The use of neuropsychological test batteries to objectively assess cognitive decline emerged in the 1980s within the field of anesthesiology. This represented a scientific approach to define a decrement in cognitive function in the period after anesthesia and surgery. Subsequently, within the anesthesiology community, a preoccupation with the details of the cognitive tests and the mathematical treatment of test results to derive an incidence of cognitive decline became a major focus of the impact of anesthesia and surgery on mental function. The concept of postoperative cognitive dysfunction (POCD) evolved as a measure of objectively defined cognitive decline identified using these methods. Although the construct of POCD has many shortcomings, this field of research identified that subtle cognitive decline in the elderly exists in the postoperative period and may not be overtly apparent unless assessed by neuropsychological testing. We now know that subtle cognitive decline occurs in the elderly population at large and, in common with POCD, requires identification by some form of neuropsychological assessment.
The appreciation of overlap between cognitive decline in the general community and that after anesthesia and surgery has led to a reappraisal of the terminology used to describe POCD. An International Nomenclature Consensus Working group has recently recommended a change in terminology used to describe cognitive decline after anesthesia and surgery.1 It is likely that POCD will be phased out of the cognitive lexicon as more appropriate terminology is introduced. It is therefore opportune to review the valuable part the term POCD has played in our understanding of cognitive decline after anesthesia and surgery.
POCD has played a useful role in understanding that cognitive decline after surgery may not be overt but may have important clinical implications. The utility and significance POCD has played in the past should not be forgotten as we seek to encompass perioperative cognitive decline into the wider appreciation of cognitive change in the elderly in general.
This review seeks to place POCD in the wider context of cognitive decline which is prevalent in the elderly population. There has been a recent tendency to conflate postoperative delirium with POCD.2 Postoperative delirium, although categorized as a perioperative neurocognitive disorder (NCD), is a different diagnosis and we have restricted the scope of this review to POCD and cognitive decline after anesthesia and surgery.
We conducted electronic searches of the literature using Pubmed and Medline in April and May 2016. We limited the review to manuscripts published in English. Articles were also obtained from the authors’ own files. The terms searched were postoperative cognitive dysfunction/decline/impairment/deficit/change; noncardiac surgery.
The recent emphasis of perioperative medicine,3 as an important component of anesthesiology practice, has increased the relevance of cognitive decline to everyday practice. What was previously viewed as an obscure research interest is now assuming everyday relevance. This issue is fueled by the aging patient demographics, because cognitive decline is essentially an issue of the elderly. The American Society of Anesthesiologists has decided to focus on perioperative Brain Health as their new Patient Safety Initiative.4 For this reason, also, it is timely to review POCD with particular emphasis on clinical relevance.
HISTORY OF COGNITIVE CHANGE AFTER ANESTHESIA AND SURGERY
An appreciation that anesthesia and surgery may be followed by cognitive change is not new. Savage5 described insanity and “chronic weak-mindedness” as a result of anesthesia. Although these case reports concentrate more on delirium than cognitive decline, his final conclusion is no less pertinent today, “One or two practical questions arise for the surgeon, one of the most important being whether neurotic inheritance or neurosis in the individual, as proved by previous attacks of insanity, should in anyway affect the prognosis in operations, and to what degree it should interfere with operations of convenience not essential for the prolonging or saving life.”
During the 20th century, this point was not lost on the great pioneering anesthesiologists on both sides of the Atlantic. In the United States, Turville and Dripps6 reported 7% of aged patients were irrational after an operation. Papper7 wrote “it must also be mentioned that postoperative psychosis is among the important complications of both spinal and general anesthesia in aged patients. …subtle changes after surgical procedures suggest that grandfather is not the same after his prostatectomy.”
In the 1950s, these speculations led to a more scientific approach. Bedford8 used retrospective analysis of elderly patients asking relatives (and other informants) for their subjective assessment of cognitive decline after surgery. Of 251 patients receiving general anesthesia, 18 (7%) met criteria for dementia which was determined to be a consequence of the general anesthesia, but this only included the most obvious and most severe cases of dementia. Simpson et al9 undertook a large comprehensive study to explore this issue in detail. Nonsurgical in-hospital controls showed a tendency to deterioration which was not seen in the surgical group. They did note, however, that because of the limitations of the mental tests, minor degrees of mental impairment may have passed unnoticed. If mental changes did occur, the prevailing explanation at the time was that these changes were the consequence of cerebral hypoxia related to the anesthetic and that cerebral vascular disease in the elderly was an important factor.
INTRODUCTION OF THE TERM POCD
The introduction of cardiopulmonary bypass for coronary artery surgery in the 1960s, a surgery performed predominantly in the elderly, focused attention on postsurgical psychiatric complications.10 , 11 The practice of using a number of cognitive tests administered before and after surgery and arbitrarily defining a cutoff for the significant decline on a minimum number of tests became the model on which many studies were based. By the late 1980s, this practice had led to the concept of POCD,12 a construct defined when patients do not return to baseline cognition as determined by a battery of neuropsychological test scores.
Although analysis of group data (using pooled cognitive results) provides more robust statistical analysis than individual analysis, it does not identify particular individuals who decline and thus fails to allow identification of characteristics of these individuals and thus identify predictors of decline. This is important because certain individuals may decline and be concealed in group data preventing risk factors from being identified.
On the other hand, individual analysis has been beleaguered by a variety of different criteria for defining POCD, leading to great heterogeneity of cognitive tests and test batteries. The Mini-Mental State Examination13 was essentially developed as a cognitive screening tool and consists of 20 individual tests spanning 11 domains and totaling 30 points. Although it performs well as a screening tool for dementia (rule out), it is limited by both floor and ceiling effects, has poor sensitivity for detecting mild cognitive impairment (MCI), and is inappropriate for assessing cognitive decline after anesthesia and surgery.14 Despite this, it has been widely used as a tool to detect POCD, no doubt the ease of administration (6–8 minutes) being a major attraction.
To adequately describe cognitive decline after anesthesia and surgery, it is essential to have a cognitive assessment both before and afterward to detect change. The degree of change and cut-offs for defining deficit has also been a source of variability. In the absence of a control group, early investigations often used a decline of ≥1 standard deviation (SD; from mean baseline score in each test) as a cutoff in a cognitive test. In response to calls for appropriate control groups,15 , 16 investigators began to use controls to account for both known and unknown confounders. When control groups were used, the calculation of decline was often referenced to the expected change in the control group using one of several formulae for the reliable change index (RCI).17 A variety of inconsistencies has complicated the calculation of POCD. These include the type and number of neuropsychological tests used in the cognitive test battery (Table), variability in the number of tests administered, and the number of tests required for decline to classify an individual with POCD.18 Additionally, the timing of postoperative testing after noncardiac surgery has ranged from within 24 hours after surgery19 to 12 months.20 In general, 3-month testing has been taken as a time point in which the acute effects of hospitalization, anesthesia, and surgery have abated and thus cognitive testing at this time point gives a true indication of the current state. In an attempt to encourage some consistency, a Consensus Statement of experts was published in 1995.15 Several neuropsychological tests were recommended, and importantly, the basic principles for perioperative cognitive testing were well espoused.
