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Neural correlates of cognitive dysfunction after cardiac surgery
Brain Research Reviews 50 (2005) 266 – 274 www.elsevier.com/locate/brainresrev
Review
Neural correlates of cognitive dysfunction after cardiac surgery Leo A. Bokeriiaa, Elena Z. Golukhovaa, Anna G. Poluninaa,b,*, Dmitry M. Davydov b, Alexey V. Begachev c a
A. N. Bakulev Scientific Center of Cardiovascular Surgery, Russian Academy of Medical Sciences, Moscow, Russia b Neuropsychology Department, Moscow Research Practical Center for Prevention of Drug Addiction, Russia c Anaesthesiology and Intensive Care Department, Medical Center of the State Bank of Russia, Russia Accepted 1 August 2005 Available online 29 September 2005
Abstract Patients who underwent cardiac surgery and their relatives often complain on postoperative memory impairment. Most prospective neuropsychological studies also found postoperative cognitive decline early after surgery. Nevertheless, recently several reports questioned the existence of long-term brain alterations in these patient cohorts. The present review was aimed to clear up the true cardiac surgery effects on brain and cognitive functions. The reviewed data evidence that cardiac surgery interventions induce persistent localized brain ischemic lesions along with rapidly reversing global brain swelling and decreased metabolism. A range of studies showed that left temporal region was especially prone to perioperative ischemic injury, and these findings might explain persistent verbal short-term memory decline in a considerable proportion of cardiac surgery patient cohorts. Speed/time of cognitive performance is commonly decreased early after on-pump surgery either. Nevertheless, no association between psychomotor speed slowing and intraoperative embolic load was found. The rapid recovery of the latter cognitive domain might be better explained by surgery related acute global brain metabolism changes rather than ischemic injury effects. Hence, analyses of performance on separate cognitive tests rather than summarized cognitive indexes are strongly recommended for future neuropsychological studies of cardiac surgery outcomes. D 2005 Elsevier B.V. All rights reserved. Theme: Disorders of the nervous system Topic: Ischemia Keywords: Cardiac surgery; Cognitive dysfunction; Ischemia; Memory; Psychomotor speed; Temporal lobe
Contents 1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Common postoperative brain alterations in cardiac surgery patients . . . . . . . . . 3. Selective effects of intraoperative microemboli on memory functions . . . . . . . . 4. Divergent dynamics of cognitive performance during the first months after surgery. 5. Possible mechanisms of localized perioperative ischemic brain damage . . . . . . . 6. Possible mechanisms of postoperative psychomotor slowing. . . . . . . . . . . . . 7. Long-term cognitive changes in cardiac surgery patients. . . . . . . . . . . . . . . 8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
* Corresponding author. Leninsky pr-t 156-368 Moscow 119571, Russia. Fax: +7 095 4387624. E-mail address: [email protected] (A.G. Polunina). 0165-0173/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.brainresrev.2005.08.001
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1. Introduction Most cardiac surgery patients demonstrate mild cognitive impairment at discharge [3,42,70], and a considerable proportion of them (7 –69% according to different criteria) do not recover in 1– 3 months after surgery. Recently, several reports questioned the existence of long-term cognitive deterioration after cardiac surgery [38,54], whereas other research groups observed surgery related decline of cognitive functions in 5 years after on-pump [43,60]. Importantly, Stygall and colleagues [60] reported the association between cognitive decline in 5 years after coronary artery bypass grafting (CABG) and the number of intraoperative microemboli. When subjective complains are questioned, these patients consistently indicate postoperative memory impairment in several years after surgery [6,56], whereas concentration, emotions, social functioning or general health is usually perceived by them as intact [6,25,56]. In the study of Bergh and colleagues [6], spouses of CABG patients also reported significant postoperative deterioration in patients’ memory, but not in other domains. Surprisingly, this study found similar negative dynamics in memory functions in patients who underwent percutaneous transluminal coronary angioplasty (PTCA). Indeed, microemboli commonly occur during PTCA either [8]. The majority