The Effects of Inhaled Anesthetic Agents on Long-Term Cognitive Decline.
Abstract
Background: anesthesia is generally considered safe, but studies have shown the
potential relationship between anesthetic agents and dementia after surgery.
Several studies have pointed out how the commonly used anesthetic drugs induce
cytotoxicity, ultimately leading to neurodegeneration and even alzheimer's
disease (ad). Specifically, inhaled anesthetics such as isoflurane,
sevoflurane, and desflurane have been shown to impact the neurophysiology of
the brain. However, there is no established relationship between anesthetics
and long-term postoperative cognitive decline.
Objective: the objective of this study is to explore the available research on
anesthetic agents and the potential role that they have played in postoperative
cognitive decline.
Methods: following prisma guidelines, a comprehensive electronic search was
conducted to identify articles discussing long-term cognitive decline with
anesthesia using pubmed, medline, and cinahl complete. We restricted the search
to (1) articles published between 2010 and 2023, (2) full texts in english, (3)
articles discussing long-term cognitive decline with anesthesia, (4) humans 19+
years of age, and (5) clinically relevant data. The initial search yielded 108
articles, 7 of which were filtered out for duplicates. The remaining papers
underwent a quality assessment procedure following the screening process. A
total of six final studies were identified that focused on the long-term
cognitive effects of anesthesia.
Results: of the six studies, three recognized inhaled halogenated anesthesia to
cause increased cognitive decline as opposed to a control group with
intravenous anesthesia or without general anesthesia. Of particular note, none
of the studies associated a correlation with an increased risk of alzheimer\'s
disease. Nitrous oxide used in adjunct to general anesthesia showed no
difference in long-term cognitive decline compared to general anesthesia
without nitrous oxide. Anesthesia without surgery in healthy participants
showed no long-term change in cognitive status from baseline. Also, regional
anesthesia was not associated with an increased risk of dementia.
Conclusion: although half of the studies showed that exposure to inhaled
halogenated anesthetics under surgery was associated with an increased risk of
long-term cognitive decline, the results were inconclusive regarding whether
anesthesia alone influenced this outcome. A study that had healthy volunteers
undergo anesthesia without surgery showed that anesthesia had no long-term
cognitive impacts. This study shows that surgery with or without chronic health
conditions may play a role in this long-term cognitive decline. Limitations of
the included studies included: limited studies done in this specific field,
different screening tests to determine cognitive decline, and variable health
conditions among participants. Overall, results showed contradictory evidence
regarding the relationship between anesthesia and postoperative cognitive
outcomes. These results demonstrate the need for further research to elucidate
a stronger link between anesthesia and long-term postoperative cognitive
outcomes.
Keywords: anesthesia; alzheimers disease; dementia
Introduction
Anesthetic drugs are a mainstay in medical
care, used for minor and major medical procedures to prevent pain and produce
loss of feeling and awareness1. While anesthesia is generally considered
safe, studies have shown the potential relationship between anesthetic drugs
and dementia after surgery.
Other proposed mechanisms involve calcium dysregulation leading to anesthetic-induced neurotoxicity6. The brain is vulnerable to anesthetic-mediated neurodegeneration7. Disruption of intracellular calcium homeostasis, particularly due to a persistent and excessive increase in the calcium concentration, can induce cell death by apoptosis. Volatile anesthetics, such as isoflurane, can induce apoptosis by significantly increasing both the cytosolic and mitochondrial calcium concentrations and decreasing the endoplasmic reticulum calcium concentration7. Isoflurane has been shown to be more potent than sevoflurane or desflurane at causing calcium release from the endoplasmic reticulum and in promoting aggregation of pathological proteins and apoptosis. These molecular pathways involved in intracellular calcium dysregulation can ultimately lead to anesthetic-mediated neurotoxicity and neuroapoptosis.
