6 quarter | 0.83 (0.70–0.97) | ||||||||
≥7 quarter | 0.91 (0.83–0.99) | ||||||||
Aiello Bowles, 2016 [ |
PC | Adult Changes in Thought (ACT) cohort which was randomly selected from members of Group Health (GH). |
Self-reported data through interview at baseline and follow-upstudy visits | Self-reported anesthesia data (reviewed by anesthesiologist) | Dementia (DSM-IV) |
Did not included lag time; adjusted for ACT study cohort, age, age at study entry, sex, education, hypertension, diabetes mellitus, smoking, stroke, coronary heart disease, exercise, self-rated health, body mass index, depression, Parkinson’s disease, Charlson comorbidity index, and difficulty with activities of daily living. | High-risk surgery with GA | 248 | HR (dementia/AD) |
Other surgery with GA | 3363 | 0.63 (0.46–0.85) | |||||||
Other surgery with neuraxial anesthesia | 123 | 0.49 (0.26–0.90) | |||||||
No anesthesia group | 254 | 1.00 | |||||||
Chen, 2014-1 [ |
RC | LHID (a subset of the Taiwan NHIRD). |
Records from the LHID between 2004 and 2007 | Record of anesthesia from the LHID | Dementia (clinical diagnosis using ICD-9-CM) | Did not included lag time; matched for exact age and sex. | HR | ||
Anesthesia group | 24901 | 1.75 (1.59–1.92) | |||||||
General | 13715 | 1.46 (1.28–1.68) | |||||||
IV or IM | 1686 | 1.60 (1.11–2.30) | |||||||
Regional | 8777 | 1.80 (1.57–2.07) | |||||||
Control group (4 or 5 patients selected for each person in anesthesia group) | 110972 | 1.00 | |||||||
Zuo, 2010 [ |
RC | From the CDR containing deidentified information of inpatients and outpatients in the University of Virginia Health System. | Medical records from the CDR | Record of spine surgery under GA | AD (clinical diagnosis using ICD-9-CM) | Did not included lag time; none | Spine surgery group (from discectomy to fusion between 1992 and 2004) | 2881 ( |
Calculated OR using number of patients |
No surgery group | 6157 |
1.00 | |||||||
Lee, 2005 [ |
RC | Veterans Affairs (VA) patients undergoing CABG or PTCA between October 1996 and September 1997. |
VA administrative databases of inpatient and outpatient encounters | History of CABG (not mentioned about GA, but necessary) | AD (clinical diagnosis using ICD-9) | Did not included lag time; adjusted for age, number of surgeries, number of diagnoses, and length of stay for index hospitalization. | CABG group (including patients who had both CABG and PTCA) | 5216 | HR |
PTCA group | 3954 | 1.00 | |||||||
Case-control studies | |||||||||
Strand, 2019 [ |
CC | Case: Swedish Dementia Quality Registry, diagnoses of AD, late-onset AD, early-onset AD, and mixed Alzheimer’s and vascular dementia in the county of Östergötland from May 2007 to April 2012 |
Medical records | Medical record of prior GA with gas | Dementia (diagnoses of AD, late-onset AD, early-onset AD, and mixed Alzheimer’s and vascular dementia from the dementia registry) | Did not included lag time; adjusted for age category, sex, hypotension under anesthesia, total time anesthesia, and number of exposures of anesthesia. | Cases | 457 | OR |
Controls | 420 | 1.00 | |||||||
Huang, 2018 [ |
CC | Case: residents in Shenyang, China, who were diagnosed with dementia between January 2007 and December 2012 |
Medical records from Chinese database of inhabitants of Shenyang | Medical record of prior GA | Dementia (DSM-IV) |
