The impact of general anesthesia on cognitive impairment is controversial and complex. A large body of evidence supports the association between exposure to surgery under general anesthesia and development of delayed neurocognitive recovery in a subset of patients. Existing literature continues to debate whether these short-term effects on cognition can be attributed to anesthetic agents themselves, or whether other variables are causative of the observed changes in cognition. Furthermore, there is conflicting data on the relationship between anesthesia exposure and the development of long-term neurocognitive disorders, or development of incident dementia in the patient population with normal preoperative cognitive function. Patients with pre-existing cognitive impairment present a unique set of anesthetic considerations, including potential medication interactions, challenges with cooperation during assessment and non-general anesthesia techniques, and the possibility that pre-existing cognitive impairment may impart a susceptibility to further cognitive dysfunction. The Effects of General Anesthesia on Cognitive Dysfunction Essay.

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Main body

This review highlights landmark and recent studies in the field, and explores potential mechanisms involved in perioperative cognitive disorders (also known as postoperative cognitive dysfunction, POCD). Specifically, we will review clinical and preclinical evidence which implicates alterations to tau protein, inflammation, calcium dysregulation, and mitochondrial dysfunction. As our population ages and the prevalence of Alzheimer’s disease and other forms of dementia continues to increase, we require a greater understanding of potential modifiable factors that impact perioperative cognitive impairment.

Conclusions

Future research should aim to further characterize the associated risk factors and determine whether certain anesthetic approaches or other interventions may lower the potential risk which may be conferred by anesthesia and/or surgery in susceptible individuals.

A growing body of evidence has explored the whether exposure to anesthesia might cause temporary or long-term cognitive dysfunction. The specific impact of anesthesia on individuals with pre-existing cognitive impairment is also gaining attention. Dementia presents with impaired learning, memory, and reasoning. The worldwide prevalence of dementia in 2015 was 46.8 million, with a projected increase to 131.5 million by 2050 [1]. The estimated worldwide cost of dementia in 2015 was US$818 billion [2]. Dementia impacts length of hospital stay, morbidity, and mortality [3, 4]. Alzheimer’s disease (AD) accounts for 60–80% of dementia cases [3]. The projected increased prevalence suggests that anesthesiologists will be confronted with managing more patients diagnosed with AD and other forms of dementia. A greater understanding of the relationship between cognitive impairment with surgery and anesthesia is critical to guiding our clinical practice. This review will summarize key existing evidence in individuals with and without pre-existing cognitive impairment and will review potential pathways which may play a role in post-operative cognitive impairment.

Postoperative cognitive dysfunction

Postoperative cognitive impairment and the potential association with surgery under general anesthesia exposure was first described in 1955 [5]. Since this time, a substantial amount of research has been published which focuses on cognitive effects including delirium, postoperative cognitive dysfunction (POCD), development of dementia, and a decline in cognitive function in pre-existing dementia. The Effects of General Anesthesia on Cognitive Dysfunction Essay.  POCD is often defined as a measurable impairment in cognition measured with neuropsychological testing in an individual over time, which may affect memory, attention, and psychomotor function [6]. In 2018, recommendations for nomenclature used to further define POCD were developed [7]. These definitions are summarized in Table 1. The implementation of more consistent terminology will allow for easier identification of trials assessing cognitive changes diagnosed up to 30 days after an operation (delayed neurocognitive recovery) vs. cognitive decline persisting beyond the 30-day recovery period (postoperative neurocognitive disorder). Due to variability in previous studies, the term POCD will be used interchangeably with the updated nomenclature throughout this review. In addition to updated nomenclature, the recent recommendations propose that screening cognitive tests are not sufficient for a diagnosis of a perioperative neurocognitive disorder, and instead diagnosis should involve assessment of performance on one or more cognitive domains. Prior literature has also exhibited wide variation in methodology employed to assess cognition, and differences in statistical analyses [6, 8,9,10,11]. The consequence of this is study heterogeneity which makes it challenging to draw definitive conclusions about various interventions or risk factors for perioperative neurocognitive disorders. Interestingly, individuals who self-report alterations in cognition postoperatively do not consistently demonstrate impairment on neuropsychological testing. Instead, some of these individuals may have higher levels of depression or anxiety [12]. This again highlights the need for the appropriate application of cognitive tests, and in the importance of considering a broad differential when patients report postoperative cognitive impairment.