Post-operative cognitive decline (pocd) is a known phenomenon explaining the short-term effects of anesthesia on memory. It has been associated with prolonged hospital stays and increased healthcare costs8. However, much remains unknown on the definitive link between intravenous and inhaled anesthetics towards dementia and long-term complications9. While many proposed mechanisms exist, the lack of a defined relationship between anesthetics and post-operative dementia has posed a risk to many individuals undergoing anesthesia prior to operative procedures. In addition, there is a lack of a universal diagnostic criteria due to the varying symptom presentation of pocd. Pocd is multifactorial, accounting for biological and pre-operative cognitive function. However, it is a perioperative priority, and the choice of anesthetic agent remains a plausible factor10. To address this, it is essential to acknowledge the current research regarding anesthetic agents and explore their significance and potential in inducing cognitive impairment. This scoping review explores the available research on anesthetic agents and their possible role that they play in post-procedural cognitive decline.
Materials & methods
A comprehensive electronic search was conducted using prisma guidelines to identify articles discussing long-term cognitive decline with anesthesia. The studies used in this scoping review were found through searches in pubmed, medline, and cinahl complete. According to the criteria described below, studies published from 2010 to 2023 were included. Based on the inclusion and exclusion criteria, two independent and blind reviewers conducted the selection process.
Search strategy
A computer-assisted literature search was conducted using the databases mentioned earlier to identify studies that met the following inclusion criteria: (1) articles published between 2010 and 2023, (2) full texts in english, (3) articles discussing long-term cognitive decline with anesthesia (4) humans 19+ years of age, (5) clinically relevant data. Articles that were excluded involved those that focused on pathophysiology, only measured cognitive decline immediately post-operatively, or were published before 2010. The search was conducted in february 2023 and yielded 109 results.
Identification of studies
((inhaled anesthetics) or (inhaled anesthesia)) and ((dementia) or (alzheimer) or (cognitive impairment) or (cognitive decline) or (memory loss))
Data extraction
All researchers assembled pertinent information on a data log that included the author and year, study type, sample size, and significant findings after screening and applying the inclusion criteria to the articles they got from the databases. A google docs spreadsheet contained the results. The information was then organized, and each article was thoroughly discussed to see if it met the criteria for inclusion and the standards for quality. Discussions were used to settle disagreements.
Based on the provided search criteria, the initial search yielded 108 articles. A further 95 were filtered out after seven duplicates were eliminated because they contained variables that did not meet the inclusion criteria or were not accessible. The remaining papers underwent a quality assessment procedure following the screening process. The final chosen articles focused on the long-term cognitive effects of anesthesia (figure 1).
figure 1. Prisma flow diagram depicting the study selection process.
Prisma: preferred reporting items for systematic reviews and meta-analyses.
|
Author |
Number of participants |
Study type |
How they measured |
Key results |
|
1. Strand et al. |
N = 457 (dementia) N = 420 (dementia-free) |
Retrospective case-control
study.
|
Exposure to anesthesia,
with different methods (ra, ga without gas and ga with gas), within 20 years
prior to diagnosis was compared against no such exposure.
|
Exposure to inhalational
anesthetics with halogenated anesthetics was associated with an increased
risk of dementia, compared to no exposure to anesthesia. However, regional
anesthesia was not significantly associated with an increased risk of
dementia. |
|
2. Sprung et al. |
N = 280
(ha w/o n2o) N = 256
(ga w/ n2o) |
Longitudinal study using
mayo clinic and olmsted medical center database.
|
Patients who have undergone
ga with and without n2o were cognitively assessed every 15 months. Most
patients had a 4 to 8-year follow-up.
|
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.
|
|
3. Baxter et al. |
N = 69 (healthy
participants who have not undergone surgery) |
Single-center cohort study of healthy adult
volunteers 40 to 80 years old. |
Cognitive function was
accessed at 15 min, 60 min, 1, 3, 7, and 30 days. Additional assessments were
done at 6 and 12 months. |
52% recovered within 60
minutes and 91% within day 1. There was no association between age group and
recovery to baseline on the postoperative quality of recovery scale (pqrs)
which correlates to recovery to baseline on secondary cognitive measures.