Did not included lag time; matched for sex and age (within 1 year). | Cases | OR | |
Dementia | 577 | 0.81 (0.71–1.09) | |||||||
AD | 485 | 0.89 (0.61–1.01) | |||||||
Controls | |||||||||
Dementia | 577 | 1.00 | |||||||
AD | 485 | 1.00 | |||||||
Chen, 2014-2 [ |
NCC | LHID (a subset of the NHIRD). |
Medical records from the LHID | Record of endotracheal tube intubation GA | Dementia (clinical diagnosis using ICD-9-CM) | Did not included lag time; matched randomly by age (every 5 years of age), sex, and index year. Adjusted for age, sex, depression, diabetes mellitus, hypertension, stroke, and atherosclerosis. | Dementia group | 5345 | OR |
Control group | 21380 | 1.00 | |||||||
Sprung, 2013 [ |
NCC | From residents of Olmsted County using Rochester Epidemiology Project (REP). |
Medical records from the REP | Medical record of exposure to GA between age 45 and the index date | Dementia (DSM-IV) |
Did not included lag time; matched randomly by sex and age (within 1 year). | Cases | OR (dementia/AD) | |
Dementia | 877 | 0.89 (0.73–1.10) | |||||||
AD | 732 | 0.88 (0.71–1.11) | |||||||
Controls | |||||||||
Dementia | 877 | 1.00 | |||||||
AD | 732 | 1.00 | |||||||
Bufill, 2009 [ |
NCC | From subjects in COGMANLLEU study (belonging to the basic health care area of Manlleu). |
Interview with participants and their relatives or caregivers | Self- or surrogate-reported | AD (DSM-IV, NINCDS-ADRDA) | Did not included lag time; matched for age and gender. |
Cases | 51 | OR |
Controls | 49 | 1.00 | |||||||
Yip, 2006 [ |
NCC | From Cognitive Function and Ageing Study (CFAS). |
Interview with participant | Self-reported exposure to GA | Dementia (AGECAT algorithm) | Did not included lag time; adjusted for age, sex, education, and social class. | Cases: |
133/142 | OR (wave 2/3/both) |
Controls: |
2453/1347 | 1.0 | |||||||
Harmanci, 2003 [ |
CC | Randomly selected from population registries (records of the Muhtars’ list). |
Interview with proxy informants | Surrogate-reported history of GA | AD (probable AD by NINCDS-ADRDA) | Did not included lag time; adjusted for level of education, use of electricity for residential heating, and occupational group. | Cases | 57 | OR |
Controls | 127 | 1.0 | |||||||
Gasparini, 2002 [ |
CC | Recruited at the Department of Neurological Sciences of “La Sapienza” University of Rome, who were treated between January 1990 and June 1997. |
Hospital records | Hospital record of exposure to GA in the 1-year and 5-year periods prior to onset of neurological disease. | AD (probable AD by NINCDS-ADRDA) | Did not included lag time; matched for sex, age (within 3 years), and geographical area of residence. | Cases | 115 | Calculated OR |
Controls (PD) | 230 | 1.00 | |||||||
Controls (others) | 230 | ||||||||
Tyas, 2001 [ |
CC | Randomly sampled from a list provided by the provincial health insurance plan. |
Interview and questionnaire | Self-reported exposure to GA | AD (probable or possible AD by NINCDS-ADRDA) | Did not included lag time; adjusted for age, sex, education. | Cases | 36 | RR |
Controls | 658 | 1.00 | |||||||
Bohnen, 1994 [ |
CC | Case: selected from patients with AD developed between 1975 and 1984 in Olmsted County by reviewing medical records |
Medical records | Anesthesia records for GA | AD (clinical diagnosis using their own preselected specific criteria) | Did not included lag time; matched for age, sex. | Cases | 252 | OR |