of neuropsychological studies of cardiac surgery outcomes defined POCD as a postoperative decline in a test score by at least 20% or 1 standard deviation (1 SD) from the baseline score. The common definition of POCD implies postoperative impairment in at least two neuropsychological tests or cognitive domains, which in turn are chosen arbitrarily. This approach refers to the suggestion of ‘‘mosaic’’ character of brain damage during cardiac surgery due to by chance delivery of microemboli to the brain vasculature [9,39,59]. At the same time, empirical findings evidenced that only memory and psychomotor speed tests demonstrated high sensitivity to the POCD, therefore only word list learning paradigm (Rey Auditory Verbal Learning Test = RAVLT) and three tests measuring speed/time of performance (Grooved Pegboard, Trail Making Test parts A and B = TMT A and B) were recommended as a core test battery by the Statement of Consensus on Assessment of Neurobehavioral Outcomes after Cardiac Surgery [39]. Hence, in the present review, we referred predominantly to the studies which reported dynamics of performance on separate neuropsychological tests rather than summarized indexes of postoperative cognitive decline. Thus, many issues concerning cardiac surgery effects on brain structure and functions remain unclear. In the present review, we made an attempt to clear up the following matters: (1) what structural and electrophysiological brain alterations are commonly seen in cardiac surgery patients without gross neurological deficits, and which of the postoperative brain changes rapidly reverse and which persist later on; (2) what
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effects of intraoperative embolic load on cognitive functions were reported; (3) what dynamics of postoperative performance on separate neuropsychological tests is characteristic for the cardiac surgery patient populations during the first weeks and months after cardiac surgery; (4) what possible mechanisms underlie localized perioperative ischemic brain injury; (5) what possible mechanisms underlie postoperative psychomotor slowing and finally, (6) what long-term neuropsychological changes were registered in the cardiac surgery patient cohorts. The reviewed literature data were summarized, and neural correlates of cognitive dysfunction after cardiac surgery were outlined.
2. Common postoperative brain alterations in cardiac surgery patients Neuroimaging studies consistently documented characteristic global and regional changes in brain structure and functioning early post cardiac surgery (Table 1). Brain swelling is commonly observed during the first 3 days after cardio-pulmonary bypass (CPB) and tends to disappear at the end of the first postoperative week [2,5,21]. Global brain metabolism decrease as measured by N-acetylaspartate/creatine ratio was also pronounced on the third postoperative day and significantly improved during the following 2 weeks in the study of Bendszus and colleagues [5]; whereas global decrease of cerebral glucose metabolism was still observed on the 8– 12th postoperative day by Jacobs and colleagues [23]. Three studies found new small ischemic lesions at diffusion-weighted MRI scans on the 4 – 5th postoperative day in more than 1/3 of cardiac surgery patients [5,28,49]; whereas T2-weighted MRI detected new ischemic lesions in 2 –6 week after surgery in 1/5 of patients [63,72]. Interestingly, two SPECT studies reported alterations in the left temporal region in patients which underwent CABG without gross neurological alterations [30,46]. Lee and colleagues [30] observed cerebral blood flow decrease in the left temporal and bilateral occipital and cerebellar lobes on the third day after surgery. Rasmussen and colleagues [46] reported significant decrease in benzodiazepine receptor density in left temporal and bilateral frontal cortex in 3 months after CABG. At the same time, Jacobs and colleagues [23] did not find asymmetry in postoperative regional glucose metabolism decrease between two hemispheres. However, authors stressed predominant impairment of cortical areas but not basal ganglia or infratentorial structures in their study. Spontaneous brain electric activity in 1 week after onpump surgery was characterized by excessive beta power in the study of Toner et al. [68]. In contrast, 2 months after surgery, the same patient sample demonstrated total power decrease most prominent in alpha and beta frequency bands. Similar data were reported by Vanninen and colleagues [72], who found global slowing of EEG total mean frequency in CABG patients in 3 months after surgery.
