’He was in a very weak condition, both of mind and body. He was restless, incoherent, repeating meaningless expressions. He had all the aspect of a man half-drunk’ . These were the words of British psychiatrist George H. Savage when describing the cognitive changes following general anesthesia in 1887. Decades later, Philip Bedford, a British surgeon, published his observations on postoperative cognitive decline in elderly patients in The Lancet, aghast at their effect on the patient's future life. He concluded by calling on his readers to adopt strategies to avoid these complications, ‘The catastrophe is so grave that the hazard must be regarded as serious’ .
For patients in their old age, even a slight decrease in cognitive function could be the straw that breaks the camel's back, leading to the loss of independent living and the necessity of care dependency. This may primarily result in reduced everyday activity and a decline in the quality of life of the patient, aspects that – compared to mortality and morbidity – have been neglected as outcome parameters in clinical trials for a long time. Neurocognitive dysfunction in elderly patients is common during illness and hospitalization, especially in – but not restricted to – those undergoing surgery.
In the face of demographic change, with a growing number of elderly patients undergoing surgery, and increased focus on patient-reported outcomes, health-related socioeconomics, and healthcare research, perioperative cognition has become an emerging field of basic, translational, and clinical research.
COGNITION AND DISEASE
Cognition (from Latin cognoscere: recognize, experience, become acquainted with) is defined as ‘the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses’ . Cognition can be divided into different domains, which can be anatomically and physiologically linked to different neuronal structures. Lacking a consistent definition, the DSM-V (Statistical Manual of Mental Disorders, 5th edition) specified six key domains that should be considered when implementing the diagnosis criteria for neurocognitive diseases – perceptual–motor function, language, learning and memory, social cognition, complex attention, and executive function .
Cognition is not a static system – it can be influenced by endogenous and exogenous conditions. Cognition, much like other organ functions, changes physiologically through aging. Cognitive performance fluctuates in the course of a day and can be affected by stress, inflammation, hormonal balance, and disease [5–11]. It can, thus, be assumed that persons seeking medical treatment due to illness or injury are already affected in terms of their cognitive performance level as compared to a healthy control before medical intervention has commenced . For the patient, surgery is an enormous challenge, mentally and physiologically, and it is associated with a (temporary) decline in cognitive function irrespective of any medication-induced side effects. In the absence of complications, the initial level of performance is attained within hours or days of the operation. In some patients, surgery can also lead to postoperative enhancement of cognitive performance as compared to the preoperative state. This phenomenon, explained by improved health conditions accompanied with increased quality of life following successful surgery, is called postoperative cognitive improvement (POCI) [13–15].
NOMENCLATURE OF POSTOPERATIVE CHANGES IN COGNITION
There are different approaches to the cause of postoperative cognitive deficiencies. The question whether POCD and POD are distinct pathologies or ‘two sides of the same coin’ is subject of scientific discourse [16,17▪,18,19▪,20▪▪]. The view that these states are more interrelated than exclusive and may be considered as different facets of perioperative cognitive impairment was supported by the Perioperative Cognition Nomenclature Working Group in 2018. This expert panel of scientists and clinicians stated that all cognitive changes occurring in the context of surgery and anesthesia should be summarized under the term ‘neurocognitive disorder’ (NCD) to facilitate research and data comparison in the field (Fig. 1) [21▪▪].
POD manifests within the first few days following operation and might occur as early as in the postanesthetic care unit. It must be distinguished from agitated awakening from anesthesia, described as ‘emergence delirium’ as this phenomenon can be directly linked to the influence of hypnotics [21▪▪,22]. POD is defined as an acute state of confusion with disturbed consciousness, perception, memory, and orientation. A deficit of attention, the most prominent feature of POD, allows differentiation from other neurocognitive disorders, such as dementia or MCI. POD fluctuates during the course of the day and can be associated with psychotic symptoms, thought disorders, and disturbances of sleep–wake cycle.
POD can manifest in a hyperactive or hypoactive form, the latter being more frequent, but often overseen and associated with poor long-term prognosis. Patients with hypoactive delirium are often mistaken as being ‘depressive’ or ‘demented’ . With an incidence ranging from 30 to 50%, POD is the most frequent postoperative complication in elderly patients [24▪▪,25▪▪,26,27]. It is associated with an increased rate of almost any postoperative complication, prolonged hospital stay, increased care dependency, decrease in functional state, and a long-term increase in morbidity and mortality [28–30]. The risk of the development of a later MCI or dementia increases threefold if POD occurs [31–35], and the progression of both pathologies is enhanced if they were already present preoperatively [36–38]. Concurrently, preexisting cognitive impairment, MCI, and dementia are the factors most predictive for the later development of POD.
The diagnostic criteria for POD are defined within the DSM-5 and ICD-10 [39,40] and a number of validated screening tools have been developed for POD diagnosis [41▪,42]. An estimated three of four cases of POD are overseen because of the high incidence of the inconspicuous hypoactive form . Therefore, regular screening for POD is recommended for elderly patients thrice a day, commencing with postanesthetic care and continued till the fifth postoperative day .