Controls | 252 | 1.00 | |||||||
CHSA, 1994 [ |
CC | Recruited from both the community and institutions in Canada. |
Risk factor questionnaires completed by proxy respondents | Surrogate-reported exposure to GA | AD (probable AD by NINCDS-ADRDA) | Did not included lag time; frequency matching by study center, residence in community or institution, and age group |
Cases | 258 | OR |
Controls | 535 | 1.00 | |||||||
Li, 1992 [ |
CC | Cases: Clinically diagnosed AD inpatients or outpatients from 1988 to 1989. |
Direct interview using a structured and standardized questionnaire with surrogate informant. | Surrogate-reported history of GA | AD |
Did not included lag time; |
Cases | 70 | OR |
Controls | 140 | 1.00 | |||||||
Kokmen, 1991 [ |
CC | Cases: Rochester, Minnesota, residents with onset of AD between 1960 and 1974 using the existing medical records resource. |
Entire community medical records. | Medical record of prior GA | AD (clinical diagnosis by reviewing clinical and postmortem data) | Did not included lag time; matched by age (within years), sex, and duration of community medical record. | Cases | 415 | OR |
Controls | 415 | 1.00 | |||||||
Graves, 1990 [ |
CC | Cases: patients living in Washington state who were diagnosed with AD between January 1980 and June 1985. |
Interview with surrogate respondents | Surrogate-reported history of surgery with GA | AD (DSM-III, NINCDS-ADRDA) | Did not included lag time; matched by sex and age (within 10 years). |
Cases | 130 | OR |
Controls | 130 | 1.00 | |||||||
Broe, 1990 [ |
CC | Cases: from consecutive new referrals to dementia clinics in Sydney by general practitioners (GPs). |
Interview with the informants of the cases and controls | Surrogate-reported exposure to GA | AD (probable or possible AD by NINCDS-ADRDA) | Did not included lag time; matched for sex and age within 2 years. |
Cases | 170 | OR |
Controls | 170 | 1.00 | |||||||
Amaducci, 1986 [ |
CC | Cases: Patients admitted to the neurology departments of the seven centers between 1982 and 1983. |
Interview with a surrogate respondent. | Surrogate-reported exposure to GA | AD |
Did not included lag time; |
Cases | 116 | Calculated OR |
Controls (hospital) | 116 | 1.00 | |||||||
Controls (population) | 97 | ||||||||
Heyman, 1984 [ |
CC | Cases: participants in a comprehensive clinical, genetic, and epidemiological study of AD at Duke University Medical Center. |
Structured interview with a close family member. | Surrogate-reported history of surgery with GA | AD (clinical diagnosis using their own diagnostic procedure) | Did not included lag time; matched for sex, race, 5-year age interval (50-54, 55-59, etc.), and residential area. | Cases | 40 | Calculated OR |
Controls | 80 | 1.00 |
Abbreviations.
Overall risks of bias evaluated using the RoBANS are shown in Table
Quality assessment of included studies using the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS).
Risk of bias | ||||||
---|---|---|---|---|---|---|
Selection of participants | Confounding variables | Measurement of exposure | Blinding of outcome assessments | Incomplete outcome data | Selective outcome reporting | |
Cohort study | ||||||
Kim, 2018 [ |
Low | Low | Low | Low | Low | Unclear |
Teipel, 2018 [ |
Low | Low | Low | Low | Low | Unclear |
Aiello Bowles, 2016 [ |
Low | Low | Unclear | Low | Low | Unclear |