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Table 1 Postoperative brain alterations in cardiac surgery Brain alterations
Time of postsurgery
Recovery
Proportion of deteriorated patients (n)
Method
References
Brain swelling
1 – 3 days
7th day
71% (7), GM (10 – 35)
Diffusion-weighted MRI FLAIR MRI
Harris et al.; Anderson et al.; Bendszus et al. ([2,5,21])
Global and regional brain metabolism changes Decreased NAA/Cr ration Decreased global cerebral glucose metabolism Regional bilateral glucose metabolism changes Global cerebral blood flow increase New ischemic lesions
3rd day 8 – 12 days 8 – 12 days 6th day 4 – 5 day
10 – 14 days – – – –
GM (35) GM (18) GM (18) GM (12) 31 – 45% (13 – 35)
MRS PET PET CASL-P-MRI Diffusion-weighted MRI
2 – 6 weeks
–
18 – 21% (27 – 38)
T2-weighted MRI
3rd day
–
GM (30)
SPECT
Bendszus et al. [5] Jacobs et al. [23] Jacobs et al. [23] Floyd et al. [18] Bendszus et al.; Restrepo et al.; Knipp et al. ([5,28,49]) Vanninen et al.; Sylivris e al. ([63,72]) Lee et al. [30]
3 months
–
GM (15)
SPECT
Rasmussen et al. [46]
7th day 2 – 3 months
2 months –
GM (62) GM (38 – 62)
EEG EEG
7th day
2 months
GM (61)
Evoked EEG potentials
Toner et al. [68] Toner et al.; Vanninen et al. ([68,72]) Toner et al. [67]
7th day
2 – 4 months
Evoked EEG potentials
4 months
–
GM (61) GM (30 – 308) GM (30)
Brain perfusion decrease in bilateral occipital and cerebellar lobes and in left temporal lobe Benzodiazepine receptor density decrease in bilateral frontal and left temporal lobe Relative beta activity power increase Total power decrease most prominent in alpha/beta bands, slowing of the total mean frequency (1.46 – 20.02 Hz) Decreased amplitude of P300 component of auditory cognitive EP Prolonged latency of P300 component of auditory cognitive EP
Toner et al. [67] Kilo et al. [26] Zimpfer et al. [79]
Abbreviations: n, number of patients in studied cohort; GM, significant difference in group means at baseline and postoperative follow-up; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NAA/Cr ratio, N-acetylaspartate-creatine ratio; FLAIR MRI, fluid attenuated inversion recovery magnetic resonance imaging; PET, positron emission tomography; SPECT, single photon emission computer tomography; CASL-P-MRI, continuous arterial spin labeling perfusion MRI; EEG, electroencephalography; EP, evoked potentials.
In 1 week after CPB, decreased amplitude and/or prolongation of latency of P300 component of evoked cognitive potentials were consistently reported in three studies [26,67,79]. The same research groups observed normalization of P300 in 2 –4 months after surgery in a considerable proportion of patients. Nevertheless, patients with prolonged CPB or aortic valve replacement were still characterized by increased P300 latency in 4 months after surgery [26,79]. In summary, during the first week after cardiac surgery, brain structure and functions are globally affected. This early postoperative period is characterized by global brain swelling, global decrease of brain metabolism, increased fast (beta) activity in EEG and slowing and weakening of brain electric potentials, which are generated at cognitive stimuli. Fortunately, most of these global changes rapidly reverse. However, the considerable proportion of patients demonstrated persisting small ischemic lesions after on-pump interventions. EEG studies also found significant slowing of brain electric activity in several months after surgery. Few neuroimaging data evidence that some brain regions (left temporal cortex) are especially prone to the postoperative alterations.
3. Selective effects of intraoperative microemboli on memory functions Significant association between the number of intraoperative microemboli and early and/or delayed postoperative decline of summarized neuropsychological indexes was consistently shown by several studies [11,16, 20,51,60,63]. Unfortunately, very few reports addressed the microemboli effects on performance on separate neuropsychological tests. In the study of Fearn and colleagues [17], number of intraoperative embolic signals at the middle cerebral artery significantly affected accuracy on the Digit Span paradigm test. These authors stressed the selectiveness of the microemboli effects on memory functions. In the study of Borger et al. [10], the number of perfusionist interventions during surgery was significantly associated with the postoperative performance on the Digit Span, Visual Span and RAVLT, but not with the TMT, Grooved Pegboard or Verbal Fluency tests. Importantly, the same authors showed that the majority of cerebral microemboli during CABG were caused by the injection of air into the venous side of the CPB circuit (i.e., by the perfusionist interventions) [66].
