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Should general anaesthesia be avoided in the elderly?

Anaesthesia 2014, 69 (Suppl. 1), 35–44 Should general anaesthesia be avoided in the elderly? C. Strøm,1 L. S. Rasmussen2 and F. E. Sieber3 1 Research Assistant, 2 Professor, Department of Anaesthesia, Centre of Head and Orthopaedics, Rigshospitalet, Copen-hagen University Hospital, Copenhagen, Denmark3 Professor of Anaesthesiology, Department of Anaesthesiology/Critical Care Medicine, The Johns Hopkins MedicalInstitutions, Baltimore, Maryland, USA SummarySurgery and anaesthesia exert comparatively greater adverse effects on the elderly than on the younger brain, mani-fest by the higher prevalence of postoperative delirium and cognitive dysfunction. Postoperative delirium and cogni-tive dysfunction delay rehabilitation, and are associated with increases in morbidity and mortality among elderlysurgical patients. We review the aetiology of postoperative delirium and cognitive dysfunction in the elderly with aparticular focus on anaesthesia and sedation, discuss methods of diagnosing and monitoring postoperative cognitivedecline, and describe the treatment strategies by which such decline may be prevented.
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Correspondence to: C. StrømEmail: camilla.stroem.01@regionh.dkAccepted: 5 October 2013 clinical management insights by discussing some of Don't have a general anaesthetic once you're 50 – the more controversial methods for monitoring the it'll wipe out a quarter of your brain.
brain during anaesthesia, and outline how postopera- — Barbara Cartland, novelist (died aged 98) tive cognitive changes might be assessed and pre-vented.
Concern has been growing over the last decade regard-ing whether anaesthesia can be harmful to the elderly Pathophysiology of age-related brain, because elderly surgical patients frequently expe- neuropsychiatric decline rience a postoperative deterioration in cognitive func- A number of anatomical and physiological changes tion, and such a decline may herald an increase in manifest themselves as the human brain ages, and both morbidity and mortality.
these may render the ageing brain more vulnerable to In this review, we will outline some of the perti- both reductions in cognitive reserve and the effects of nent changes in human brain structure and function surgery and anaesthesia (Table 1).
related to ageing, in order to understand the possiblemechanisms behind cognitive and behavioural changes seen after surgery and anaesthesia. We will review At approximately 45–50 years of age, a progressive some of the pre-clinical evidence that has given rise to decline in brain weight begins, reaching a nadir after the hypothesis that progressive neurodegeneration may the age of 86 years [1]. Grey matter volume increases be exacerbated by anaesthesia. Finally, we will provide in childhood, but then begins to decrease slowly.
2013 The Association of Anaesthetists of Great Britain and Ireland Anaesthesia 2014, 69 (Suppl. 1), 35–44 Strøm et al. Use of general anaesthesia in the elderly Table 1 Predisposing factors and possible mechanisms evidence supports the hypothesis that age-associated for the development of postoperative delirium/cogni- injury to the blood–brain barrier plays a role in the tive deterioration in elderly patients.
pathogenesis of white matter disease [3]. Blood–brainbarrier changes may also alter the response to ischae-mia, as well as drug entry to the central nervous Predisposing factors Structural changes system (CNS) [3].
decreased whole-brain volume blood–brain barrier damage reduction of neurogenesis hippocampal changes In humans, neural stem cells are constitutively active in amyloid or tau accumulation the hippocampal dentate gyrus and subventricular Brain inflammationCerebrovascular disease regions of the lateral ventricles, and proliferate into pro- Disturbances in levels of genitors that differentiate into neurons in all age groups Pre-operative cognitive impairment [4]. Neurogenesis in the dentate gyrus may cause a Reduction in cognitive reserve unique form of neural plasticity that is involved in cog- nitive and emotional functions. A gradual reduction in increased frailty neurogenesis occurs with ageing, limiting the ability to increased incidence of pre-existing learn and contributing to cognitive decline [4].
increased incidence of Systemic vascular disease Lower educational level Communication between the peripheral immune sys-tem and cytokine-mediated signals within the CNS Potential mechanisms Neurohumoral inflammatory surgical stress response form a co-ordinated response to stress. Signals initiated in the peripheral immune system may result in CNS Direct anaesthetic agent toxicityIschaemia (hypoperfusion, hypoxaemia) inflammatory responses that can manifest as changes in behaviour or cognition. Immunity in the CNS is Hospital environment mediated by microglia, astrocytes and CNS-associatedmacrophages. Microglia respond to, and propagate,inflammatory signals from the peripheral immune sys- White matter volume increases until the age of approxi- tem. During the peri-operative period, for example, mately 45 years, reflecting increases in connectivity microglia might release cytokines or perform macro- between brain regions, and thereafter starts to decrease.