Initial research on POCD revealed that patients undergoing coronary artery bypass graft (CABG) procedures with cardiopulmonary bypass were more likely to develop intellectual dysfunction when compared with a similar subset of patients undergoing peripheral vascular surgery [13]. One week following cardiac surgery, cognitive decline is observed in 50–70% of patients [14]. Long lasting cognitive decline has also been observed, with 13–40% of individuals affected ≥1 year postoperatively [15,16,17]. One potential contributing factor to the high incidence of POCD in this population is the presence of microemboli from cardiopulmonary bypass [18]. In addition to microemboli, several other factors have been proposed, many of which are highlighted throughout this review. Interestingly, the progression of cerebrovascular disease itself in this patient population has also been proposed as a major contributor to the high incidence of neurocognitive disorder identified post-operatively. In support of this hypothesis, a prospective study comparing a group of patients undergoing CABG to patients undergoing medical management for CAD over a 6 year study demonstrated that patients in both groups showed a similar degree of cognitive decline over the study period [19].

The International Study of Post-Operative Cognitive Dysfunction (ISPOCD1) from 1998 increased interest in the association between surgery and perioperative neurocognitive disorders in non-cardiac surgery. The study enrolled 1218 patients aged 60 and older. Delayed neurocognitive recovery was present in 25% of patients 1 week after surgery, and postoperative neurocognitive disorder was present in 10% of patients 3 months after surgery [20]. Several risk factors for POCD were identified at the 1 week time point including age, level of education, duration of surgery/anesthesia exposure, a second operation, and postoperative infection or respiratory complications. At the 3 month time point, age was the only significant risk factor for POCD. The Effects of General Anesthesia on Cognitive Dysfunction Essay. Hypoxemia and hypotension were not identified as risk factors at either time point. Multiple trials have since been published to identify risk factors or interventions which can help to mitigate the potential impact on cognitive function.

The effects of anesthetic agents on POCD

Several studies have aimed to determine whether general anesthesia itself is a risk factor for POCD. Many of these studies have chosen to compare general anesthesia (GA) to non-GA techniques such as neuraxial, regional, local anesthesia, and sedation. A meta-analysis published in 2010 looked at the existing literature on the topic. In their analysis, non-GA techniques included spinal, epidural, regional, and combination GA plus neuraxial or regional. POCD was defined by any objectively measured cognitive impairment. There was a non-significant trend toward increased POCD with GA vs. non-GA, with a 95% confidence interval (CI) of 0.93–1.95 [21]. Since the publication of this meta-analysis, a randomized controlled trial was published which compared GA to spinal without co-administration of confounding sedative medications. The trial population was patients ≥55 years of age undergoing extracorporeal shock wave lithotripsy. The authors concluded that the type of anesthesia did not impact rates of POCD at 7 days or 3 months postoperatively [22]. Of note, the trial did conduct an interim analysis and the trial was stopped early for futility at 50% of the a priori calculated required sample size. Furthermore, the mean age of the study population was 63.9 and 66.9 in the GA and spinal groups, respectively, and patients with pre-existing cognitive dysfunction were excluded from the study, which limits generalizability of the findings to individuals of advanced age and individuals with dementia. Indeed, the practice guidelines for perioperative brain health published in 2018 concluded that, based on current available data, there is insufficient evidence to recommend the use of regional anesthesia instead of general anesthesia [23].