L.A. Bokeriia et al. / Brain Research Reviews 50 (2005) 266 – 274
Selnes and colleagues [52] found the significant association between the degree of aortic atherosclerosis (degree of surgeon’s difficulty in selecting a cross-clamp site) and the postoperative deterioration of short-term memory (sum of the scores on the Digit Span and RAVLT immediate recall). The former intraoperative factor did not correlate with the postoperative decline in performance on Grooved Pegboard, Digit Symbol or Stroop tests. In turn, the speed/time of performance on the latter test paradigms was associated with the diabetes mellitus, blood urea nitrogen level and/or serum creatinine level at discharge. Mora and colleagues [37] also found selective positive effect of intraoperative hypothermia on the postoperative performance on Digit Span, but not on Digit Symbol or Grooved Pegboard tests. Authors referred to the results of animal studies, which showed that mild hypothermia ameliorated cerebral ischemic damage. Lee and colleagues [30] observed slight left-sided predominance of intraoperative microemboli in both onpump and off-pump patient groups. As it might be expected, the number of microemboli was significantly higher in on-pump patients, and only this group demonstrated significant reduction of brain perfusion to the left temporal lobe early after surgery. Moreover, the on-pump patients did not show practice effect on RAVLT which was prominent in the off-pump cohort in 2 weeks and 1 year after surgery. The authors concluded that intraoperative microembolic damage of left temporal region might underlie the relative impairment of verbal memory in their on-pump patient cohort. Hence, the results of several prospective studies evidenced that intraoperative embolic load selectively affected memory (especially verbal short-term memory) functions in comparison to psychomotor speed or verbal fluency. Two research groups directly pointed to the association between intraoperative embolic load and postoperative decline in verbal short-term memory.
4. Divergent dynamics of cognitive performance during the first months after surgery We analyzed the postoperative group mean changes of the performance on 12 neuropsychological test paradigms, which were used in the assessment of cardiac surgery outcomes most often (Table 2). As original test paradigms are often being modified and used under various names, we referred to the Compendium of Neuropsychological Tests by Spreen and Strauss [57] in order to determine the identity of a reported neuropsychological tool. Hence, names of the discussed tests designate original paradigms rather than primary versions of tests. Overall, data on dynamics of cognitive performance were extracted from 40 prospective studies of on-pump patient cohorts. As might be seen from figures in the Table 2, tests measuring speed/time of performance demonstrated prom-
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inently high sensitivity to the early POCD. All 13 patient groups (10 studies) which performed Pegboard test during the first postoperative week demonstrated significant group mean worsening. At the same time, only one of 20 patient groups showed decline on Grooved Pegboard in 1 – 3 months postoperatively. Similar dynamics was characteristic for Digit Symbol test. Thirteen from fifteen patient cohorts significantly worsened on this psychomotor speed test paradigm early after surgery. In contrast, only one from 20 groups performed this test poorly in 1– 3 months after CPB. Fewer data are available on computer reaction time tasks, Stroop word/color and Letter Cancellation tests. Nevertheless, most examined cardiac surgery cohorts demonstrated significant decline on these speed/time paradigms during the first postoperative week, and none patient group was significantly ‘‘impaired’’ in 1 – 3 months after surgery. It should be noted, that part A of the Trail Making Test (TMT A) was the only test paradigm of this type, which did not demonstrate consistent group mean changes early after surgery. However, TMT A is too easy to perform (trailing numbers from 1 to 25 in forward order), and this may explain its low sensitivity in the context of cardiac surgery outcomes research. Hence, speed of cognitive performance is commonly impaired early after cardiac surgery, but fortunately, this brain functional deficit rapidly recovers during the first months after CPB in the majority of patients. Delayed recall of learned words (RAVLT was used in most studies) was also impaired early after CPB in most (10 from 12) tested patient groups. In contrast to the speed/time tasks, delayed recall did not recover in four from nine (44%) patient cohorts in 1– 3 months after cardiac surgery. Immediate recall in word list learning tests or Digit Span test showed less sensitivity to the early POCD, i.e., only 1– 2 thirds of patient groups significantly declined on these tasks at discharge. Again, at delayed follow-up, somewhat larger proportion of patient groups (10 – 12%) demonstrated significant impairment on these cognitive tests in comparison to speed/time paradigms. Hence, the speed of cognitive performance is commonly impaired early after surgery and rapidly recovers during the first postoperative weeks. Decline of verbal short-term memory represents a rarer postoperative event in comparison to psychomotor slowing. However, a considerable proportion of on-pump patients showed persistent deficits in verbal short-term memory in several months after surgery.
