University Hospitals of Leicester and University of Leicester, Leicester, UK
E-mail: chris.hanning{at}uhl-tr.nhs.uk
Keywords: cognitive dysfunction, postoperative ; measurement techniques ; psychology
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Introduction |
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The increasingly aged population has stimulated research into premature cognitive decline from all causes. A number of studies have investigated postoperative cognitive dysfunction (POCD), predominantly in the elderly, and these will be discussed together with theories on causation and the limited animal work available thus far.
One of the difficulties of human research in this area is that anaesthesia is hardly ever administered as a sole procedure but is almost invariably given to facilitate surgery. As will be discussed below, the stress response to surgery has been suggested as a possible mechanism for POCD. Thus, in all human studies, the term operation should be understood to include both anaesthesia and surgery.
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Definition and measurement |
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The degree of change in a test deemed to constitute POCD has varied widely between studies ranging from a deterioration of 1 SD in one or more tests in a battery to the more rigorous z-score.10 Mean changes in control group scores from baseline to 1 week and baseline to 3 months provide measures of average learning effects, which are subtracted from changes in individual patient's scores from baseline to postoperative test. Each result is divided by the standard deviation of the change in control group scores to give a z-score for individual patients in each subtest. Composite scores are averaged from the individual test scores of the battery. A value of more than/equal to 2 in two or more tests or a composite score more than/equal to 2 from all tests has been used in the International Studies of PostOperative Cognitive Dysfunction (ISPOCD)1 9 24 26 36 to define POCD.
Testretest reliability
Testretest reliability of neuropsychological tests is important in determining whether a true change in cognitive dysfunction has occurred. Random variation will result in an equal proportion of subjects showing improvement or deterioration, even if no true change has occurred. If testretest reliability is poor and only data from subjects showing a reducing score are analysed, a large apparent decline in cognitive function will be claimed even if there has been no true change in cognitive function. Rasmussen has recently reanalysed the data from 2536 patients and 359 control subjects studied in the four published ISPOCD studies,37 and calculated the ratio of subjects showing improvement to those showing a decline (Table 1). Using this analysis, statistically significant differences between the incidence of POCD and PostOperative Cognitive Improvement (POCI) were present only 1 week after operation in elderly (60 yr) patients undergoing major surgery. The POCD/POCI ratio ranged from 3.3 to 6.2 at the 1-week test in these patients and from 1.6 to 2.8 at the 3-month time point. Testretest reliability ranged from 0.9 for Letter-Digit Coding to 0.2 for the error score of Part C of the Concept Shifting test.
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Objective tests do not always agree with the patient's assessment of his or her cognitive status.15 A university educated, middle-aged, professional man was a normal control subject studied in our centre as part of the ISPOCD 2 programme.24 Subsequently, he underwent urgent major abdominal surgery followed by early re-operation. In the late postoperative period, he complained of poor cognitive function to a degree where he was forced to take early retirement. We retested his cognitive function using the ISPOCD test battery, which he had completed previously. There were no significant changes from the values obtained previously. It is clear that there is still room for development in cognitive test batteries for the detection of POCD.