Most studies refer to an incidence at each time point but fail to describe whether the same patients classify at each time point or whether some improve, and others decline. Thus, while some patients may satisfy criteria for POCD at 7 days, they may not at 3 or 12 months, or they may fluctuate between time points. This is similar to the fluctuating nature of cognitive decline described in the general medical community wherein individuals identified as cognitively impaired may subsequently revert to normal at a later time. However, longitudinal assessment has revealed that even with this fluctuating pattern, a single diagnosis of cognitive decline is associated with a higher incidence of long-term dementia.21 , 22 While cognitive improvement has been documented after cardiac surgery,23 and in population studies,21 , 24 longitudinal cognitive improvement after noncardiac surgery has been mostly overlooked.
POCD EMERGES AS A UNIQUE CONSTRUCT
In 1998, investigators revisited the earlier anecdotal descriptions of cognitive change after noncardiac anesthesia which had been observed by the early anesthesiologists (vide supra). A large multicentre trial was undertaken by the International Study of PostOperative Cognitive Dysfunction (ISPOCD) group.25 Over 1000 patients (>60 years) undergoing a variety of major noncardiac surgeries were tested with a comprehensive neuropsychological test battery both before and after surgery. A form of RCI using Z scores was used to robustly assess POCD. POCD was defined when the Z score on 2 or more tests or the combined Z scores was below −1.96 SD. Cognitive dysfunction was found in 25.8% (95% CI, 23.1–28.5) of patients 1 week after surgery and in 9.9% (95% CI, 8.1–12.0) 3 months after surgery, compared with 3.4% and 2.8%, respectively, of the UK controls (P < .0001 and P = .0037, respectively). Age showed the strongest association with cognitive dysfunction. This trial was important for a number of reasons.
- It established that objective cognitive dysfunction as determined by a battery of neuropsychological testing was present in nearly 10% of elderly individuals at 3 months after noncardiac surgery.
- Because both perioperative blood pressure and hypoxemia were monitored continually, these time-honored physiological perturbations were eliminated as the cause of POCD.
- The study found associations of POCD with increasing age and fewer years of education, 2 factors that have been repeatedly associated with cognitive decline in the wider community.
These findings after noncardiac surgery were later confirmed by Monk et al.26 They investigated 365 patients (>60 years) undergoing noncardiac surgery using a similar study design to the ISPOCD group. They found an incidence of POCD of 41.4% (95% CI, 36.2–46.7) at discharge and 12.7% (95% CI, 8.9–16.4) at 3 months. Again age and fewer years of education were associated with POCD. An additional finding was that patients with POCD at hospital discharge were more likely to die in the first 3 months after surgery, while those with POCD at discharge and 3 months were more likely to die in the first year after surgery. This was the first clinical implication for a construct which had, up to that time, been restricted to research findings.
The occurrence of POCD after noncardiac surgery indicated factors at play within the anesthesia and surgery process which were not related to either cardiac surgery or CPB as had been the prevailing concept until that time. This was further supported when it was shown that for cardiac surgery, the incidence of POCD after off-pump surgery was not significantly different from on-pump surgery.27–30 Further studies by Selnes et al31 indicated that the cognitive dysfunction after cardiac surgery is of a similar incidence to individuals with coronary artery disease who undergo percutaneous interventions (coronary angioplasty), and noncardiac surgery or coronary angiography,32 providing confirmatory evidence that cardiac surgery is not the culprit but rather suggesting that cardiovascular disease or modest interventional procedures may contribute to cognitive decline. The accumulated evidence now strongly indicates that cardiac surgery, rather than directly causing POCD as a result of CPB, may have been linked to POCD by virtue of the patients being elderly, having cardiovascular disease and being subjected to the trauma of surgery or an invasive procedure.
UNIQUE ASPECTS OF POCD
It should be remembered that the concept of POCD relies solely on the outcome of the neuropsychological testing, but with no uniformity on the methods used to measure this. Moreover, the tests used were never specifically designed for repeated administration, and the criteria for classification are arbitrary without clinical correlation. Sources of variability in deriving POCD are shown in the Table. The construct has been confined to research and has not made its way into clinical practice. Nevertheless, some research has described important clinical consequences associated with POCD. Phillips-Bute et al33 found that decline in cognitive function was associated with a decrease in quality of life at 1 year after cardiac surgery. Steinmetz et al34 found that individuals with POCD at 3 months after noncardiac surgery were at increased risk of mortality, risk of leaving the labor market prematurely, and dependency on social transfer payments34; and importantly POCD has been associated with increased mortality after both noncardiac35 and cardiac surgery.36
Despite these observations, POCD does not appear in the International Classification of Diseases or Diagnostic and Statistical Manual of Mental Disorders (DSM); indeed outside the fields of anesthesiology and surgery, it has received little attention. Too often, the focus of POCD has been in the detail of how the construct is derived and calculated, rather than recognizing the overarching concept of subtle cognitive decline which may exist before, and/or evolve or worsen after, anesthesia and surgery.
Newman et al37 comprehensively reviewed POCD after noncardiac surgery. Forty-six articles satisfied the inclusion criteria of which 20 were observational with single group or controlled studies, 17 compared regional and general anesthesia, and 9 compared a particular aspect which was thought to influence cognitive outcome. This review highlighted “major differences in the surgery, participants, the diversity in the number and range of neuropsychological tests used with varying sensitivity to change and learning, and the variety of definitions used to classify POCD.” Most of the studies were underpowered. Despite these caveats, the review concluded that POCD was present in a significant proportion of people in the early weeks after major noncardiac surgery, with the elderly being most at risk.
To ascertain the true incidence of POCD after noncardiac surgery, Paredes et al38 more recently undertook a systematic review restricting inclusion criteria to studies which had used an acceptable and appropriately administered neuropsychological test battery before and at 3 months after surgery with general or regional anesthesia. Nineteen studies used individual analysis of neurocognitive testing thus allowing for an incidence calculation of POCD of 11.7% (95% CI, 10.9–12.5).