POSTOPERATIVE NEUROCOGNITIVE DISORDERS BEYOND DELIRIUM
A new cognitive impairment following surgery but resolving within the first 30 days of the operation is described as delayed neurocognitive recovery [21▪▪]. If cognitive decline persists for more than 30 days but less than 12 months following surgery, it is termed POCD or postoperative neurocognitive disorder (pNCD). In these cases, unlike during POD, consciousness, orientation, and attention are not typically affected. However, impairment lies in the domains of memory, perceptual–motor function, learning, language, and executive function, although evidence is still scarce in this regard [44–46]. Any cognitive impairment still present after one year is termed merely NCD and comprises dementia (major NCD) as well mild cognitive impairment (mild NCD).
The incidence of pNCD ranges from 30 to 60% [47–50,51▪▪]. Although several trials have been reported, comparison of data is difficult, as the eliciting of cognitive performance differs largely between the experimental settings. This is related to the choice and number of cognitive domains taken into account and the methods of cognitive testing being applied. Cognitive impairment after surgery can occur in any patient, however, its incidence rises with increasing age. Often, delayed neurocognitive recovery dissolves within the first few months after surgery. Three months after surgery, a decrease in cognitive performance compared to the preoperative level can be found in about two-third of patients who are 70 years and older. This percentage reduces to 10–30% at 6 months and 4–10% after 1 year postoperatively [47,52–55]. In younger patients, pNCD occurs less frequently and resolves more quickly . The occurrence of NCD is associated with increased morbidity and mortality, loss of independence and everyday activities, functional decline, and reduced quality of life for the patients and their relatives [57,58].
Compared with POD, the diagnosis of pNCD is more complex, as it requires neuropsychometric testing. It can be diagnosed if the subjective impression of a postoperative decrease in cognitive function is mentioned by the patient, proxy, or healthcare provider and neuropsychometric testing exhibits a new postoperative difference of more than 1 standard deviations compared to norm sample results in any of the DMS-5 cognitive domains [21▪▪]. Because psychometric testing requires neuropsychological expertise, extensive operator training and is time-consuming, it is seldom applied in the clinical routine. However, validated short-form tests assessing overall cognitive function are available. Although most of them were developed to distinguish demented from healthy patients, they provide an overview of the patient's cognitive performance (Table 1).
PATHOPHYSIOLOGY OF PERIOPERATIVE COGNITIVE DISORDERS
Although research on delirium pathogenesis is growing, the pathogenesis of pNCD beyond delirium is rarely addressed scientifically. This might be due to the lack of a definition and the present complexity of pNCD diagnosis. However, because delirium and other pNCDs share the same predisposing factors, similar mechanisms of pathogenesis are assumed for both entities, and their long-term effects and outcomes are comparable, it might be acceptable to refer to models of delirium pathogenesis as models for pNCD pathogenesis in general.
THE VULNERABLE BRAIN IN AGING
Cognitive dysfunction following surgery and hospitalization can be considered as ‘functional cerebral decompensation’, caused by multiple noxious stimuli eventually reaching a critical mass to tilt over an unstable cerebral homeostasis . This instability, resulting from a reduced capacity of the aging brain to cope with adverse conditions, can be explained by a series of changes in the central nervous system physiologically associated with advanced age [60▪▪]. The proinflammatory processes initiated through perioperative stress seem to notably contribute to the development of neurocognitive disorders. The systemic release of inflammatory mediators leads to endothelial dysfunction, the disruption of tight junctions, and increased blood–brain–barrier permeability. The intracerebral migration of inflammatory mediators activates microglia and astrocytes, maintaining neuroinflammation with a release of reactive oxygen species and inflammatory cytokines. This results in increased synaptic dysfunction and neuronal death, accompanied by the inhibition of neurogenesis, especially in the hippocampus – a crucial region associated with the emergence of cognitive impairment . In addition to this, neuronal aging itself promotes a proinflammatory state with neuronal loss, reduction in the blood–brain–barrier function, and increased sensitivity to oxidative stress. Neurotransmission changes with advancing age and results, among others, in a latent deficit in acetylcholine and excess in dopamine. The cholinergic system plays a key role in maintaining cognitive performance, and the ‘anticholinergic burden’ of the aging brain is a salient hypothesis for an age-related decrease in cognitive abilities [62–64].
EFFECTS OF SURGERY, ANESTHESIA, AND HOSPITALIZATION
Age-associated changes in the brain lead to an increased vulnerability towards internal and external noxi. However, not every aged patient develops pNCD. A patient's overall vulnerability in this regard is determined by multiple endogenous predisposing factors that superimpose on the fragile aging brain . Preexisting cognitive impairment ranges between the most predisposing factors, together with frailty and multimorbidity. Malnutrition, sensory impairment, polypharmacy, and pain contribute to the patient's risk for postoperative neurocognitive dysfunction.