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Risk of POCD |
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Motivation may be a problem also in the early postoperative period. In a subjective account reported by Pockett,33 a patient describes how she felt after consciousness returned: The thing was, I felt actually rather good in general, but nothing seemed to matter ... Thus when a nurse came to see if I was awake, although I was actually very much awake and feeling quite pleasant and well disposed towards this solicitous person, it seemed to be just too much trouble to answer the questions. She went away convinced I was still asleep. False negatives were encountered in a study of mid latency auditory evoked responses to awareness with patients who heard the command (and thus were aware) but could not be bothered to respond.28
Post-cardiac surgery
The greatest incidence of POCD and the greatest number of studies is in patients undergoing cardiopulmonary bypass surgery (CPB) (for example see22 34 45). Many of the studies do not meet the stringent criteria set out by Rasmussen,36 but there are sufficient large scale studies using appropriate test batteries and control groups to be sure that POCD, both early and late, does occur in these patients and is common. The potential for brain injury in these patients, including hypoperfusion and micro-emboli, is self-evident and POCD is thus not surprising. However, two studies used the same test battery and methodology in both cardiac and major abdominal surgical patients and reported a similar or greater incidence of POCD in the non-cardiac group.40 50
Before the 1990s, most reports of POCD in non-cardiac surgery were anecdotal and were generally felt to be a response to some perioperative catastrophe, which may or may not have been noted by the medical attendants. The advent of pulse oximetry in the early 1980s and its subsequent widespread adoption into anaesthetic practice resulted in a large number of studies of oxygenation throughout the perioperative period. A number of studies demonstrated marked hypoxaemia at night which was at its worst on the second to the fourth night after surgery.16 41 Other studies showed that this was a result of rebound of slow wave and rapid eye movement sleep on those nights, following their suppression on the first postoperative night coupled with the parallel decline in lung function. This previously unreported hypoxaemia seemed to be the obvious cause of several postoperative complications including myocardial ischaemia and infarction and cognitive dysfunction. Möller, having conducted a major study of the benefits of pulse oximetry in anaesthetic practice,25 co-ordinated an international group of investigators (ISPOCD) to test the hypotheses that POCD existed, that it was more likely in the elderly and that it was because of postoperative hypoxaemia and/or hypotension. 1218 patients, aged over 60 yr, were studied with a brief neuropsychological test battery and continuous physiological monitoring before and 1 week and 3 months after major surgery. A subgroup of 336 patients was studied again 12 yr later. Forty-seven normal subjects were studied with the same test battery at the same time intervals. POCD was defined as a z-score of more than 2.0 as described above. The results are shown in Table 1.1 26 The investigators concluded that POCD existed and age was a major risk factor. Neither hypoxaemia nor hypotension nor the combination, were risk factors for POCD. The same group went on, in a second multicentre collaborative programme of research (ISPOCD2) using very similar methodology and the same test battery, to investigate further whether POCD followed minor surgery in the elderly and major surgery in the middle aged. They concluded that POCD was present to a very small degree in the elderly after in-patient minor surgery after 1 week but not at 3 months.9 The same was true for the middle aged undergoing major surgery (Table 1).24
While there are a number of other studies of POCD in non-cardiac patients,3 they have generally been small and the differences in methodology and criteria for the definition of POCD have been such that a meta-analysis is not appropriate. The ISPOCD studies remain the largest and best controlled of the studies conducted to date although it could properly be questioned whether the psychometric test battery was sufficiently sensitive and robust. As noted above, Rasmussen37 has re-analysed data from all patients who participated in the ISPOCD studies to examine the effects of testretest variability. He concluded that by comparing the ratio of POCD with POCI, he could be confident of cognitive decline only in elderly patients 1 week after major surgery. Only 3048% of patients with POCD at 3 months also had POCD at 1 week. POCD may be progressive and only become apparent several months after surgery. Similar results have been found after cardiac44 and carotid artery surgery.19
The evidence for POCD following cardiopulmonary bypass (CPB) is much stronger, not least because the incidence is generally greater. Newman27 found an incidence of 53% at discharge from hospital and an incidence of 36, 24, and 42% 6 weeks, 6 months, and 5 yr, respectively, after surgery. Early decline predicted late decline. Similar findings have been reported by Stygall and colleagues.47 However, neither study used a rigorous definition of POCD nor a control group to control for learning effects. Such studies raise the possibility that operation is a risk factor for early cognitive decline, including in Alzheimer's disease (AD). Further evidence comes from recent studies by Bednar and colleagues (B. Wolozin, personal communication, 2004). The development of AD 56 yr after surgery was determined in 5216 patients who had undergone coronary artery bypass grafting (CABG) and compared with 3954 patients who had undergone percutaneous transluminal coronary angioplasty (PTCA). The adjusted risk of CABG vs PTCA was 1.71 (95% CI, 1.022.87, P=0.04). However, in a further study, the same group compared the incidence of AD patients who had undergone either a prostatectomy or a herniorraphy under general (GA) or loco-regional anaesthesia (LA). After controlling for age, duration of hospitalization, co-morbidity, and number of procedures in a Cox proportional hazard model, the adjusted risk of GA vs LA was 0.65 (0.430.98) and 0.71 (0.491.04) for herniorraphy and prostatectomy, respectively. The authors suggest that this may indicate that GA may delay the onset of AD. As the patients were not randomly allocated to LA or GA however, it may indicate also that frailer patients had their operations under LA. (Abstracts of these papers (S1-03-06 and P3-437) may be found at: http://www.elan.com/icadrd/.)