phage-like activities. Exaggerated or prolonged produc- Decreases in whole-brain volume cannot be accounted tion of cytokines can occur in response to peripheral for solely by ageing-associated losses in either white or immune system stimuli as a result of impaired anti- grey matter, and seem to be multi-factorial in aetiology.
inflammatory feedback in the aged brain [5]. An For example, co-morbidities associated with ageing, increasing body of evidence suggests that increases in such as diabetes and hypertension, can adversely affect brain inflammation with ageing and systemic disease changes in white matter tracts [2].
(e.g. metabolic syndrome) are associated with cognitivechanges [6].
Blood–brain barrierWith ageing, the blood–brain barrier decreases in microvascular density and capillary lumen size, and Cognition changes with age in two main ways. First, the number of mitochondria per endothelial cell is measures that reflect acquired knowledge, such as reduced, changes that affect blood–brain barrier vocabulary, improve up to 60 years of age, after permeability [3]. Risk factors for acceleration of these which they decline. Secondly, there is a nearly linear changes include hypertension, hyperlipidaemia, diabe- decline from early adulthood in cross-sectional and tes mellitus and adverse drug reactions. Accumulating longitudinal measures of processing speed, including 2013 The Association of Anaesthetists of Great Britain and Ireland Strøm et al. Use of general anaesthesia in the elderly Anaesthesia 2014, 69 (Suppl. 1), 35–44 reasoning, memory and spatial cognitive abilities [7].
Anaesthesia and the elderly brain Memory decline occurs in more than 40% of people Anaesthetic agents work on a relatively small number aged over 60 and can dramatically affect the perfor- of CNS targets, and most of these are postsynaptic mance of daily living activities, but is not a universal ligand-gated ion channels. Some drugs act at excit- finding [8].
atory receptors, whereas others potentiate inhibitorysynaptic receptors, such as gamma-aminobutyric acid Cognitive reserve (GABA) receptors [12]. Intravenous anaesthetics may Cognitive reserve describes the inconsistency between have effects on GABA (propofol, etomidate), alpha-2 anatomic and functional age-related decline, and can be classified as passive or active. Passive reserve relates acetylcholine, adenosine and dopamine (opioids) to brain size or neuronal count, and is measured, for receptors [13]. Inhalational anaesthetic agents affect example, by brain volume, synaptic count or dendritic multiple ion channel receptors, including GABA, gly- branching. Active reserve relates more to functional cine, acetylcholine [14], glutamate, and serotonin cognitive integrity, and is preserved better in people [15]. The variety and complexity of anaesthetic with higher socioeconomic status and educational agent/ion channel interactions underlie the postopera- attainment, although no ‘best measure' of active tive cognitive problems experienced by the elderly.
reserve exists. Higher educational attainment, for Interactions between anaesthetic agents and the CNS example, modifies the association between post-mortem cholinergic system may be of particular importance Alzheimer's disease pathology and pre-mortem cogni- [16], due to the close relationship between acetylcholine tive function: for the same degree of brain pathology, and cognition. Age-related decline in prefrontal cholin- cognitive function is better with each year of education ergic neurons may render the elderly more susceptible [9]. Epidemiological evidence suggests that a patient's than younger patients to anaesthesia-mediated depres- cognitive reserve determines their cognition, rather than sion of CNS cholinergic neurotransmission [17, 18].
their underlying neuropathology [9].