Although the incidence of POCD at 3 months is well established, the incidence at longer time intervals remains controversial. The longest time point in which POCD for noncardiac surgery has been measured is 12 months. Abildstrom et al39 found an incidence of POCD of 10.4% (95% CI, 7.2%–13.7%) which did not differ significantly from normal controls 10.6% (95% CI, 11.8%–19.4%). Silbert et al20 also found no difference in POCD between postsurgical patients and nonsurgical controls at 12 months. To date, there is no prospective long-term follow-up >12 months in individuals after noncardiac surgery.
These results suggest that the incidence of POCD may be a transitory phenomenon identifiable at 3 months which becomes indistinguishable from the nonsurgical population at 12 months. It is important to note that because POCD is a rigidly defined construct, the absence of detection at 12 months does not strictly exclude subtle cognitive decline defined by other methods40; nor does the lack of a significant incidence when compared against control patients signify that cognitive decline has not occurred. This is because a certain percentage of the elderly population is likely to experience a decrease in cognitive function and thus both the surgical population and the controls may both decline at 12 months.20 , 39 The question of whether the anesthesia surgical process has exacerbated this decline is unknown. Regardless of whether anesthesia and surgery have exacerbated long-term cognitive decline, there remains a significant prevalence of cognitive decline in the elderly population, many of whom have coincidentally undergone anesthesia and surgery. Identifying whether this cognitive decline is related to prior anesthesia and surgery has not been investigated. Verifying or refuting this may prove difficult as the vast majority of individuals over the age of 40 years have received general anesthesia and surgery. Sprung et al41 noted 84.7% of subjects in a population study in the United States had received anesthesia and surgery since age 40 years, which would make finding an age-matched control group who have not undergone anesthesia and surgery difficult.
Although the prospect of long-term cognitive decline after cardiac surgery has been the subject of dispute,36 , 42 , 43 there is little information on the long-term cognitive decline after noncardiac surgery. No prospective study tracking cognition >12 months after noncardiac surgery has been documented. An association between anesthesia and surgery and long-term cognitive decline is unresolved. There has been no large prospective study which has examined this question. The conclusions of retrospective studies are mixed. While Sprung et al44 and Avidan et al45 found no association with long-term cognitive decline, Schenning et al46 found surgery and anesthesia was a risk factor. A meta-analysis by Seitz et al47 failed to show an association between anesthesia and surgery and subsequent Alzheimer dementia but recognized the paucity of good prospective studies.
COMPARING POCD WITH OTHER TERMINOLOGY OF COGNITIVE DECLINE
Perhaps one of the most intriguing aspects of POCD is the unique manner in which it has developed within the fields of anesthesia and surgery as a research construct with little interaction with clinical, cognitive sciences in the nonsurgical population. From a research perspective, POCD represents subtle cognitive decline detectable only by neuropsychological tests. Within the field of geriatric psychiatry, such subtle cognitive deficits were being described in the elderly general population in the 1980s and 1990s in parallel, but completely independently of POCD.48–50 Furthermore, the recognition that POCD is an entity confined to anesthesia and surgery with little acknowledgment in the wider medical community prompted calls to invoke the terminology used for cognitive impairment in geriatric psychiatry, neurology, and gerontology. Although a variety of terminology was used in geriatric medicine in the early stages,48 , 49 , 51 , 52 the term MCI has gradually become recognized as representing a transitional state between normal cognition and dementia in the elderly. The current definition of MCI according to the National Institute of Aging and Alzheimer Association53 includes the following 4 factors:
- Cognitive concern reflecting a change in cognition reported by patient or informant or clinician (ie, historical or observed subjective evidence of decline over time).
- Objective evidence of impairment in 1 or more cognitive domains, typically including memory (ie, formal or bedside testing to establish level of cognitive function in multiple domains).
- Preservation of independence in functional abilities.
- Not demented.
This definition closely follows that of DSM-5 which uses the term mild NCD to describe a similar impairment.54
Although the domain of memory (amnestic) MCI is thought to be predictive of Alzheimer disease (AD), other cognitive domains or multiple cognitive domains may also be impaired. In fact, MCI of any domain indicates an increased likelihood of further cognitive decline, most commonly due to AD, but also due to vascular dementia, and other rarer causes or combinations. The importance of MCI is that it may indicate the earliest clinical feature of dementia. Although in some individuals with MCI cognition may improve over time, remain the same or even fluctuate, cognition will eventually decline in the majority of individuals. Those with MCI over the age of 70 years progress to dementia at 14%–18% per year compared to a conversion rate of 1%–2% per year for those with normal cognition.55
There are similarities between MCI and POCD but also distinctions. First, MCI measures a cross-sectional state in time rather than change, although if circumstances permit, change in cognition is the preferred measurement in geriatric psychiatry (DSM-5).54 Second, both measure objective decline, although the criteria for change in POCD have been variable. Rudolph et al56 reviewed methods of ascertaining POCD after cardiac surgery. Four definitions of POCD emerged: percent decline (n = 15), SD decline (n = 14), factor analysis (n = 13), and analysis of performance on individual tests (n = 12). Because of variability in its measurement, the prevalence of POCD varied by over 10-fold across studies. A commonly used method, RCI (1.96 SD decline on 2 or more tests) is far stricter than that which is required for MCI (1.5 SD decline below norms in only 1 cognitive test). Finally, MCI requires a subjective decline reported by the individual or informant and consideration of any change in the functional status of the individual. Very few studies on POCD have published subjective decline and there has been no systematic examination of the impact of subjective memory decline, an important factor in prognosticating the long-term outcome of MCI. Subjective memory impairment is a good indicator of cognitive decline57 and its omission from the POCD construct may have limited the utility as a predictor for future decline. Regardless of these differences, the basic concept of both constructs of POCD and MCI convey the same state—subtle cognitive decline detectable by objective neuropsychological testing. Further, clinical data repeatedly show associations with increasing age, poor preoperative cognition, and fewer years of education (or IQ) for POCD, the same factors associated with progressive cognitive decline in the nonsurgery population.
However, here the constructs diverge. MCI is a clinically relevant diagnosis because it broadly predicts a decline in cognitive function over the following years.55 In the majority of cases, cognition eventually deteriorates to the point that the individual can be classified with dementia. Dementia, in contrast to the subtle cognitive decline of MCI, is marked by greater decrease in cognition on objective testing, but in addition, the cognitive deficits are advanced to the point where they interfere with daily function.55 , 58
In contrast to MCI, the long-term outcome of POCD after noncardiac surgery is not well known. Longitudinal assessment of POCD, while of interest, provides limited information because POCD still remains the result of cognitive testing with no clinical correlate. The important questions which need to be answered are: if POCD is associated with poor clinical or functional recovery in the long term, and second, if POCD predicts progressive cognitive decline ultimately leading to dementia.