Chen, 2014-1 [ |
Low | Low | Low | Low | Low | Unclear |
Zuo, 2010 [ |
Low | High | Low | Low | Low | Unclear |
Lee, 2005 [ |
Low | Low | Low | Low | Low | Unclear |
Case-control study | ||||||
Strand, 2019 [ |
Low | Low | Low | Low | Low | Unclear |
Huang, 2018 [ |
Low | Low | Low | Low | Low | Unclear |
Chen, 2014-2 [25] | Low | Low | Low | Low | Low | Unclear |
Sprung, 2013 [ |
Low | Low | Low | Low | Low | Unclear |
Bufill, 2009 [ |
Low | Low | Unclear | Low | Low | Unclear |
Yip,2006 [ |
Low | Low | Unclear | Low | Low | Unclear |
Harmanci, 2003 [ |
Low | Low | Unclear | Low | Low | Unclear |
Gasparini, 2002 [ |
Unclear | Low | Low | Low | Low | Unclear |
Tyas, 2001 [ |
Low | Low | Unclear | Low | Low | Unclear |
Bohnen 1994 [ |
Low | Low | Low | Low | Low | Unclear |
CHSA, 1994 [ |
Low | Low | Unclear | Low | Low | Unclear |
Li, 1992 [ |
Low | Low | Unclear | Low | Low | Unclear |
Kokmen, 1991 [ |
Low | Low | Low | Low | Low | Unclear |
Graves, 1990 [ |
Low | Low | Unclear | Low | Low | Unclear |
Broe, 1990 [ |
Low | Low | Unclear | Low | Low | Unclear |
Amaducci, 1986 [ |
Low | Low | Unclear | Low | Low | Unclear |
Heyman, 1984 [ |
Low | Low | Unclear | Low | Low | Unclear |
After pooling all available data, we observed a significant positive association between the risk of AD and general anesthesia exposure (
Summary estimates, heterogeneity, and publication bias for meta-analyses of overall studies and subgroups.
Characteristics | Summary estimates | Heterogeneity | Publication bias | Trim and fill | ||||
---|---|---|---|---|---|---|---|---|
No. of studies | Pooled ES (95% CI) | 95% PI | Coef (95% CI) | Pooled ES (95% CI) | ||||
Total | 23 | 1.11 (1.06–1.15) | 0.98-1.21 | <0.001 | 79.4 | 0.096 | -0.91 (-1.99–0.24) | 1.09 (0.94–1.27) |
Design | ||||||||
Cohort | 6 | 1.11 (1.06–1.16) | 0.93-1.27 | <0.001 | 88.5 | |||
Case-control | 17 | 1.15 (1.03–1.17) | 0.81-1.20 | <0.001 | 74.8 | 0.088 | -1.02 (-2.22–0.17) | 1.07 (0.87–1.32) |
Region | ||||||||
America | 10 | 0.83 (0.72–0.94) | 0.48-1.1 | 0.354 | 9.6 | 0.626 | 0.49 (-1.73–2.71) | |
Australia | 1 | 0.95 (0.50–1.81) | ||||||
Asia | 5 | 1.23 (1.17–1.28) | 0.98-1.41 | <0.001 | 87.5 | |||
Europe | 7 | 0.96 (0.88–1.05) | 0.68-1.22 | 0.055 | 51.3 | |||
Exposure assessment | ||||||||
Medical record | 12 | 1.15 (1.10–1.19) | 1.01-1.25 | <0.001 | 84.1 | 0.442 | -0.89 (-3.38–1.59) | |
Self or surrogate-reported | 11 | 0.73 (0.59–0.87) | 0.28-1.08 | 0.777 | 0.0 | 0.155 | 1.11 (-0.51–2.72) | |
Dementia definition | ||||||||
Alzheimer’s disease | 17 | 0.86 (0.76–0.95) | 0.58-1.07 | 0.703 | 0.0 | 0.260 | 0.72 (-0.60–2.04) | |
Dementia | 6 | 1.18 (1.13–1.23) | 0.99-1.28 | <0.001 | 90.6 | |||
Case ascertainment | ||||||||
Standard criteriaa | 13 | 0.82 (0.72–0.92) | 0.73-1.07 | 0.478 | 0.0 | 0.147 | 1.09 (-0.45–2.63) | |
Clinical diagnosis | 10 | 1.18 (1.13–1.23) | 1.08-1.39 | <0.001 | 81.2 | 0.493 | -0.75 (-3.17–1.67) |
Abbreviations. Pooled ES: pooled estimates; PI: prediction interval; Coef: coefficient. aStandard criteria represent the diagnosis for Alzheimer’s disease or dementia using object criteria or algorithm such as Diagnostic and Statistical Manual of Mental Disorders (DSM), National Institutes of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders (NINCDS-ADRDA), and Automated Geriatric Examination for Computer Assisted Taxonomy (AGECAT) algorithm.