5. Possible mechanisms of localized perioperative ischemic brain damage The cited data of SPECT and neuropsychological studies give serious grounds to suggest that cardiac surgery is associated with predominant suffering of the left temporal
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Table 2 Dynamics of cognitive performance after cardiac surgery
Speed of performance Pegboard test Digit symbol test Reaction time tasks Stroop test Letter cancellation TMT, part B TMT, part A Accuracy of performance Word list learning (delayed recall) Word list learning (immediate recall) Digit span WMS nonverbal memory subtests Verbal fluency test Benton VRT Block design
Proportion of studies with significant mean group decline
Incidence of POCD (1 SD criterion)a
1 week follow-up
6 – 30 months follow-up
1 week follow-up
0% 0% 30% 0% 0% 0% 0%
18% (n 6% (n – 8% (n 11% (n 25% (n 13% (n
100% (n = 13) 87% (n = 15) 80% (n = 5) 75% (n = 4) 73% (n = 11) 69% (n = 13) 13% (n = 15)
1 – 3 months follow-up 5% 5% 0% 0% 0% 4% 0%
(n (n (n (n (n (n (n
= = = = = = =
20) 20) 11) 3) 9) 26) 17)
83% (n = 12)
44% (n = 9)
58% (n = 12)
10% (n = 21)
31% (n = 13) 22% (n = 9) 33% (n = 9) 33% (n = 3) 25% (n = 4)
(n (n (n (n (n (n (n
= = = = = = =
7) 7) 3) 5) 3) 9) 8)
–
= 6) = 9) = 1) = 1) = 2) = 5)
References (in alphabetic order)
1 – 3 months follow-up 6% 0% 7% 1% 9% 9% 7%
(n (n (n (n (n (n (n
= = = = = = =
5) 5) 6) 3) 2) 3) 4)
24% (n = 2)
16% (n = 3)
0% (n = 5)
28% (n = 2)
7% (n = 3)
12% (n = 17) 20% (n = 5)
0% (n = 5) –
11% (n = 5) 8% (n = 2)
7% (n = 3) 20% (n = 2)
0% (n = 9) 0% (n = 2) 0% (n = 2)
50% (n = 2) 30% (n = 3) 0% (n = 2)
15% (n = 2) 41% (n = 2) –
10% (n = 1) – –
Ahlgren et al. [1]; Bendszus et al. [5]; Borger et al. [10]; Brækken et al. [11]; Browne et al. [13]; Bruggemans et al. [15]; Fearn[17]; Grieco et al. [19]; Jacobs et al. [23]; Kilo et al. [26]; Kneebone et al. [27]; Knipp et al. [28]; Lee et al. [30]; Lloyd et al. [32]; Mahanna et al. [34]; McKhann et al. [35]; Millar et al. [36]; Mora et al. [37]; Mu¨llges et al. [38]; Nagels et al. [40]; Neville et al. [41]; Reents et al. [47]; Regragui et al. [48]; Robson et al. [50]; Selnes et al. [54]; Silbert et al. [55]; Steed et al. [58]; Stygall et al. [60]; Sugiyama et al. [61]; Taggart et al. [64]; Taggart et al. [65]; Toner et al. [68]; Uebelhack et al. [69]; Van Dijk et al. [71]; Vanninen et al. [72]; Vingerhoets et al. [73]; Wang et al. [74]; Westaby et al. [77]; Zamvar et al. [78]; Zimpfer et al. [79]
Abbreviations: n, number of patient groups; POCD, postoperative cognitive decline; SD, standard deviation; TMT, trail making test; VRT, visual retention test; WMS, Wechsler memory scale. a Incidence of decline on individual tests is presented as medians of the cited data.