A UNIFIED NOMENCLATURE OF COGNITIVE DECLINE
While POCD and MCI are both measures of subtle cognitive impairment, the discrepancies between them are problematic. POCD has been used primarily as a research construct confined to the anesthesia and surgical specialties with little clinical application. MCI, on the other hand, has found increasing clinical utility as a primary marker of subtle cognitive impairment in the clinical arena in geriatric medicine.24 Considering the prevalence of cognitive decline in the community and the increasing numbers of the elderly presenting for surgery, it would seem opportune to align the classification and terminology used within the fields of anesthesia and surgery (in particular POCD) with that used by the wider medical community, particularly, geriatric psychiatry, gerontology, and neurology. This would provide a number of benefits:
- The terminology would incorporate a clinical entity rather than a research-based definition.
- The terminology would allow cross-talk between specialties, no longer isolating POCD as a term purely confined to anesthesia and surgery.
- The terminology would indicate prognosis as determined by other areas of cognitive research.
- The terminology would allow an indication of severity consistent with other classification systems.
Recognizing the advantages of unifying the terminology, a multidisciplinary international working group was established in 2015 with the aim of incorporating the nomenclature for cognitive decline used in other disciplines into the perioperative period.1
Currently, there are 2 major sources of classification of cognitive impairment in the community. The National Institute for Aging and Alzheimer Association uses the terms MCI and dementia to signify mild and more severe cognitive impairment, respectively.59 These terms follow closely those used in the DSM-554 which uses the terms mild NCD and major NCD to signify similar conditions. Both classification systems encompass objective neurocognitive testing, subjective or informant complaints and assessment of activities of daily life. Redefining POCD using these established definitions will unify the terminology used in anesthesia and surgery with that used in the wider medical community, providing clinical meaning and help with prognosis.
Standardization of definitions will not only provide clinical advantages but enhance research by providing standardized terms and thus allow comparisons between studies (an issue which has been extremely difficult with POCD because of variable definitions and criteria).
The recommendations of the working group were accepted for publication in Anesthesia & Analgesia (concurrently with 5 other journals) in 2018.1 These recommend the term “perioperative neurocognitive disorders” as an overarching term for POCD.1
It should be noted that the comprehensive classification of NCDs describes syndromic entities followed by diagnostic criteria for different etiological subtypes. NCDs which persist after anesthesia and surgery (after a time period which has allowed for the acute effects to resolve) would carry the descriptor “postoperative” to indicate the temporal association with anesthesia and surgery.
It will be interesting to reclassify patients using the new terminology and see how these classifications parallel the natural history of cognitive impairment in the general community or whether cognitive impairments in the surgical arena have a different course.
Although a temporal relationship to anesthesia and surgery can be identified, this does not in any way imply causation. The exact cause of cognitive decline after anesthesia and surgery remains unknown, but logic would indicate that this could result from the anesthesia, the surgery, the patient, or a combination of these. Perhaps the biggest impetus for investigating this area derived from the realization that cognitive decline after anesthesia and surgery was not the direct consequence of physiological perturbations such as hypoxemia and hypotension. Inadequate supply of oxygen to the brain had been historically taken as the sine qua non, by which all poor cerebral outcomes are derived. Certainly, poor cerebral oxygenation will most definitely lead to poor cerebral and cognitive outcomes, but it has become increasingly clear that cognitive decline after anesthesia and surgery in the elderly most often develops in the absence of cerebral hypoxemia. This issue was finally settled when the ISPOCD study monitored perioperative blood pressure and oxygenation and showed that POCD occurred in the absence of perioperative hypoxemia or hypotension.25
Because the target organ of all anesthetic agents is the brain, anesthetic agents have been circumstantially implicated. There have been conflicting claims of better outcomes with sevoflurane and propofol,60 , 61 but there is at present no convincing evidence that a specific general anesthetic, either intravenous or volatile, leads to POCD more than any other. Furthermore, because POCD may occur in the absence of centrally acting drugs,62 it seems unlikely that centrally acting anesthetic agents are the sole causative factor.
Clinical studies of POCD after noncardiac surgery have provided some useful clues as to the etiology. Most studies of POCD after noncardiac surgery have included those >60–65 years of age undergoing major surgery (eg, joint arthroplasty or abdominal surgery). The rationale has been that if major surgery such as cardiac surgery induced POCD, then it was likely that other major noncardiac surgery would also lead to POCD. Indeed, it has now been shown that the 3-month incidence of POCD is similar for cardiac surgery, joint arthroplasty, and cardiac angiography, an investigative procedure performed under oral or intravenous sedation in the absence of general anesthesia.32 A similar incidence is also seen when joint arthroplasty is performed under regional anesthesia with sedation.63 These clinical findings infer that general anesthesia is unlikely to be the sole cause of POCD and other factors must be involved. Such factors may include the effect of the inflammatory response resulting from the surgery and patient vulnerability.
A current theory which implicates surgery as a cause of POCD posits that the inflammatory response to anesthesia and surgery in susceptible individuals may account, at least in part, for POCD. Animal models directly implicate inflammation as a cause of POCD.64 , 65 Proinflammatory cytokines are released after surgery into the systemic circulation and these have been shown to directly affect the central nervous system leading to neuroinflammation. Molecular mechanisms involving damage-associated molecular patterns such as the high mobility group box chromosomal protein 1 and cytokines appear to initiate the response to surgical trauma which leads to neuroinflammation and subsequent cognitive decline.66
Eckenhoff and Laudansky67 have likened this to “a mine that has been fused and is lying in wait.” The trigger, in this case, is the occurrence of an acute peripheral inflammatory event such as surgery, infection, or illness.67 Clinically, it is well recognized that pneumonia, urinary tract infection, and other inflammatory processes cause cognitive deterioration in the elderly who have AD.68–70 Expansion of this model to the inflammatory response to surgery is a reasonable extension. Such a hypothesis would be well supported by testing for POCD or further cognitive decline in individuals who already have MCI or early-stage AD. Unfortunately, most studies of POCD have excluded individuals with poor baseline cognition, thus excluding every patient who may be susceptible to further cognitive decline.