|
|
4. Silber et al.
|
N = 54,996 (appendectomy
and anesthesia)
N = 274,980 (no
appendectomy and no anesthesia) |
Retrospective study using
medicare data. |
Follow-up ranged from 5-15
years.
|
Exposure to appendectomy
surgery and anesthesia did not increase the subsequent rate of alzheimer
disease and related dementia (adrd).
|
|
5. Liu et al. |
N = 60
(sevoflurane) N = 60
(propofol) N = 60
(lidocaine epidural) N = 60 (control) |
Prospective, randomized
parallel-group study
|
Patients had an l3 to l4 or
an l4 to l5 spinal surgery. Patients with a history of ga or neurologic
diseases were excluded. Patients’ cognitive function was then measured two
years after surgery.
|
Results: two years after
anesthesia, the number of ad cases that emerged did not differ significantly
between the groups. However, the number of cases of progressive mild
cognitive impairment (mci) was greater in the sevoflurane group than in the
control group. Age correlated linearly with amnestic mild cognitive
impairment (amci progression), whereas sex did not.
|
|
6. Zuo et al. |
N = 10,161 (spine surgery
patients)
N = 25 (new onset
alzheimer)
N = 10,135 (control) |
Univariate and multivariate
logistic regression analyses
|
Searched the clinical data
repository for spinal surgery recipients. The patients would then be followed
up at a 5-year minimum to assess if there is new-onset alzheimer disease.
|
These results suggest that
increasing age is a risk factor for ad in patients after spine surgery.
Anesthesia and surgery are not independent factors for ad development.
|
Table 1. The summary of findings in selected studies.
Results
Of the six studies, three recognized inhaled halogenated anesthesia to cause increased cognitive decline as opposed to a control group without general anesthesia. No study could associate a correlation with an increased risk of alzheimer's disease. Regional anesthesia was not associated with an increased risk of dementia.
Several additional variables were involved in many of these studies, which provided additional data concerning the overall relationship between anesthesia and potential cognitive decline.
N2o and dementia
Anesthesia without surgery
Inhaled general anesthesia versus intravenous anesthesia
Alzheimer’s disease and anesthesia
Discussion
Three of the six
analyzed studies recognized inhaled halogenated anesthetics to cause increased
cognitive decline1,2,9. Strand et al.
Showed that any exposure to surgery with anesthesia resulted in an increased
risk of cognitive decline, especially with multiple exposures. They also showed
how exposure to inhaled anesthetics with halogenated gasses increased the risk
of dementia1. The other studies
showed how other variables, such as age, gender, and anesthesia type, could
influence the potential risk for dementia and cognitive decline. Data by liu et
al. Also showed how the inhaled anesthetic class, with sevoflurane in particular,
may promote the progression of cognitive impairment9. Finally, the study by sprung et al. Also showed the
influence of anesthesia on cognitive decline, as those participants exposed to
surgery and general anesthesia had accelerated cognitive decline2.
These findings
illustrate the significant contributory role of halogenated inhaled
anesthetics, specifically in cognitive decline. Conversely, nitrous oxide, a
non-halogenated anesthetic, did not contribute to long-term cognitive decline
and thus may be a potentially safer alternative to employ in anesthesia.
Additionally, with all three studies, multiple confounding factors such as age,
type of surgery, and other comorbidities make it challenging to correlate the
potential cognitive decline directly to the specific anesthetic employed,
making these results inconclusive.
On the contrary,
studies from 3, 4, and 6 as shown in (table
1) demonstrated no association with anesthesia as an independent
contributory factor resulting in post-operative cognitive decline4,6,11. Baxter et al. Concluded that anesthesia
alone may not be associated with cognitive recovery in patients without
surgery, which aligns with most studies due to the many confounding factors involved4. Even when surgery involves anesthesia, in the
form of appendectomy, as silver et al. Showed, there was no increase in the
rate of alzheimer's disease and related dementia6.