Loss of olfactory function has been shown to be an early marker of cognitive decline, often preceding clinical symptoms by up to 2 yr.14 Using the same protocol and test battery as in the ISPOCD studies, odour identification ability was measured in a pilot study, before and after major surgery in the elderly, to examine whether any perioperative change in olfactory function correlated with development of POCD, or whether preoperative odour identification deficit predicted POCD.38 Neither hypothesis was supported by the results.
Some circumstantial support for a link between POCD and early cognitive decline comes from the work of Houx and colleagues on biological life events (BLE).20 21 Subjects were subjected to a battery of cognitive function tests and then, blindly, divided into those who had suffered BLE, which included minor closed head injury, self poisoning and operations lasting more than 2 h, and those who had not. Older patients without BLE had better preservation of cognitive function.
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Causation of POCD |
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Animal studies
Hanning and colleagues18 investigated the effects, in rats, of repeated anaesthesia throughout life with pentobarbital, compared with a control group. Central cholinergic function was estimated by radiolabelled -bungarotoxin and epibatidine binding in the cortex, striatum and hippocampus when the rats were 26 months old. There was a highly significant reduction in a bungarotoxin binding in the superior cortex and in the molecular cortex.
-Bungarotoxin binds to the
7 subunit of the nicotinic receptor, which is also one of the sites for anaesthetic binding,4 and is often most reduced in patients with AD.5 13 31 This was a small study with an agent no longer used in human anaesthetic practice and the results should be treated with caution. There is however, some support for an effect of long-term administration of cholinergic drugs on cognitive function from other fields. For example, patients with Parkinson's disease treated with anti-muscarinic drugs are more likely to show Alzheimer pathology at post-mortem examination;32 nicotine has been shown to be protective of nicotinic cholinergic receptors;6 49 and low level exposure to organophosphorus esters may cause neurotoxicity.22
Greater impulsivity in behavioural task performance was noted between the elderly rats that had been subject to repeated anaesthesia throughout life and the control animals mentioned above.7 Culley and colleagues have reported long-term effects of anaesthesia on cognitive function in rats with agents commonly used in human practice.11 12
Genotypes
Subjects with the apolipoprotein 4 allele are known to have worse cognitive and neurological outcomes after brain injury and stroke,48 and to be at greater risk of AD.43 The role of APOE genotype was investigated in 976 patients undergoing major surgery in the ISPOCD2 studies,2 and in the smaller odour identification study mentioned above.38 In neither study was the
4 allele a risk factor for POCD. This does not rule out the possibility of a genetic propensity for POCD but suggests that other candidate genes should be sought.
Cortisol
Hypercortisolaemia has been known for some time to impair cognitive function.30 42 It was hypothesized that hypothalamic cell loss in the elderly impaired the normal mechanisms that damp down the increased cortisol secretion that follows stress and that the normal hypercortisolaemia of surgery would be enhanced and prolonged. Morning and afternoon salivary cortisol concentrations were measured in patients receiving a general anaesthetic in the randomized study of major surgery in the elderly, which formed part of the ISPOCD2 studies.36 Other stress markers such as IL-6 were measured also. There was no evidence of greater or prolonged cortisol release in subjects with POCD although there was a loss of circadian effect in those patients (L. S. Rasmussen, personal communication, 2004). The significance of these findings remains to be elucidated.
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Conclusions |
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Acknowledgments |
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References |
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