L.A. Bokeriia et al. / Brain Research Reviews 50 (2005) 266 – 274
Neuropsychological tests
L.A. Bokeriia et al. / Brain Research Reviews 50 (2005) 266 – 274
region, which serves verbal short-term memory processes. Few studies addressed the distribution pattern of major perioperative ischemic strokes, nevertheless, two of them also pointed to predominant left hemisphere damage during cardiac interventions. Both studies found preponderance of left hemisphere strokes (75% and 81.5%, respectively), which occurred within 1– 3 days since coronary artery bypass grafting [75] and percutaneous transluminal coronary angioplasty [31]. Several explanations for these findings may be suggested. First, medial temporal cortex which mediates verbal memory processing is supplied by the posterior circulation, which in turn was shown to be compromised during general anesthesia in a large subgroup of patients. Weintraub and Khoury [76] demonstrated that neck hyperextension during tracheal intubation induced reduction of blood flow in the basilar artery, which was especially prominent in patients with vertebral and/or carotid stenoses or occlusions. Kostylyov [29] also observed slowing of blood flow in occipital venous sinus along with increased intracranial pressure at tracheal intubation and general anesthesia in patients with chronic cerebrovascular disease. High risk of perioperative ischemic stroke in posterior circulation was also demonstrated in this subgroup of general anesthesia patients [7]. Hence, even when massive microemboli are lacking, the posterior circulation, including left medial temporal cortex, is especially prone to intraoperative ischemia in atherosclerotic patients. Second, in their neuropathological study, Brown and colleagues [12] showed that with increasing survival time the total embolic load along with percentage of large and medium emboli significantly declined in brain specimen of patients after CPB. Authors explained these findings by pumping of the lipid emboli through the brain and by breaking larger emboli into smaller globules as they pass through the capillary network. Clearly, the compromised posterior circulation may hamper these sanative processes in posterior brain structures in contrast to anterior brain. Finally, some anatomical characteristics of left temporal circulation or particular sensitivity of left temporal cortex to ischemic damage may predispose patients to the selective postoperative decline of verbal short-term memory. For instance, Fearn and colleagues [17] observed greater deteriorative effects of asymmetric delivery of microemboli to the left hemisphere in comparison to the right one. Thus, the cited data give serious grounds to suggest that the left temporal region, which serves verbal short-term memory, is especially prone to perioperative ischemia in cardiac surgery patients. Several reports pointed to prominent disturbances in posterior arterial and venous circulation during intubation and general anesthesia, which might considerably contribute to postoperative memory decline even when massive microemboli are lacking. Finally, some anatomical factors also may underlie the prominent sensi-
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tivity of left temporal cortex to perioperative ischemic damage.
6. Possible mechanisms of postoperative psychomotor slowing Slowing of speed/time of performance in a variety of neuropsychological test paradigms, which is commonly seen in cardiac surgery patients during the first postoperative week, does not seem to relate directly to the embolic load effects. Indeed, the rapid postoperative recovery of psychomotor speed is similar to the positive dynamics of postoperative brain swelling and global metabolism decrease, which were reported by neuroimaging studies. Hence, the acute psychomotor slowing after cardiac surgery may be better explained by diffuse brain biochemistry/metabolism disturbances rather than true postoperative Fbrain injury_. Interestingly, Bendszus and colleagues [4,5] reported similar global decrease of brain metabolism as measured by NAA/Cr ratio in acute alcohol withdrawal and cardiac surgery patient cohorts. Moreover, psychomotor slowing was also pronounced and significantly correlated with NAA/Cr decrease in both patient groups. Importantly, the symptoms dramatically improved in 2 –4 weeks in both alcoholics and cardiac surgery patients. The pronounced increase in spontaneous EEG beta activity early after cardiac surgery is also akin to the conditions with pronounced neurobiochemical imbalances as acute alcohol or heroin withdrawal is [44,45]. Moreover, strong correlation between psychomotor slowing as measured by performance on Digit Symbol and increased beta activity in spontaneous EEG is a well known phenomenon, demonstrated in many studies [24,33]. Probably, these acute postoperative disturbances in brain functioning represent stress/inflammatory response to a series of intraoperative traumatic events as surgical injury, CPB and general anesthesia are. Moreover, some postoperative factors may also contribute to this condition. For instance, Browne and colleagues [14] demonstrated direct association between composite cognitive index at the 5th postoperative day and the hypoxia (mean arterial oxygen tension) due to postoperative respiratory impairment. It seems very probable that patients with any complication would perform slower on psychomotor speed tests in comparison to patients with Fideal_ postoperative course. Many studies showed (Table 2) that 6– 9% of cardiac surgery patients continued to perform ‘‘speed’’ tests significantly slower in 1 –3 months after cardiac surgery. These findings might be very well explained in the context of the data of Selnes and colleagues [52], who showed that psychomotor slowing in 1 month and 1 year after CABG was significantly related to the conditions (diabetus mellitus and renal dysfunction) compromising brain metabolism.