An individual’s response may be exacerbated by an underlying vulnerability signaled by markers of an already declining cognitive function.40 , 71 Patient susceptibility may encompass those pathologies which lead to cognitive decline independent of anesthesia or surgery. The 2 most common are AD and vascular pathology. The recent expansion of our understanding of AD recognizes that the disease has 3 phases59:
- A preclinical phase (detected only by biomarkers in the cerebrospinal fluid or positron emission tomography scanning of the brain with radioligands).
- An early clinical phase characterized by subtle cognitive impairment and a subjective complaint by the individual or an informant.
- Late clinical phase (dementia).
Individuals in the first 2 stages are unlikely to be recognizable on routine preoperative assessment. However, the presence of AD biomarkers in the cerebrospinal fluid has been shown to be linked to POCD at 3 months,71 lending support to patient susceptibility being an important element in the etiology of POCD. These clinical observations have been supported by a number of laboratory studies which implicate AD-like processes in the etiology of POCD. A comprehensive review entitled “Influence of Anesthetics on Alzheimer’s Disease: Biophysical, Animal Model, and Clinical Reports” was published by Silverstein.72
The part played by vascular pathology may also be highly relevant. Vascular dementia is not a single entity but arises from a wide variety of impairments in the cerebrovascular circulation. These can include large vessel disease leading to single or multiple strokes, lacunar infarcts, microinfarcts, and diffuse subcortical small vessel disease. The exact correlation between vascular disease and the manifestation of cognitive impairment is not known. However, vascular cognitive impairment is recognized as an early stage of cognitive decline which may progress to dementia over the longer term, following a course which may mimic the slow deterioration of cognitive function in AD.73 Vascular pathology frequently appears in conjunction with AD pathology (mixed dementia) and has also been reported to exacerbate AD pathology.74 Many elderly patients carry multiple risk factors for cardiovascular disease or clinical cardiovascular disease and thus separating these 2 pathologies becomes extremely difficult.
Recently, it has been reported that 2 biomarkers of neuronal injury, neurofilament light and tau, are increased in plasma after anesthesia and surgery.75 , 76 Although this finding does not directly implicate a causal factor, it confirms that the process of anesthesia and surgery is not benign and that the CNS may be damaged during the process. Although it is too early to link this damage to cognitive outcomes, the use of these plasma biomarkers may offer a convenient tool to study perioperative NCD in the future.
Decreasing both the magnitude and incidence of POCD (NCD-postoperative) remains an important challenge for anesthesiology. For noncardiac surgery, there has been a dearth of research aimed at improving outcomes. Most studies have been descriptive in nature and at best have sought associations with POCD but have not studied approaches to actually improve cognitive outcomes. This may be the consequence of the inconsistency in assessing cognitive outcomes making it difficult to identify improvements, although group comparisons rather than individual comparisons would reduce this difficulty. At this point in time, there has been no convincing evidence that a particular anesthetic agent, either volatile or intravenous, leads to worse POCD61 , 77–80; so, our current understanding is the choice of anesthetic agent does not impact on POCD outcomes. Chan et al81 found that depth of anesthesia (monitored by bispectral index [BIS]) may be associated with a higher incidence of POCD at 3 months,81 but Radtke et al82 were unable to confirm this. Studies in animal models suggest that blocking the inflammatory process may improve postoperative cognition,65 but there are no studies in man. We cannot find any studies which examine the effect of neuroprotective agents on POCD after noncardiac surgery. There have been several studies examining the neuroprotective effects of a number of pharmacological agents during cardiac surgery, targeting a diverse range of mechanisms including blunting the inflammatory response, but none has proved useful.83–89
Without a suitable pharmacological intervention to decrease POCD, options for improving outcomes are limited. Treatments for cognitive decline such as MCI or dementia in the general population rely on improving lifestyle and limiting risk factors.
These have demonstrated that effective strategies on reducing symptoms and delaying the onset of cognitive decline in the community are multidomain interventions which have the ability to improve or maintain cognition.90 Seven key modifiable risk factors have been identified (diabetes mellitus, hypertension, obesity, smoking, depression, cognitive inactivity, and physical inactivity) which account for approximately 50% of all AD.91 Several proof-of-concept randomized controlled studies have been undertaken to develop population-level interventions with positive results. Five intervention components have been identified (nutrition, physical exercise, cognitive training, management of vascular and metabolic risk factors, and stimulation of social engagement) demonstrating a significant effect on overall cognition.92 However, we are not aware of any investigations examining these lifestyle interventions for prevention of POCD.
Pharmacological treatments are used with limited success for cognitive decline in the general population. These include a number of cholinesterase inhibitors (Aricept, Exelon, Razadyne) and the NMDA receptor antagonist memantine (Namenda). We cannot find any reports of these being used perioperatively to decrease POCD.
CHALLENGES FOR THE FUTURE
Incorporation of the terminology recommended by the International Nomenclature Consensus Working group1 will greatly enhance our understanding of cognitive decline after anesthesia and surgery by unifying the terminology used outside the fields of anesthesia and surgery. This will enable research in geriatrics, geriatric psychiatry, and neurology to be directly transferable to the context of anesthesia and surgery. It will remove the construct of POCD from the lexicon and replace it with terms which have direct clinical significance. Importantly, this will enable longitudinal studies to ascertain if the cognitive decline after anesthesia and surgery follows the same trajectory as population cognitive decline or whether there is an increase decline or even an initiation of decline which was not previously present. Understanding the relationship of perioperative NCD to MCI and dementia as encountered in the general population is essential to tell us if we are dealing with population cognitive decline in a different context or whether the anesthesia and surgery initiate or exacerbate cognitive decline via a different mechanism. This essential question is a fork in the road. If we are dealing with MCI and dementia but purely in a different context, then anesthesia and surgery can join forces with those of other medical disciplines, which are currently trying desperately to confront cognitive decline in the general population. If perioperative NCD derives from mechanisms linked to solely to anesthesia and surgery, then the challenge for these disciplines is to define the exact etiology. This would allow the process of anesthesia and surgery to be tailored to minimize cognitive decline and even introduce pharmacological therapies targeting the mechanism.
In summary, POCD has been used primarily as a research tool but has played a major role in drawing attention to the subtle cognitive decline in the elderly after anesthesia and surgery. The subtle cognitive decline, such as MCI or mild NCD, is now recognized as a harbinger of further cognitive deterioration which may ultimately lead to dementia. It is unclear if the subtle decline of POCD is also associated with further cognitive deterioration or dementia. The incidence of POCD in the elderly at 3 months after noncardiac anesthesia and surgery is approximately 12%38–21%,32 but there is little information if these individuals suffer further cognitive decline over the longer term as a result of the anesthesia and surgery. It would seem appropriate for the criteria defining POCD, which have been enormously variable, to incorporate the elements used to define MCI or NCD and consequently allow any association between POCD and prior cognitive impairment or future cognitive outcome to be determined.