Although both biochemical and anatomical Monitoring the elderly brain during changes have been described in the ageing brain, the general anaesthesia exact mechanisms that cause changes in functional Monitoring brain oxygenation/perfusion and depth of reserve are unclear. Decreases in functional reserve anaesthesia have been advocated for reducing postop- are manifest as decreases in activities of daily living, erative cognitive decline in the elderly. Studies have increased sensitivity to anaesthetic agents, and found an association between cerebral oxygen desatu- increased risk for both postoperative delirium ration detected by intra-operative near-infrared spec- (POD) and postoperative cognitive dysfunction troscopy (NIRS) and poorer cognitive outcomes [19], but are limited by non-uniform definitions of desatura-tion and cognitive decline, as well as inadequate sam- Cerebrovascular disease ple size. Randomised controlled trials designed to Risk factors, including hypertension, diabetes mellitus assess the postoperative cognitive effects of minimising and elevated plasma homocysteine and apolipoprotein intra-operative cerebral oxygen desaturation have been E, are associated with age-related large vessel arterio- inconclusive [19]. The relevance of diminished age- sclerotic and small vessel angiopathic cerebrovascular related autoregulation of cerebral blood flow in the disease, resulting in infarction and haemorrhage [10].
elderly as a contributory factor to cerebral oxygen de- Subclinical vascular disease, manifest as white matter saturation is also unclear [20].
hyperintensities on magnetic resonance images, is asso- Commercially available means of monitoring ciated with changes in cognition, including attention, anaesthetic depth include electroencephalogram (EEG, psychomotor speed and executive function [11], processed or raw) and auditory evoked potentials. The although the volume of these that is necessary to cause most common EEG device in clinical use is the bispec- cognitive changes is unknown.
tral index (BIS) monitor. The association between 2013 The Association of Anaesthetists of Great Britain and Ireland Anaesthesia 2014, 69 (Suppl. 1), 35–44 Strøm et al. Use of general anaesthesia in the elderly depth of anaesthesia and postoperative cognition remains uncertain, with some studies concluding that Postoperative delirium ‘lighter' levels of general anaesthesia guided by either Postoperative delirium is an acute organic brain syn- the BIS monitor or auditory evoked potentials improve drome that usually develops within the first few days postoperative cognitive outcomes [21, 22], whereas after an operation. Postoperative delirium exhibits a others have reported no association or the opposite fluctuating course and is often accompanied by abnor- [23, 24]. Studies utilising both BIS and NIRS suggest mal circadian rhythm. The core symptom is inatten- that reducing both cerebral oxygen desaturation and tion, but other cognitive changes are also common, the duration and depth of anaesthesia may be of bene- including memory deficit and disorientation. Changes fit in reducing POCD [25].
in psychomotor behaviour define whether delirium isclassified hypoactive, hyperactive or mixed variation The elderly patient and sedation [30]. The hypoactive form is associated with relatively The sedation of elderly patients is a commonly higher mortality, but is underdiagnosed because employed, but under-researched, adjunct to regional patients are quiet and relatively motionless, or misdi- anaesthesia, often for orthopaedic procedures. Dosage agnosed as symptomatic manifestations of dementia and method of administration are invariably extrapo- and/or depression [31]. Following a lucid interval, lated from clinical trials involving younger patients, POD symptoms tend to appear 24–72 h after surgery, and fail to take into account the altered pharmaco- and are distinct from cognitive ‘emergence phenom- kinetics and pharmacodynamics of elderly patients, ena' that occur during the transition from anaesthesia resulting in relative overdosage and peri-operative cog- to wakefulness [32]. ‘Subsyndromal delirium' has been nitive alteration [26]. Patient-controlled sedation may suggested as a diagnosis for elderly patients who dis- avoid over-sedation, and has been used safely during play one or more symptoms of, but do not meet cataract surgery with a high level of patient satisfaction defined diagnostic criteria for, delirium [33].
[27], although use of this technique requires validation Approximately 10% of elderly surgical patients in other elderly populations, and may be limited to develop POD, rising to 30–65% after certain types of patients without pre-morbid cognitive dysfunction.
surgery, such as hip fracture, cardiac and emergency Evidence suggests that depth of sedation monitor- surgery [34, 35]. Patient-specific factors including ing is important for elderly surgical patients. In a advanced age, cognitive impairment, lower educational randomised double-blind study of 114 patients aged level and pre-existing medical conditions predispose to 65 years or over administered spinal anaesthesia for POD, as do potentially reversible risk factors such as hip fracture repair, patients who received deep seda- pre-morbid CNS co-medication, infection, malnutri- tion (BIS 50) had a significantly higher prevalence of tion, electrolyte imbalance, dehydration, environmental POD than those patients who received light sedation disturbances and substance withdrawal (alcohol, medi- (BIS 80) (40% vs 19%, p = 0.02) [28]. The type of cation). Severe pain and inadequate analgesia increase sedation monitor used appears less important than the the risk of POD in cognitively intact patients [36].