Several studies have also been designed to assess whether the risk of POCD differs with general anesthesia using inhalational agents, vs. GA with TIVA (total intravenous anesthesia). A recent meta-analysis combined data from seven studies, and concluded that TIVA may reduce the risk of POCD, with an odds ratio (OR) of 0.52; however, this certainty of this conclusion is low due to heterogeneity of diagnostic tools utilized, variability in time of assessment, and inconsistent data reporting [24]. Furthermore, the authors reported that there were 11 ongoing studies on the topic at the time of the meta-analysis in 2018. At this time, it would be premature to conclude superiority of one mode of anesthetic.

The effect of depth of anesthesia on cognitive impairment has also been proposed as a potential risk factor for POCD. A meta-analysis recently compared cognitive outcomes in patients receiving low vs. high depth anesthesia as measured by bispectral index (BIS) monitoring. The Effects of General Anesthesia on Cognitive Dysfunction Essay. Included studies used either Propofol or Isoflurane. The authors concluded that depth of anesthesia did not significantly impact risk of POCD [25]. This conclusion was based on only 3 RCTs, and in one study the age of the participants was 45 ± 7.93 in the low BIS group, and 48.8 ± 10.2 in the high BIS group, which is unlikely to represent a patient population at risk for perioperative cognitive disorders. Furthermore, Hou and colleagues identified that there may have been variations in analgesic requirements between groups in the studies included in the meta-analysis which could confound results. Hou et al. (2018) proceeded to investigate patients aged 60 and older without pre-existing dementia scheduled to undergo elective total knee replacement. They randomized these patients to different depths of anesthesia as measured by BIS monitoring, with analgesic requirements controlled for using femoral and sciatic nerve blocks in both groups. Hemodynamic targets and induction doses were standardized. All patients received sevoflurane at 0.3MAC and a Propofol infusion titrated to target the appropriate BIS. On postoperative day 1, cognitive performance as measured by the Montreal cognitive assessment (MoCA) was significantly lower in the group with a target BIS of 40–50, when compared with the group with a target BIS of 55–65, indicating that a greater depth of anesthesia may increase POCD in the immediate postoperative period when other factors are carefully controlled [26]. There was no difference in cognition measured on postoperative days 3 or 7 which brings into questions whether a lower BIS has any meaningful clinical or economic significance. It should also be noted that the validity of BIS and other EEG-based depth of anesthesia monitoring does not correct for age or the presence of underlying cognitive dysfunction, and therefore may not serve as a reliable surrogate of depth of anesthesia in this patient population [27, 28]. Additional studies are required to validate depth of anesthesia monitoring in the elderly patient population, and also to investigate whether depth of anesthesia impacts the risk for cognitive impairment in the elderly population.

The effect of perioperative dexmedetomidine has been explored as a potential intervention to reduce the risk of POCD. The precise mechanism is still under investigation, but may relate to decreased requirements of other sedative and anesthetic medications, decreased opioids, modulation of the systemic stress response, promotion of natural sleep patterns, and potentially direct neuroprotective effects [29,30,31].The Effects of General Anesthesia on Cognitive Dysfunction Essay.  A landmark study published in 2016 demonstrated reduced delirium when low dose dexmedetomidine was administered postoperatively to elderly patients admitted to the intensive care unit following elective non-cardiac surgery [31]. The role of dexmedetomidine in prevention of POCD is less well studied, but has been the focus of a 2016 meta-analysis which concluded that dexmedetomidine may reduce the incidence of delayed neurocognitive recovery, and improve scores on the mini-mental state exam (MMSE) on postoperative day one [32]. This meta-analysis was limited by a small number of included studies with a small overall sample size, and study heterogeneity relating to patient inclusion and exclusion criteria and variations in dexmedetomidine administration. Since this time, many more studies have been designed to assess the impact of intraoperative and postoperative dexmedetomidine infusions in a variety of patient populations. Many of these studies are still underway. In the published literature, Deiner and colleagues (2017) randomized 404 elderly patients undergoing major elective non-cardiac surgery to dexmedetomidine infusion intraoperatively and 2 h postoperatively vs. placebo, with a primary outcome of delirium. A secondary outcome of cognitive impairment at 3 and 6 months postoperatively was also investigated. There were no differences in either delirium or cognitive performance; however, the study was designed and powered for the primary outcome of delirium, and the study was stopped for futility prior to reaching the calculated sample size of 706 [33]. Further high quality studies designed to assess cognitive function as the primary outcome are required to determine whether dexmedetomidine administration reduces the risk for perioperative neurocognitive disorders.