Forest plot for overall studies showing the risk of Alzheimer’s disease (AD) following general anesthesia. An effect size of 1 (red vertical line) indicates no effect of general anesthesia in development of AD. The gray-colored box of each study means the weight of the study data. Overall pooled effect size showed significantly increased risk of AD following general anesthesia. Above 6 studies are subgroup of cohort studies, and following 17 studies are subgroup of case-control studies. Both of them showed significantly high risk of AD following general anesthesia.
As the heterogeneity for ES was considerable, metaregression was conducted to determine the origin of heterogeneity. According to metaregression, the study design, region, exposure assessment, case ascertainment, definition of dementia or AD, and year of publication were not likely to be a source of heterogeneity (Table
Meta-regression for overall studies.
Category | Coef | 95% confidence interval | |
---|---|---|---|
Study design | -0.00 | -0.13–0.13 | 0.944 |
Region | 0.02 | -0.09–0.13 | 0.755 |
Exposure assessment | -0.03 | -0.40–0.34 | 0.866 |
Case ascertainment | -0.00 | -0.34–0.34 | 0.992 |
Outcome definition | -0.08 | -0.53–0.36 | 0.694 |
Year of publication | 0.00 | -0.02–0.02 | 0.899 |
Constants | -2.09 | -39.28–35.09 | 0.906 |
Abbreviation. Coef: coefficient.
The results of the subgroup analyses are displayed in Table
Subgroup analysis based on the exposure assessment method showed conflicting results. In subgroup of studies using medical records, the risk of AD was significantly high in general anesthesia-exposed patients (
Forest plot for subgroups based on exposure assessment: self- or surrogate-reported and medical record. The risk of dementia following general anesthesia was significantly high in medical record subgroup, but it was significantly low in self or surrogate-reported subgroup.
In the subgroup analysis according to the definition of outcome, general anesthesia was associated with an increased risk of dementia when the outcome was defined as all-cause dementia (
Forest plot for subgroups according to outcome definition: Alzheimer’s disease and all-cause dementia. An increased risk of dementia following general anesthesia was detected among all-cause dementia group, but with considerable heterogeneity. However, decreased risk of AD with general anesthesia exposure was detected among the studies with outcome definition limited to only Alzheimer’s disease.
Subgroup analysis of the studies that used clinical diagnosis showed a significant positive association between general anesthesia and AD (
Forest plots for subgroups based on case ascertainment: standard criteria and clinical diagnosis. Whereas the pooled effect size of the studies, which clinically diagnosed dementia, showed a significant positive association between general anesthesia and dementia, inversely negative association was observed among the studies using standard diagnostic criteria of dementia.
Sensitivity analysis was performed by excluding one study at a time; no change in statistical significance occurred.
Contour-enhanced funnel plots were asymmetric for overall studies and case-control studies (Figure
Contour-enhanced funnel plots of total studies (a) and case-control studies (b). Asymmetry was observed in funnel plots of both total studies and case-control studies.
The effect of general anesthetics, especially inhalation agents, on neurocognitive function is currently controversial; it is unknown whether general anesthetics are neurotoxic or neuroprotective [
Notably, this outcome was contrary to the results of two previous meta-analyses [
Given the various designs and methods used in the involved studies, we performed subgroup analyses to better understand the results of our meta-analysis. In the subgroup analysis based on exposure assessment, an increased risk of AD following exposure to general anesthesia was observed in studies using medical records. Because medical records are more objective and reliable data source than self-reported data collected through interview, this result enhances the validity of the positive association between general anesthesia and AD observed in overall analysis. In addition, as shown in Figure
However, according to the subgroup analysis based on case ascertainment, a negative association was observed in studies using standard criteria. Standard criteria are usually considered more reliable diagnostic tool because it is less likely to involve physician’s subjectivity compared to clinical diagnosis. This finding suggests that the results of the overall analysis must be interpreted with caution.