fact that the depth of sedation should always be moni- The pathogenesis of POD is still to be elucidated, tored; indeed, BIS monitoring correlates poorly with but is generally thought to be multifactorial. Normal clinical sedation scale scores [29].
brain function relies on numerous well-functioninghormonal and neuromodulatory systems. Disturbances POD and POCD – an update on in CNS acetylcholine, dopamine and melatonin levels classification, assessment and have been associated with POD [37]. It has been pro- posed that the high prevalence of POD after major The most common types of deterioration in cognitive surgery is related to the inflammatory component of the function are POD and POCD. Both are associated with stress response to surgery. However, although a variety significant morbidity and mortality, reinforcing the of inflammatory biomarkers have been investigated, importance of their peri-operative assessment.
postoperative elevations of only a few cytokines have 2013 The Association of Anaesthetists of Great Britain and Ireland Strøm et al. Use of general anaesthesia in the elderly Anaesthesia 2014, 69 (Suppl. 1), 35–44 been linked (weakly) to POD [38, 39]. It is of interest bypass circuits [46], or intra-operative hypoxaemia or that microglial cytokine responses to peripheral hypotension [47].
immune system stimuli in vitro differ depending on Similar to POD, several hypotheses regarding the whether cultures are exposed to isoflurane, sevoflurane aetiology of POCD have been suggested, including sur- or propofol [40].
gical stress-associated systemic or localised inflamma- Prolonged duration and increased severity of POD tory reactions, alterations in hormonal homeostasis, increase postoperative mortality [41]. Postoperative and direct anaesthetic agent toxicity [48, 49]. Patterns delirium is independently associated with prolonged of diurnal salivary cortisol excretion, for example, are hospital stay, short- and long-term risk of death and significantly related to the development of POCD [48].
higher rates of institutionalisation after discharge, lead- Intriguingly, serum levels of S-100B protein, a biomar- ing to a cumulative increase in healthcare expenses [41].
ker of cerebral damage, are significantly elevated inabdominal and vascular surgery patients who develop Postoperative cognitive dysfunction POCD, when compared with those patients who do Postoperative cognitive dysfunction is a syndrome of not develop POCD [50] and after hip fracture in prolonged impairment of cognitive function after sur- patients who develop POD [51]. Experimental studies gery, with limitations in memory, intellectual ability in rats have shown that inhaled anaesthetics (in the and executive function that usually last for weeks or absence of surgical stress) have sustained effects on months, but is distinct from delirium and dementia. It memory formation, and are capable of inducing neuro- is a subtle condition; some patients only have minor degenerative changes on a cellular level [52]. Hippo- symptoms, such as mild memory loss, whereas others campal damage correlates with cognitive impairment are severely affected with pronounced inability to con- in rats [53], and reduction in hippocampal volume in centrate, process information or execute formerly humans measured by MRI may be valuable in predict- uncomplicated tasks. Subjective symptoms or behavio- ing POCD [54, 55]. Despite intensive investigation, the ural changes observed before and after surgery may pathogenesis of POCD remains poorly elucidated. It is arouse suspicion, but formal neuropsychological testing still to be established to what extent postoperative is necessary to diagnose POCD. Mild cases can easily decline in cognitive function is attributable specifically be overlooked or dismissed as just normal signs of to either surgical or anaesthetic management, as dis- ageing, and often the patients or their relatives are the tinct from patient-related risk factors such as extensive only ones to notice that deterioration has occurred.
co-morbid cerebrovascular and systemic vascular dis- To date, no formal diagnostic criteria have been ease, or undiagnosed mild cognitive dysfunction, which established for POCD, which makes it difficult to may be of greater aetiological importance (Table 2) evaluate in daily clinical practice. Nevertheless, recog- nition is essential, as POCD has been associated with Recent research interest has focused on whether increased mortality, risk of prematurely leaving the POCD and POD are prodromal forms of Alzheimer's work market and dependence on socio-economic disease. The cerebral accumulation of b-amyloid support [42, 43].