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Hence, postoperative psychomotor slowing appears to represent prominent nevertheless reverse global brain metabolism changes rather than true ‘‘perioperative brain injury’’. Therefore, summarized indexes of postoperative cognitive decline which are commonly used in the research of cardiac surgery outcomes do not seem to represent an Fevidencebased_ approach. The literatures cited in the present review give strong grounds to recommend separate neuropsychological test analyses rather than summarized indexes for future research of cardiac surgery outcomes.
7. Long-term cognitive changes in cardiac surgery patients We compared the incidence of POCD (proportion of declined patients) at discharge to the incidence at 6 and more months after surgery in the same five patient cohorts [22,34,41,43] by paired t tests. As expected, the difference in incidence of POCD at discharge and at long-term follow-up was significant (54 T 12% vs. 16 T 12%, t = 9.89, P = 0.001). When similar analyses compared the incidence at 1– 3 months follow-up and the incidence at 6 and more months after cardiac surgery in 6 patient cohorts [30,34,41,43,71], no significant difference was found (23 T 8% vs. 21 T 9%, t = 0.64, P = 0.54). One study [43] reported the secondary increase of the incidence of POCD from 6 months (24% of patients) to 5 years (42% of patients) after cardiac surgery. Few data are available on long-term dynamics of performance on separate neuropsychological tests after cardiac surgery. Some reports consistently demonstrated secondary decline of cognitive performance in 6 and more months after on-pump interventions. In the study of Fearn and colleagues [17], CABG patients did not show any slowing of reaction time in 6 cognitive tests at 2 months follow-up, whereas the same patient group performed the same tests significantly slower in 6 months after surgery. McKhann and colleagues [35] reported secondary decline on Stroop test, Boston Naming test and Rey Complex Figure Test in 11 –24% of CABG patients, who performed these tests normally at 1 month follow-up and demonstrated 0.5 SD decline in 1 year after surgery. In the same patient population, Selnes and colleagues [53] found secondary decline of group means of performance on the latter three tests along with performance on Pegboard test from 1 year to 5 years after CABG. Indeed, the proportion of middle age healthy individuals, who declines on the Digit Symbol test (a change >1 SD) during the 5-year interval is rather high and constitutes about 35– 39% [62]. Hence, secondary cognitive decline after 6 months since cardiac surgery was consistently reported; nevertheless, no data indicated that this deterioration is related to cardiac surgery effects rather than aging or concomitant pathological processes.
8. Conclusion Cardiac surgery induces long-term localized brain ischemic lesions along with rapidly reversing global brain swelling and decreased metabolism. A range of studies evidenced that left temporal region is especially prone to perioperative ischemic injury, and these findings may explain persistent verbal short-term memory decline in a considerable proportion of cardiac surgery patients. Speed/ time of cognitive performance is commonly decreased early after on-pump surgery either. Nevertheless, no associations between slowing of psychomotor speed and intraoperative embolic load were found. The rapid recovery of the latter cognitive domain might be better explained by surgery related acute global brain metabolism changes rather than ischemic injury effects. Hence, analyses of performance on separate cognitive tests rather than summarized cognitive indexes are strongly recommended for future neuropsychological studies of cardiac surgery outcomes.