Considering that AD cases comprise the largest portion of dementia cases (60–80% in one study) [
One of the factors important in outcome assessment is lag time, which means the latency period before the diagnosis of disease. In studies without including the lag time, the patients with incidental dementia not severe enough to be diagnosed may be misinterpreted as having dementia caused by general anesthesia exposure. As highlighted in the meta-analysis conducted to verify the association between dementia and benzodiazepine which was published in 2018 [
Therefore, although a significant association between general anesthesia exposure and AD was observed, the results of this meta-analysis should be interpreted with caution. The possibility of publication bias was demonstrated by contour-enhanced funnel plots and Egger’s test. The statistical significance disappeared after trim and fill analysis. In addition, the 95% prediction interval computed from overall studies implied that any future study could alter the statistical significance of association between general anesthesia and AD. These findings support the need for prudence to properly interpret the results of this meta-analysis.
Our study has some limitations. First, substantial heterogeneity was observed among the included studies. Although various approaches were attempted to reveal the origin of heterogeneity, they were not successful. Second, because of insufficient details on the context of anesthesia including number of exposure, the agent used for induction and maintenance, dose and duration of exposure, and intraoperative events or perioperative complications such as hemodynamic instability and hypoxia, we could not conduct analysis adjusting for these variables. Moreover, surgery itself might contribute to an increased risk of AD. Although there are no data on the risk of AD, high-risk surgeries such as cardiac surgery have been reported as raising the risk of cognitive impairment such as delirium and postoperative cognitive dysfunction [
According to the limitations discussed, additional well-designed studies are necessary to clarify the relationship between general anesthesia and dementia or AD. Future studies are recommended to be conducted with the following considerations: large-scale study with adequate statistical power; prospective cohort studies with long-term follow-up including lag time, ensuring the subjects free of dementia before exposure of anesthesia; using reliable data source such as medical records; reporting sufficient details on the characteristics of exposure such as number of exposure, agents, and doses used; adequate adjustments for confounding variables; and outcome assessment with standard diagnostic tool of dementia. Recent review published by American scholars reported a wide variety of diagnostic methods for dementia used in large cohort studies, while emphasizing the need for the development of well-described and reproducible methods for diagnosing dementia in epidemiologic studies [
Despite the limitations above, our systematic review and meta-analysis demonstrate the strengths of a rigorous methodology based on a published, preplanned protocol to provide evidence of the relationship between general anesthesia exposure and risk of AD. Furthermore, our study has a value of suggesting general anesthesia exposure as a potential risk factor of AD and raising the necessity of further related studies for better management of the elderly. Recently, there was a meta-analysis reported the significantly high mortality rates of the patients with dementia after undergoing hip fracture surgery, emphasizing the importance of perioperative care for dementia [
In conclusion, we observed a significant association between exposure to general anesthesia and an increased risk of AD. However, considering the substantial heterogeneity, evidence of publication bias, and inconsistent results of the subgroup analyses, the results of our meta-analysis should be interpreted with caution. Moreover, it was nearly impossible to discriminate the influence of general anesthesia from the effect of surgery itself on the development of AD. Further, large-scale prospective cohort studies designed to reduce the risk of bias considering lag time, using standardized methods and reliable data with adequate adjustments of confounding factors, are needed to elucidate the evidence of an association between general anesthesia and AD.
The study data supporting this systematic review and meta-analysis are from previously reported studies and datasets, which have been cited. The processed data are available in the article.
The authors declare no conflicts of interest.
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2018R1A2A2A05021467). No assistance in the preparation of this article is to be declared.
Appendix S1. Search terms used in literature search.