and tau proteins are pathognomonic features of The incidence of POCD varies according to the Alzheimer's disease, and anaesthetic agents appear to definitions used in various studies [44]. Higher inci- enhance this process, as well as potentiating the cyto- dences are demonstrated in populations of elderly toxicity of b-amyloid proteins, and tau phosphoryla- patients undergoing major surgery. For example, fol- tion and aggregation [58, 59], although evidence lowing coronary artery bypass grafting, the quoted remains inconclusive. Surgery may have an indepen- prevalence of POCD varies between 10 and 80% early dent effect on these processes [60], and one study sug- after the procedure and is thought to be associated gested that elevation of b-amyloid concentrations with emboli, atherosclerosis and intra-operative ischae- might simply reflect synaptic activity [61]. The apoli- mia [45]. Postoperative cognitive dysfunction does not poprotein E genotype is strongly associated with Alz- appear to be related to the use of cardiopulmonary heimer's disease and vascular dementia, but has not 2013 The Association of Anaesthetists of Great Britain and Ireland Anaesthesia 2014, 69 (Suppl. 1), 35–44 Strøm et al. Use of general anaesthesia in the elderly been shown to be associated with POCD [62–64].
Other diagnostic tools have been developed and Although it is methodologically difficult to establish validated to diagnose POD. The confusion assessment any correlation between POD and POCD, a recent method (CAM) is easy to perform and sensitive, spe- prospective study suggested that POD and POCD cific and reliable across populations [68], but is unable might represent a trajectory of postoperative cognitive to stratify delirium according to severity; delirium is impairment [65], perhaps as a progression of unrec- diagnosed by patient inattention of acute onset and ognised pre-operative mild cognitive impairment [66].
fluctuating course, accompanied by either/or alteredconsciousness and disorganised thinking (Table 3).
Subsequently, a CAM-ICU non-verbal screening tool Postoperative delirium was developed to diagnose delirium in intubated and Diagnostic criteria are defined in the International Sta- critically ill patients [68].
tistical Classification of Diseases and Related Health Other scoring systems stratify POD severity, but Problems, 10th Revision (ICD-10) and the Diagnostic are less sensitive in diagnosing delirium, and should and Statistical Manual of Mental Disorders, 4th edition only be employed once a diagnosis of POD is estab- (DSM-IV) (Table 3), the former including more specific lished. Repeated testing is important as POD exhibits a criteria than the latter, and proving more useful in estab-lishing the diagnosis of POD (after cardiac surgery) [67].
Table 3 The confusion assessment method (CAM)diagnostic algorithm adapted from Inouye et al. [89].
Table 2 Diagnostic criteria for postoperative delirium(POD).
Acute onset and fluctuating courseThis feature is usually obtained from a family member or nurse and is shown by positive A. Disturbance of consciousness (i.e. reduced clarity of responses to the following questions: isthere evidence of acute change in mental awareness of the environment) with reduced ability status from the patient's baseline? Did the to focus, sustain or shift attention B. A change in cognition (e.g. memory deficit, (abnormal) behaviour fluctuate during the disorientation, language disturbance) day, that is, tend to come and go, orincrease and decrease in severity? C. Development of a perceptual disturbance that is not better accounted for by a pre-existing, established, or evolving dementia This feature is shown by a positive response D. Disturbance develops over a short period of time to the following question: did the patient (usually hours to days) and tends to fluctuate have difficulty focusing attention, for during the course of the day example, being easily distractible, or evidence from the history, physical having difficulty keeping track of what examination or laboratory findings that the disturbance is caused by the direct physiological Disorganised thinking consequences of a general medical condition This feature is shown by a positive response to the following question: was the patient's thinking disorganised or An aetiologically non-specific organic cerebral syndromecharacterised by concurrent disturbances of incoherent, such as rambling or irrelevantconversation, unclear or illogical flow of consciousness and attention, perception, thinking, ideas, or unpredictable switching from memory, psychomotor behaviour, emotion and the sleep– wake schedule. The duration is variable and the subject to subject? degree of severity ranges from mild to very severe Altered level of consciousnessThis feature is shown by any answer other than ‘alert' to the following question: overall, how would you rate this patient's confusional state (non-alcoholic) level of consciousness? (alert [normal]), infective psychosis vigilant (hyperalert), lethargic [drowsy, organic reaction easily aroused], stupor [difficult to rouse] psycho-organic syndrome or coma [unrousable]) The diagnosis of delirium by CAM requires the presence delirium tremens, alcohol-induced or unspecified of features 1 and 2 and either 3 or 4 2013 The Association of Anaesthetists of Great Britain and Ireland Strøm et al. Use of general anaesthesia in the elderly Anaesthesia 2014, 69 (Suppl. 1), 35–44 fluctuating time course, which is often overlooked in systematic review suggested avoidance of opioids, studies of POD [69]. Developing composite risk scores may enhance the prediction of delirium.