The etiology of perioperative cognitive disorders is almost certainly not due to cerebral hypoxemia, but despite extensive investigations, our understanding of the etiology still remains largely speculative. Without definitive mechanisms, preventative measures must still rely on nonspecific approaches used to decrease delirium and optimize cognition in general. The recent finding that anesthesia and surgery may increase biomarkers of neuronal injury may offer a new approach to limit neuronal injury and perhaps improve cognitive outcomes.
As the aging population present in ever increasing numbers for surgery, many individuals with overt or subclinical dementia require anesthesia. Anesthesiologists must be equipped to understand and manage these patients. Anesthesiologists rose to the challenge of pervasive coronary heart disease in the 1980s, with a depth of understanding and formulated strategies to enhance management. It now behooves the specialty to deal with cognitive decline and dementia in the same manner. At the present time, we do not have proven anesthetic or surgical strategies to minimize cognitive impact. There is a dire need for both preclinical and clinical studies to investigate techniques which would minimize such impact.
Name: Lisbeth A. Evered, PhD.
Contribution: This author helped with the conception of the narrative review, undertook the literature review, analyzed the data, wrote and edited the review.
Name: Brendan S. Silbert, MB, BS.
Contribution: This author helped with the conception of the narrative review, undertook the literature review, analyzed the data, wrote and edited the review.
This manuscript was handled by: Robert Whittington, MD.
1. Evered L, Silbert B, Knopman D, et al; the Nomenclature Consensus Working Group. Recommendations for the nomenclature of cognitive change associated with anesthesia and surgery-2018. BJA. 2017. In press.
2. Berger M, Terrando N, Smith SK, et al. Neurocognitive function after cardiac surgery: from phenotypes to mechanisms. Anesthesiology. 2018 [Epub ahead of print].
3. Kain ZN, Fitch JC, Kirsch JR, Mets B, Pearl RG. Future of anesthesiology is perioperative medicine: a call for action. Anesthesiology. 2015;122:1192–1195.
4. Fleisher LA. Brain health initiative: a new ASA Patient Safety Initiative. ASA Newsletter. 2016;80:10–11.
5. Savage GH. Insanity following the use of anaesthetics in operations. BMJ. 1887;3:1199–200.
6. Turville CS, Dripps RD. The anesthetic management of the aged. Pa Med J. 1948;51:434–436.
7. Papper EM. Anesthesia in the aged. Bull N Y Acad Med. 1956;32:635–642.
8. Bedford PD. Adverse cerebral effects of anaesthesia on old people. Lancet. 1955;269:259–263.
9. Simpson BR, Williams M, Scott JF, Smith AC. The effects of anesthesia and elective surgery on old people. Lancet. 1961;2:887–893.
10. Kornfeld DS, Zimberg S, Malm JR. Psychiatric complications of open-heart surgery. N Engl J Med. 1965;273:287–292.
11. Blundell E. A psychological study of the effects of surgery on eighty-six elderly patients. Br J Soc Clin Psychol. 1967;6:297–303.
12. Shaw PJ, Bates D, Cartlidge NE, et al. Neurologic and neuropsychological morbidity following major surgery: comparison of coronary artery bypass and peripheral vascular surgery. Stroke. 1987;18:700–707.
13. Folstein MF, Folstein S, McHugh P. The Mini-Mental State Examination. J Psychiat Res. 1975;12: 189–198.
14. Mitchell A. Larner AJ. The Mini-Mental State Examination (MMSE): update on its diagnostic accuracy and clinical utility for cognitive disorders. In: Cognitive Screening Instruments. 2017.Cham, Switzerland: Springer International Publishing;
15. Murkin JM, Newman SP, Stump DA, Blumenthal JA. Statement of consensus on assessment of neurobehavioral outcomes after cardiac surgery. Ann Thorac Surg. 1995;59:1289–1295.
16. Selnes OA, Royall RM, Grega MA, Borowicz LM Jr, Quaskey S, McKhann GM. Cognitive changes 5 years after coronary artery bypass grafting: is there evidence of late decline? Arch Neurol. 2001;58:598–604.
17. Lewis MS, Maruff P, Silbert BS, Evered LA, Scott DA. The influence of different error estimates in the detection of post-operative cognitive dysfunction using reliable change indices with correction for practice effects. Arch Clin Neuropsychol. 2006;21:421–427.
18. Lewis MS, Maruff P, Silbert BS, Evered LA, Scott DA. Detection of postoperative cognitive decline after coronary artery bypass graft surgery is affected by the number of neuropsychological tests in the assessment battery. Ann Thorac Surg. 2006;81:2097–2104.
19. Silbert BS, Scott DA, Doyle TJ, et al. Neuropsychologic testing within 18 hours after cardiac surgery. J Cardiothorac Vasc Anesth. 2001;15:20–24.
20. Silbert B, Evered L, Scott DA, et al. Preexisting cognitive impairment is associated with postoperative cognitive dysfunction after hip joint replacement surgery. Anesthesiology. 2015;122:1224–1234.
21. Roberts RO, Knopman DS, Mielke MM, et al. Higher risk of progression to dementia in mild cognitive impairment cases who revert to normal. Neurology. 2014;82:317–325.
22. Lopez OL, Becker JT, Chang YF, et al. Incidence of mild cognitive impairment in the Pittsburgh Cardiovascular Health Study-Cognition Study. Neurology. 2012;79:1599–1606.
23. Fontes MT, Swift RC, Phillips-Bute B, et al; Neurologic Outcome Research Group of the Duke Heart Center. Predictors of cognitive recovery after cardiac surgery. Anesth Analg. 2013;116:435–442.
24. Petersen RC, Caracciolo B, Brayne C, Gauthier S, Jelic V, Fratiglioni L. Mild cognitive impairment: a concept in evolution. J Intern Med. 2014;275:214–228.
25. Moller JT, Cluitmans P, Rasmussen LS, et al. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancet. 1998;351:857–861.
26. Monk TG, Weldon BC, Garvan CW, et al. Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology. 2008;108:18–30.
27. Van Dijk D, Jansen EW, Hijman R, et al; Octopus Study Group. Cognitive outcome after off-pump and on-pump coronary artery bypass graft surgery: a randomized trial. JAMA. 2002;287:1405–1412.