Almost all aspects of hospitalization and medical treatment have the potential to trigger a neurocognitive disorder, ranging from surgery to anticholinergic medication, anesthesia and sedation depth, sleep deprivation, anxiety, dehydration, and immobilization. A pNCD might be triggered by medication, especially substances affecting the central nervous system and those with high anticholinergic potential. A patient with few predisposing factors might ‘require’ a major trigger to decompensate into POD, whereas in a person with a strong predisposition, merely staying in the foreign surroundings of the hospital or immobilization might trigger it [24▪▪,27,29,66–68].
POD often emerges as the first symptom of a so far undiscovered pathologic state (Table 2). Identifying a possible causative somatic complication has a high priority whenever a POD is diagnosed [69–71]. It has to be emphasized, however, that NCD even occur in patients who do not undergo surgery at all [72,73]. About 10% of elderly patients in emergency departments with acute illness or injury present with delirium upon arrival at the hospital, 20–30% of nonsurgical patients experience delirium during their hospitalization [74,75,76]. This is crucial to the understanding of NCD, especially because former scientific discussions were controversial regarding whether anesthesia or the surgical stimulus itself could be made responsible for its development. pNCD genesis is likely to be multifactorial can only be linked to the interplay of different factors, not to single events .
PREVENTION: WHAT CAN THE ANAESTHETIST DO?
Increasing evidence shows that pNCD prevention can only be realized in a multiprofessional perioperative approach [24▪▪]. Patients with a high risk for pNCD are likely to benefit from a special perioperative care concept that might not be applicable to all patients in routine care because of personal and financial resources. A preoperative assessment of cognitive function is essential and recommended to identify those at risk (Table 1). In patients with preoperative NCD, further preoperative assessment might discover other frequently associated predisposing factors that could be modified before surgery takes place. Assessment should include structured medication reconciliation intended to reduce potentially inadequate medication. Frailty and malnutrition have been found to be common in patients with cognitive impairment and should be assessed as well [77▪▪].
Perioperative neurocognitive disorder prevention
Patients at risk for NCD should be carefully prepared for the planned operation in elective surgery. Involving relatives or confidantes when informing the patient about the upcoming procedure and including information about pNCD and preventive measures have been found to be advantageous (Odds Ratio (OR) 0.47) . Preoperative fasting should not exceed the minimum time required, and unnecessary postponement of the scheduled surgery should be avoided, because dehydration and discomfort add to the risk of the development of POD (OR 2.7–10.6) . Routine premedication with benzodiazepines should be refrained from, as these drugs have high delirogenic potential [43,80,81].
Perioperative sensory orientation and patient-orientated care are well established measures of pNCD prevention and have shown to reduce the incidence of POD by 10–30% [82,83]. Patients should be encouraged to wear their glasses, hearing aids, and dentures until the induction of anesthesia. Pain and opioids increase the risk of POD. Although sufficient analgesia is mandatory, an opioid-saving concept is preferable. Perioperative warming and sufficient analgesia are preventive measures that ensure the patient's comfort and reduce anxiety and postoperative complications . In pNCD prevention, multicomponent programs have shown to be more effective than single interventions (reduction of POD: OR 0.4–0.6) [84,85].
No recommendation can be given in favor or against a specific anesthetic regime for the patient at risk for pNCD. Although there is a trend that intravenous anesthesia with Propofol is associated with a lower pNCD rate than volatile anesthetics, data in this regard are scare, and the low evidence makes a final conclusion inadmissible [86▪▪]. Large meta analyses have failed to show the protective effects of regional over general anesthesia with regard to POD incidence . These results, however, might be biased by the fact that many patients routinely undergoing regional anesthesia receive additional sedation, which can be as deep as during general anesthesia .
Deep sedation has been identified as a risk factor for pNCD genesis and should be avoided. Therefore, continuous monitoring of sedation depth is recommended as it has the potential to reduce pNCD incidence by 20–30% [43,89]. Inadequate or highly anticholinergic medication can be considered potentially delirogenic [90▪▪] and should also be avoided during anesthesia. Although the evidence is still low, it can be assumed that fluctuations in blood pressure contribute to the risk of pNCD [91▪▪]. Maintenance of homeostasis and careful hemodynamic management might, therefore, play an important role in the patient's anesthetic care. Early postoperative mobilization and re-orientation have been proven to be protective for pNCD and can be considered as a primary objective in perioperative care for these patients. This can be ensured through early removal of catheters and lines, (nonpharmacological) regulation of the sleep–wake cycle, involvement of relatives, and a stimulating environment.
Although many pNCD preventive measures have been recommended for several years, they have only recently begun to be adopted into clinical practice. With anesthesiology at the interface of all surgical disciplines having a designated role as coordinator and manager of perioperative processes, the implementation of multiinterventional interdisciplinary NCD prevention into routine perioperative care is one of the major challenges in our field in the coming years.
I would like to thank Louise Bloeck for her assistance.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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