Cerebral perfusion and cerebral oxygen saturation have been implicated in the development of POCD. Chernov and colleagues (2006) utilized seven neuropsychological tests prior to and following CABG, and defined POCD as a 20% or greater reduction in score on 2 or more tests. Regional cerebral blood flow (rCBF) was measured with single photon emission computed tomography (SPECT) imaging. The study identified a relationship between reduced rCBF and cognitive performance [34]. Similarly, in patients who underwent CABG under hypothermic nonpulsatile cardiopulmonary bypass(CPB), a relationship was identified between reduced cognitive performance on the incidental memory assessment with cerebral blood flow measured by ¹³¹Xe clearance [35]. In another study, regional cerebral oxygen saturation was monitored with the INVOS cerebral oximeter in patients undergoing CABG. Patients were randomized to either a blinded control group or to an unblinded intervention group in which providers could intervene to improve cerebral oxygenation. Although there was no difference in cognitive decline between the groups, the study demonstrated that prolonged cerebral desaturation was associated with a higher risk of POCD [36]. Notably, there has also been research which has not replicated the relationship between cerebral blood flow and POCD. Specifically, Abildstrom and colleagues (2002) identified a global reduction in CBF following CABG using SPECT imaging, without any associated regional differences in CBF. In this study, there was no correlation between performance on neuropsychological testing and either global or regional CBF [37]. In the non-cardiac surgery population, a cohort study of elderly patients measured intraoperative cerebral autoregulation using bilateral transcranial doppler probes, and cerebral oxygenation using near-infrared spectroscopy (NIRS). Due to a large number of patients lost to follow-up, only the pre-operative and 1-week postoperative data was analyzed. The primary endpoint was assessed with a multivariable regression analysis, and did not identify an association between impaired intraoperative cerebral oxygenation or perfusion with POCD; however, a secondary analysis using a univariable logistic regression model did reveal a potential relationship between cerebral autoregulation and POCD [38].  The Effects of General Anesthesia on Cognitive Dysfunction Essay.Whether the potential association between cerebral perfusion or oxygenation with POCD is causative, or whether other confounds may explain the association observed is still unclear.

Limited available data also demonstrates mixed results regarding the impact of other modifiable factors on POCD risk including hypothermia [39, 40] and pre-operative and intraoperative glycemic control [41, 42]. Further prospective RCT evidence is required to evaluate the contribution of these factors to delayed neurocognitive recovery.

Although there is a need for further research and additional data to guide perioperative management of elderly individuals, recommendations have been developed based on current evidence [23]. The fifth international perioperative neurotoxicity working groups included over 30 experts who developed recommendations specific to postoperative brain health in individuals > 65 years of age. This article focused on pre-procedural consent, preoperative cognitive assessment, intraoperative management, and postoperative follow-up. We direct readers to the article by the working group for a more detailed description of their recommendations. Their recommendations are briefly summarized below:

(1) Consent: Individuals over the age of 65 should be informed of the risk of postoperative delirium and perioperative neurocognitive disorder prior to their procedure;

(2) Baseline cognitive assessment: Cognitive function should be assessed preoperatively using a brief screening tool. Examples of screening tools provided included the Minicog, MoCA, MMSE, clock-drawing test, verbal fluency test, or the cognitive disorder examination;