28. Marasco SF, Sharwood LN, Abramson MJ. No improvement in neurocognitive outcomes after off-pump versus on-pump coronary revascularisation: a meta-analysis. Eur J Cardiothorac Surg. 2008;33:961–970.
29. Sun JH, Wu XY, Wang WJ, Jin LL. Cognitive dysfunction after off-pump versus on-pump coronary artery bypass surgery: a meta-analysis. J Int Med Res. 2012;40:852–858.
30. Selnes OA, Grega MA, Borowicz LM Jr,, et al. Cognitive outcomes three years after coronary artery bypass surgery: a comparison of on-pump coronary artery bypass graft surgery and nonsurgical controls. Ann Thorac Surg. 2005;79:1201–1209.
31. Selnes OA, Grega MA, Borowicz LM Jr, Royall RM, McKhann GM, Baumgartner WA. Cognitive changes with coronary artery disease: a prospective study of coronary artery bypass graft patients and nonsurgical controls. Ann Thorac Surg. 2003;75:1377–1384.
32. Evered L, Scott DA, Silbert B, Maruff P. Postoperative cognitive dysfunction is independent of type of surgery and anesthetic. Anesth Analg. 2011;112:1179–1185.
33. Phillips-Bute B, Mathew JP, Blumenthal JA, et al. Association of neurocognitive function and quality of life 1 year after coronary artery bypass graft (CABG) surgery. Psychosom Med. 2006;68:369–375.
34. Steinmetz J, Christensen KB, Lund T, Lohse N, Rasmussen LS; ISPOCD Group. Long-term consequences of postoperative cognitive dysfunction. Anesthesiology. 2009;110:548–555.
35. Monk TG, Saini V, Weldon BC, Sigl JC. Anesthetic management and one-year mortality after noncardiac surgery. Anesth Analg. 2005;100:4–10.
36. Evered LA, Silbert BS, Scott DA, Maruff P, Ames D. Prevalence of dementia 7.5 years after coronary artery bypass graft surgery. Anesthesiology. 2016;125:62–71.
37. Newman S, Stygall J, Hirani S, Shaefi S, Maze M. Postoperative cognitive dysfunction after noncardiac surgery: a systematic review. Anesthesiology. 2007;106:572–590.
38. Paredes S, Cortínez L, Contreras V, Silbert B. Post-operative cognitive dysfunction at 3 months in adults after non-cardiac surgery: a qualitative systematic review. Acta Anaesthesiol Scand. 2016;60:1043–1058.
39. Abildstrom H, Rasmussen LS, Rentowl P, et al. Cognitive dysfunction 1-2 years after non-cardiac surgery in the elderly. ISPOCD group. International Study of Post-Operative Cognitive Dysfunction. Acta Anaesthesiol Scand. 2000;44:1246–1251.
40. Evered LA, Silbert BS, Scott DA, Maruff P, Ames D, Choong PF. Preexisting cognitive impairment and mild cognitive impairment in subjects presenting for total hip joint replacement. Anesthesiology. 2011;114:1297–1304.
41. Sprung J, Roberts RO, Knopman DS, et al. Association of mild cognitive impairment with exposure to general anesthesia for surgical and nonsurgical procedures: a population-based study. Mayo Clin Proc. 2016;91:208–217.
42. Avidan MS, Evers AS. Review of clinical evidence for persistent cognitive decline or incident dementia attributable to surgery or general anesthesia. J Alzheimers Dis. 2011;24:201–216.
43. Avidan MS, Evers AS. The fallacy of persistent postoperative cognitive decline. Anesthesiology. 2016;124:255–258.
44. Sprung J, Jankowski CJ, Roberts RO, et al. Anesthesia and incident dementia: a population-based, nested, case-control study. Mayo Clin Proc. 2013;88:552–561.
45. 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;111:964–970.
46. Schenning KJ, Murchison CF, Mattek NC, Silbert LC, Kaye JA, Quinn JF. Surgery is associated with ventricular enlargement as well as cognitive and functional decline. Alzheimers Dement. 2016;12:590–597.
47. Seitz DP, Shah PS, Herrmann N, Beyene J, Siddiqui N. Exposure to general anesthesia and risk of Alzheimer’s disease: a systematic review and meta-analysis. BMC Geriatr. 2011;11:83.
48. Crook T, Bartus R, Ferris S, Whitehouse P, Cohen GD, Gershon S. Age-associated memory impairment: proposed diagnostic criteria and measures of clinical change - report of a National Institute of Mental Health Workgroup. Develop Neuropsychol. 1986;2:261–276.
49. Graham JE, Rockwood K, Beattie BL, et al. Prevalence and severity of cognitive impairment with and without dementia in an elderly population. Lancet. 1997;349:1793–1796.
50. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56:303–308.
51. Richards M, Touchon J, Ledesert B, Richie K. Cognitive decline in ageing: are AAMI and AACD distinct entities? Int J Geriatr Psychiatry. 1999;14:534–540.
52. Christensen H, Henderson AS, Jorm AF, Mackinnon AJ, Scott R, Korten AE. ICD-10 mild cognitive disorder: epidemiological evidence on its validity. Psychol Med. 1995;25:105–120.
53. Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:270–279.
54. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 2013.5th ed. Washington, DC: American Psychiatric Association
55. Petersen RC, Roberts RO, Knopman DS, et al. Mild cognitive impairment: ten years later. Arch Neurol. 2009;66:1447–1455.
56. Rudolph JL, Schreiber KA, Culley DJ, et al. Measurement of post-operative cognitive dysfunction after cardiac surgery: a systematic review. Acta Anaesthesiol Scand. 2010;54:663–677.
57. Jessen F, Wolfsgruber S, Wiese B, et al; German Study on Aging, Cognition and Dementia in Primary Care Patients. AD dementia risk in late MCI, in early MCI, and in subjective memory impairment. Alzheimers Dement. 2014;10:76–83.
58. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:263–269.
59. Jack CR Jr, Albert MS, Knopman DS, et al. Introduction to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:257–262.
60. Schoen J, Husemann L, Tiemeyer C, et al. Cognitive function after sevoflurane- vs propofol-based anaesthesia for on-pump cardiac surgery: a randomized controlled trial. Br J Anaesth. 2011;106:840–850.
61. Tang N, Ou C, Liu Y, Zuo Y, Bai Y. Effect of inhalational anaesthetic on postoperative cognitive dysfunction following radical rectal resection in elderly patients with mild cognitive impairment. J Int Med Res. 2014;42:1252–1261.
62. Silbert BS, Evered LA, Scott DA. Incidence of postoperative cognitive dysfunction after general or spinal anaesthesia for extracorporeal shock wave lithotripsy. Br J Anaesth. 2014;113:784–791.