H1-receptor antagonists in patients at risk of POD[74].
Postoperative cognitive dysfunction The multifactorial aetiology of POD appears ame- There are no generally agreed criteria for the assess- nable to improvement by using multi-domain inter- ment of POCD, and the diagnosis is not yet described ventions, including BIS-guided depth of anaesthesia in either ICD-10 or DSM-IV. There are considerable monitoring combined with cerebral oxygen saturation inconsistencies between the multiple studies that have monitoring [25], and proactive, multidisciplinary investigated POCD, which makes it difficult to formu- assessment, goal-directed optimisation of oxygen deliv- late diagnostic criteria. No single test can adequately ery, blood volume and serum electrolytes, and non- measure cognitive function with acceptable sensitivity.
pharmacological support, including early mobilisation Instead, a battery of neuropsychological tests is and sleep facilitation [75, 76]. Hypothetically, long- required to assess individual cognitive domains, such as term cognitive outcomes might be improved by pre- verbal skills and memory. When testing a new diagnos- operative diet, exercise and drug modification of tic screening tool, baseline tests must have been underlying, undiagnosed systemic and cerebrovascular obtained pre-operatively and specific definitions of disease [57].
what constitutes a decline in cognitive function must Pharmacological intervention is rarely of benefit in be pre-defined [70], but there is no agreed definition of treating POD/POCD. Haloperidol can be used in cases what constitutes a significant decline, even though most of severe agitation, and may decrease the incidence of studies are powered to detect a cognitive decline of one delirium [77] and reduce the severity and duration of standard deviation from pre-operative levels.
POD [77–79], but evidence is inconclusive. Pharmaco- In addition, the constituent tests of the battery logical modification of circadian disturbance using administered vary between studies, and the intervals diazepam, flunitrazepam and pethidine reduced POD between testing are inconsistent [71]. Timing is crucial, in a small randomised controlled trial (RCT) of 40 as factors such as postoperative pain, opioid use and elderly patients after laparotomy [80], but this contra- sleep disturbances all influence cognitive deterioration dicts more recent evidence proscribing benzodiazepine early after surgery. Furthermore, composite cognitive administration [74]. Peri-operative dexmedetomidine testing is associated with low sensitivity and specificity, infusion may be useful in reducing the prevalence of and floor/ceiling effects (the test is too easy or too dif- POD if patients require intensive care postoperatively ficult, reducing discrimination between individuals [81]. A recent meta-analysis of 38 RCTs comparing scoring near the highest/lowest possible values), and prevention strategies for POD concluded that trials may not always reflect specific patient symptoms.
showed great inconsistencies in definition, incidence, Finally, many studies fail to use an appropriate control severity and duration of POD, but supported the effec- group, invalidating inter-individual and intra-individ- tiveness of dexmedetomidine sedation (compared with ual comparisons over time.
propofol or benzodiazepine sedation), multicomponentinterventions and antipsychotics in preventing POD, Prevention of POD and POCD without finding any benefit relating to type of anaes- Treatment of POD is directed towards the correction thesia (general/spinal) or analgesia (nerve block) or of contributing factors after diagnosis, but prevention use of anticholinesterase inhibitors (donepezil/rivastig- can reduce prevalence and improve outcome, and the mine) [82]. Other studies have found the risk of both same probably applies for POCD. Postoperative delir- POD and POCD to be similar after both regional and ium may be predictable pre-operatively and therefore general anaesthesia [83, 84], but may be confounded preventable to a degree [72], but attempts to create by concomitant use of sedation with regional anaesthe- universal risk scales have failed, due to wide variation sia. It is not yet clear whether the choice of general in surgical, patient and anaesthetic factors [73]. A anaesthesia agent is important, but recent studies 2013 The Association of Anaesthetists of Great Britain and Ireland Anaesthesia 2014, 69 (Suppl. 1), 35–44 Strøm et al. Use of general anaesthesia in the elderly suggest that volatile anaesthetic agents (isoflurane, 6. Ownby RL. Neuroinflammation and cognitive aging. Current Psychiatry Reports 2010; 12: 39–45.
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2013 The Association of Anaesthetists of Great Britain and Ireland

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