(3) Intraoperative management: Current literature is insufficient to define a specific anesthetic regimen to decrease risk of perioperative neurocognitive disorder; however, cautious use or avoidance of medications such as first-generation antihistamines, centrally acting anticholinergics, benzodiazepines, and meperidine was recommended. The authors also suggest avoiding relative hypotension, maintenance of normothermia, use age-adjusted minimal alveolar concentration (MAC) of volatile anesthetic agents, and use EEG-based depth of anesthesia monitoring to titrate anesthetic delivery.

(4) Postoperative follow-up: additional research is required to determine feasibility, efficacy, and cost-effectiveness of postoperative follow-up to assess cognitive outcomes [23].The Effects of General Anesthesia on Cognitive Dysfunction Essay.

In our opinion, the above recommendations reflect the evidence, as well as the continued uncertainty in the field. We do recognize that baseline cognitive assessment is often challenging to implement with limited time for preoperative assessment. Furthermore, without established postoperative follow-up, the utility of baseline cognitive assessment could be questioned. This highlights the need to establish assessments with strong reliability and validity which are relatively easy to administer, and which can be applied postoperatively to identify patients with impaired cognition in the perioperative period.

As summarized above, there is a large body of evidence which supports the existence of delayed neurocognitive recovery and postoperative neurocognitive disorder. Perioperative neurocognitive disorder is a distinct clinical presentation which is separate from Alzheimer’s disease and other forms of dementia. Based on our current knowledge, it is unclear whether the presence of delayed neurocognitive recovery or postoperative neurocognitive disorder confers an increased susceptibility to Alzheimer’s disease or other dementia. Indeed, the pathological mechanisms may be distinct from those involved in Alzheimer’s disease and other forms of dementia. Furthermore, it is currently unclear whether surgery and/or anesthesia increases the risk of subsequent diagnosis of dementia. A meta-analysis published in 2017 showed no significant association between GA and incident dementia (95% CI 0.90–1.19). Importantly, reporting bias may impact study results as patients may be unsure of the type of anesthesia they received. Indeed, a subgroup analysis did show a small but significant association between GA and risk of dementia when only studies using anesthesia records to collect exposure data were included (OR1.22; 95% CI 1.01–1.47) [43]. Since the publication of this metanalysis, a large prospective cohort study using data from the Korean National Health Insurance Service – National Sample Database was published which adds to the debate in the field [44]. The study followed patients 50 years of age and older without pre-existing dementia over a 12 year period and assessed for incident dementia as defined by an ICD-10 code of dementia and documented history of dementia medication. There were 44,956 individuals in the GA group, and 174,469 in the control group. The authors used a time-varying Cox hazard model to minimize time-dependent bias, and utilized propensity score matching to reduce potential confounding biases between groups. Exposure to GA was determined by a general anesthesia operation code in NHIS-NSC database. Individuals who did not have a general anesthesia operation code were assigned to the control group. Similar to prior studies, this study design would not be able to separate the effects of anesthesia exposure from the effects of surgical stress and other potential confounders (for example, perioperative hypothermia or administration of narcotics and other medications). After adjusting for important covariates, a multivariable survival analysis determined there was a 1.285-fold increased risk for developing dementia in the GA group when compared with controls [44]. The authors also conducted a multivariable analysis which demonstrated that the risk of incident dementia was increased with desflurane with a hazards ratio (HR) of 1.27, and isoflurane (HR 1.33), but was decreased with sevoflurane (HR 0.71) [44]. Although the difference hazards ratio of the inhalational agents is intriguing, the observational study design may include unaccounted for confounding variables which influenced choice of anesthetic agent, and independently increase the risk of dementia. A randomized controlled trial would be required to compare the risk profile of various anesthetic agents on cognition and risk for incident dementia. If a difference between volatile agents can be reproduced with a well designed RCT, further research would be required to explore the biological mechanisms differentially altered by various volatile agents. The Effects of General Anesthesia on Cognitive Dysfunction Essay.