63. Rasmussen LS, Johnson T, Kuipers HM, et al; ISPOCD2(International Study of Postoperative Cognitive Dysfunction) Investigators. Does anaesthesia cause postoperative cognitive dysfunction? A randomised study of regional versus general anaesthesia in 438 elderly patients. Acta Anaesthesiol Scand. 2003;47:260–266.
64. Cibelli M, Fidalgo AR, Terrando N, et al. Role of interleukin-1beta in postoperative cognitive dysfunction. Ann Neurol. 2010;68:360–368.
65. Terrando N, Monaco C, Ma D, Foxwell BM, Feldmann M, Maze M. Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline. Proc Natl Acad Sci U S A. 2010;107:20518–20522.
66. Terrando N, Brzezinski M, Degos V, et al. Perioperative cognitive decline in the aging population. Mayo Clin Proc. 2011;86:885–893.
67. Eckenhoff RG, Laudansky KF. Anesthesia, surgery, illness and Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry. 2013;47:162–166.
68. Perry VH, Cunningham C, Holmes C. Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol. 2007;7:161–167.
69. Holmes C, Cunningham C, Zotova E, et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology. 2009;73:768–774.
70. Dunn N, Mullee M, Perry VH, Holmes C. Association between dementia and infectious disease: evidence from a case-control study. Alzheimer Dis Assoc Disord. 2005;19:91–94.
71. Evered L, Silbert B, Scott DA, Ames D, Maruff P, Blennow K. Cerebrospinal fluid biomarker for Alzheimer disease predicts postoperative cognitive dysfunction. Anesthesiology. 2016;124:353–361.
72. Silverstein JH. Influence of anesthetics on Alzheimer’s disease: biophysical, animal model, and clinical reports. J Alzheimers Dis. 2014;40:839–848.
73. Stephan BC, Matthews FE, Khaw KT, Dufouil C, Brayne C. Beyond mild cognitive impairment: vascular cognitive impairment, no dementia (VCIND). Alzheimers Res Ther. 2009;1:4.
74. Doraiswamy PM. Silent cerebrovascular events and Alzheimer’s disease: an overlooked opportunity for prevention? Am J Psychiatry. 2012;169:251–254.
75. Evered LSB, Scott D, Zetterberg H, Blennow K. Association of changes in plasma neurofilament light and tau levels with anesthesia and surgery: results from the CAPACITY and ARCADIAN studies. JAMA Neurol. 2018;75:542–547.
76. Saxena S UY, Maze M. Restoring order to postooperative neurocognitive disorders JAMA Neurol. 2018;75:535–536.
77. Qiao Y, Feng H, Zhao T, Yan H, Zhang H, Zhao X. Postoperative cognitive dysfunction after inhalational anesthesia in elderly patients undergoing major surgery: the influence of anesthetic technique, cerebral injury and systemic inflammation. BMC Anesthesiol. 2015;15:154.
78. Liu Y, Pan N, Ma Y, et al. Inhaled sevoflurane may promote progression of amnestic mild cognitive impairment: a prospective, randomized parallel-group study. Am J Med Sci. 2013;345:355–360.
79. Micha G TP, Zalonis I, Kotsis K, Papadopoulos G, E. A. Propofol vs sevoflurane anaesthesia on postoperative cognitivedysfunction in the elderly. A randomized controlled trial. Acta Anaesth Belg. 2016;67:129–137.
80. Egawa J, Inoue S, Nishiwada T, et al. Effects of anesthetics on early postoperative cognitive outcome and intraoperative cerebral oxygen balance in patients undergoing lung surgery: a randomized clinical trial. Can J Anaesth. 2016;63:1161–1169.
81. Chan MT, Cheng BC, Lee TM, Gin T; CODA Trial Group. BIS-guided anesthesia decreases postoperative delirium and cognitive decline. J Neurosurg Anesthesiol. 2013;25:33–42.
82. Radtke FM, Franck M, Lendner J, Krüger S, Wernecke KD, Spies CD. Monitoring depth of anaesthesia in a randomized trial decreases the rate of postoperative delirium but not postoperative cognitive dysfunction. Br J Anaesth. 2013;110(suppl 1i98–105.
83. Arrowsmith JE, Harrison MJ, Newman SP, Stygall J, Timberlake N, Pugsley WB. Neuroprotection of the brain during cardiopulmonary bypass: a randomized trial of remacemide during coronary artery bypass in 171 patients. Stroke. 1998;29:2357–2362.
84. Fish KJ, Helms KN, Sarnquist FH, et al. A prospective, randomized study of the effects of prostacyclin on neuropsychologic dysfunction after coronary artery operation. J Thorac Cardiovasc Surg. 1987;93:609–615.
85. Mathew JP, Mackensen GB, Phillips-Bute B, et al; Neurologic Outcome Research Group (NORG) of the Duke Heart Center. Randomized, double-blinded, placebo controlled study of neuroprotection with lidocaine in cardiac surgery. Stroke. 2009;40:880–887.
86. Nagels W, Demeyere R, Van Hemelrijck J, Vandenbussche E, Gijbels K, Vandermeersch E. Evaluation of the neuroprotective effects of S(+)-ketamine during open-heart surgery. Anesth Analg. 2004;98:1595–1603.
87. Wang D, Wu X, Li J, Xiao F, Liu X, Meng M. The effect of lidocaine on early postoperative cognitive dysfunction after coronary artery bypass surgery. Anesth Analg. 2002;95:1134–1141.
88. Uebelhack R, Vohs K, Zytowski M, Schewe HJ, Koch C, Konertz W. Effect of piracetam on cognitive performance in patients undergoing bypass surgery. Pharmacopsychiatry. 2003;36:89–93.
89. Ottens TH, Dieleman JM, Sauër AM, et al; DExamethasone for Cardiac Surgery (DECS) Study Group. Effects of dexamethasone on cognitive decline after cardiac surgery: a randomized clinical trial. Anesthesiology. 2014;121:492–500.
90. Chong TW, Loi SM, Lautenschlager NT, Ames D. Therapeutic advances and risk factor management: our best chance to tackle dementia? Med J Aust. 2016;204:91–92, 91.e1.
91. Deckers K, van Boxtel MP, Schiepers OJ, et al. Target risk factors for dementia prevention: a systematic review and Delphi consensus study on the evidence from observational studies. Int J Geriatr Psychiatry. 2015;30:234–246.
92. Ngandu T, Lehtisalo J, Solomon A, et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. 2015;385:2255–2263.