Tis is also in line with zuo and zuo's findings which state that anesthesia and
surgery are not independent factors leading to increased risk for ad
development11.
These findings
from studies 3, 4, and 6 as shown in (table
1) display the noncontributory impact of anesthesia and surgery as
independent factors affecting cognitive decline and definitively state that
many other factors may be involved, such as other prior chronic health conditions4,6,11.
Furthermore, the
cognitive decline observed in patients who underwent general anesthesia may be
attributed to the event that led to the need for surgery. For example,
following cardiac surgery, cognitive decline was observed in 50-70% of
patients, with long lasting cognitive decline greater than one year impacting
13-40% of patients12. However, the
contributing factor could be microemboli from cardiopulmonary bypass or a
chronic contributor such as cerebrovascular disease12.
Monitored
anesthesia care (mac) is a type of anesthesia service for procedures performed
under local anesthesia in addition to sedation and analgesia. Mac preserves
spontaneous breathing and airway reflexes, has fewer physiologic disturbances,
and results in a more rapid recovery than general anesthesia13. Through the use of various nerve blocks
prior to surgery and analgesic medications, mac can be used as an alternative
sedating procedure that can be used to reduce post-operative recovery time and
risks associated with general anesthesia14.
Mac does not use fluorinated anesthetics, so the patient is not at risk of the
proposed cognitive decline associated with these volatile anesthetics. However,
mac is inadequate in some surgical procedures where general anesthesia is
indicated.
Limitations
of the included studies
An important
limitation of this scoping review is the use of studies with no specific
selection criteria for the age of adult participants. Age is a significant
contributor to cognitive decline, as it is widely believed that increased age
contributes to greater cognitive decline. The selection of studies in which
there were no criteria in our review for the age of participants could
potentially be a confounding variable affecting post-operative cognitive
decline, as age is a significant contributor to cognitive decline. Future
research may benefit from the inclusion of a strict age range of participants
in the selected studies. Some of the studies also used healthy participants
with normal cognition at baseline. This limits the application of these studies
to clinical populations, in which individuals often have multiple comorbidities
alongside poor baseline cognition levels. Another limitation is the design of
the studies analyzed, in which cognition was measured one-day post-anesthetic
administration, whereas this may not reflect long-term clinical outcomes years
down the line, for dementia and cognitive decline. A large limiting factor in
most of the studies analyzed focuses on the aspect of whether the surgery
itself is a contributory factor towards neurocognitive decline rather than the
anesthesia administered, as surgery has been shown to cause neuroinflammation,
leading to post-operative cognitive decline11.
Limitations
of the review process
Articles prior to
2010 were excluded from our search criteria; thus earlier studies relevant to
this topic were not included. The application of strict inclusion and exclusion
criteria may have further excluded many relevant articles, particularly with the
strict exclusion of animal studies. Also, all articles selected and reviewed
were in the english language only.
Implications for future research and clinical practice
The findings of
this review point to an inconclusive relationship between anesthesia and
post-procedural cognitive decline. While some of the studies investigated in
this review1,2,9point to a possible
relationship between inhaled anesthetics and cognitive decline, the other
studies4,6,11 point to the many other
confounding factors in refuting the direct relationship between anesthesia and
cognitive decline. These other factors include the age of participants, existing
chronic medical conditions, and even the type of anesthetics administered.
Overall, limited
research exists within the field of anesthetic agents and cognitive decline, so
more research is needed to develop stronger conclusions regarding the direct
impact of anesthesia on cognitive decline, and that can better differentiate
between the different confounding variables that may also serve as contributory
factors.
Conclusion
Conflicts of interest
This study does not have any conflict of interest.
References
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