In summary, it still unclear whether anesthesia itself causes POCD, or whether other surgical or patient factors might explain the observed cognitive impairment. Conflicting data also exists regarding the potential link between anesthesia exposure and risk of developing AD or other forms of dementia. Research assessing the risk profile of various anesthetic techniques is heterogeneous, and there is no strong evidence in favour of one technique over another. The debate in the field highlights the need for further high-quality research. Furthermore, whether there are additional considerations that should be applied to the individual with pre-existing cognitive impairment is unclear.

Anesthesia in individuals with cognitive impairment

Alzheimer’s disease accounts for the majority of cases of dementia [3]. AD is a fatal progressive neurodegenerative disorder, characterized by neuronal degeneration in the basal forebrain, entorhinal cortex, hippocampus, and cortex [45,46,47]. Pathological hallmarks include the presence of senile plaques which contain Amyloid-β (Aβ), and neurofibrillary tangles which form in the presence of pathological modifications to the microtubule-associated protein, tau. The pathways underlying neurodegeneration are complex and involve many players including soluble and insoluble Aβ, hyperphosphorylated tau, neuroinflammation and microglia dysfunction, cholinergic deficits, and oxidative stress [48,49,50,51,52,53].

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AD and other forms of dementia can impact the ability of anesthesiologists to collect a detailed history and elicit appropriate cooperation for physical examination. The potential for confusion and limited cooperation may make approaches such as neuraxial anesthesia, peripheral nerve blocks, or sedation more challenging. In terms of pharmacologic management, it is commonly accepted that short-acting medications should be used, and medications which may increase risk of postoperative confusion should be avoided [23, 54, 55]. Available evidence does not support the hypothesis that these patients are more sensitive to anesthetic agents; however, the sample size employed in these studies and use of the BIS monitor as a surrogate of anesthetic depth make it challenging to draw any definitive conclusion [27, 56].

Anesthesiologists must also be aware of drug-drug interactions, such as the interaction between neuromuscular blocking agents and acetylcholinesterase inhibitors [57, 58]. Donepezil (Aricept), a commonly prescribed medication in AD, is a reversible non-competitive cholinesterase inhibitor. It has a half-life of approximately 72 h, and requires 2–3 weeks for complete wash out [59]. Published case reports demonstrate that patients on donepezil may exhibit high intraoperative requirements for non-depolarizing neuromuscular blockers including atracurium, rocuronium, and vecuronium [57, 60]. In contrast, prolonged paralysis has been described with administration of succinylcholine to a patient on donepezil, potentially due to reduced pseudocholinesterase inhibitor activity [58]. In addition to these anesthetic considerations, it is also important to consider the potential long-term impact of anesthesia on cognition, morbidity, and mortality in patients with dementia. The Effects of General Anesthesia on Cognitive Dysfunction Essay.

The prevalence of preoperative dementia varies in different patient groups requiring surgery. For example, in the vascular surgery population, 3.8% of individuals have a pre-operative diagnosis of dementia [61]. In patients undergoing hip fracture surgery, an estimated 20% of individuals have a diagnosis of dementia [62]. In the vascular surgery population, dementia was identified as the strongest predictor for postoperative complications, increased hospital expenditures and was an independent predictor of increased mortality (HR 1.37) [61]. In a retrospective study, a multivariate analysis identified pre-existing dementia as an independent predictor of 30-day mortality following hip fracture surgery (p = 0.01) [63]. In a population-based retrospective cohort study, individuals with dementia who received GA were matched to similar patients receiving regional anesthesia. The type of anesthetic did not affect postoperative 30 day mortality, length of stay, or measured postoperative complications [64]. The Effects of General Anesthesia on Cognitive Dysfunction Essay.