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Review
Neural correlates of cognitive dysfunction after cardiac surgery Leo A. Bokeriiaa, Elena Z. Golukhovaa, Anna G. Poluninaa,b,*, Dmitry M. Davydov b, Alexey V. Begachev c a
A. N. Bakulev Scientific Center of Cardiovascular Surgery, Russian Academy of Medical Sciences, Moscow, Russia b Neuropsychology Department, Moscow Research Practical Center for Prevention of Drug Addiction, Russia c Anaesthesiology and Intensive Care Department, Medical Center of the State Bank of Russia, Russia Accepted 1 August 2005 Available online 29 September 2005
Abstract Patients who underwent cardiac surgery and their relatives often complain on postoperative memory impairment. Most prospective neuropsychological studies also found postoperative cognitive decline early after surgery. Nevertheless, recently several reports questioned the existence of long-term brain alterations in these patient cohorts. The present review was aimed to clear up the true cardiac surgery effects on brain and cognitive functions. The reviewed data evidence that cardiac surgery interventions induce persistent localized brain ischemic lesions along with rapidly reversing global brain swelling and decreased metabolism. A range of studies showed that left temporal region was especially prone to perioperative ischemic injury, and these findings might explain persistent verbal short-term memory decline in a considerable proportion of cardiac surgery patient cohorts. Speed/time of cognitive performance is commonly decreased early after on-pump surgery either. Nevertheless, no association between psychomotor speed slowing and intraoperative embolic load was found. The rapid recovery of the latter cognitive domain might be better explained by surgery related acute global brain metabolism changes rather than ischemic injury effects. Hence, analyses of performance on separate cognitive tests rather than summarized cognitive indexes are strongly recommended for future neuropsychological studies of cardiac surgery outcomes. D 2005 Elsevier B.V. All rights reserved. Theme: Disorders of the nervous system Topic: Ischemia Keywords: Cardiac surgery; Cognitive dysfunction; Ischemia; Memory; Psychomotor speed; Temporal lobe
Contents 1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Common postoperative brain alterations in cardiac surgery patients . . . . . . . . . 3. Selective effects of intraoperative microemboli on memory functions . . . . . . . . 4. Divergent dynamics of cognitive performance during the first months after surgery. 5. Possible mechanisms of localized perioperative ischemic brain damage . . . . . . . 6. Possible mechanisms of postoperative psychomotor slowing. . . . . . . . . . . . . 7. Long-term cognitive changes in cardiac surgery patients. . . . . . . . . . . . . . . 8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
* Corresponding author. Leninsky pr-t 156-368 Moscow 119571, Russia. Fax: +7 095 4387624. E-mail address: [email protected] (A.G. Polunina). 0165-0173/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.brainresrev.2005.08.001
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1. Introduction Most cardiac surgery patients demonstrate mild cognitive impairment at discharge [3,42,70], and a considerable proportion of them (7 –69% according to different criteria) do not recover in 1– 3 months after surgery. Recently, several reports questioned the existence of long-term cognitive deterioration after cardiac surgery [38,54], whereas other research groups observed surgery related decline of cognitive functions in 5 years after on-pump [43,60]. Importantly, Stygall and colleagues [60] reported the association between cognitive decline in 5 years after coronary artery bypass grafting (CABG) and the number of intraoperative microemboli. When subjective complains are questioned, these patients consistently indicate postoperative memory impairment in several years after surgery [6,56], whereas concentration, emotions, social functioning or general health is usually perceived by them as intact [6,25,56]. In the study of Bergh and colleagues [6], spouses of CABG patients also reported significant postoperative deterioration in patients’ memory, but not in other domains. Surprisingly, this study found similar negative dynamics in memory functions in patients who underwent percutaneous transluminal coronary angioplasty (PTCA). Indeed, microemboli commonly occur during PTCA either [8]. The majority of neuropsychological studies of cardiac surgery outcomes defined POCD as a postoperative decline in a test score by at least 20% or 1 standard deviation (1 SD) from the baseline score. The common definition of POCD implies postoperative impairment in at least two neuropsychological tests or cognitive domains, which in turn are chosen arbitrarily. This approach refers to the suggestion of ‘‘mosaic’’ character of brain damage during cardiac surgery due to by chance delivery of microemboli to the brain vasculature [9,39,59]. At the same time, empirical findings evidenced that only memory and psychomotor speed tests demonstrated high sensitivity to the POCD, therefore only word list learning paradigm (Rey Auditory Verbal Learning Test = RAVLT) and three tests measuring speed/time of performance (Grooved Pegboard, Trail Making Test parts A and B = TMT A and B) were recommended as a core test battery by the Statement of Consensus on Assessment of Neurobehavioral Outcomes after Cardiac Surgery [39]. Hence, in the present review, we referred predominantly to the studies which reported dynamics of performance on separate neuropsychological tests rather than summarized indexes of postoperative cognitive decline. Thus, many issues concerning cardiac surgery effects on brain structure and functions remain unclear. In the present review, we made an attempt to clear up the following matters: (1) what structural and electrophysiological brain alterations are commonly seen in cardiac surgery patients without gross neurological deficits, and which of the postoperative brain changes rapidly reverse and which persist later on; (2) what
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effects of intraoperative embolic load on cognitive functions were reported; (3) what dynamics of postoperative performance on separate neuropsychological tests is characteristic for the cardiac surgery patient populations during the first weeks and months after cardiac surgery; (4) what possible mechanisms underlie localized perioperative ischemic brain injury; (5) what possible mechanisms underlie postoperative psychomotor slowing and finally, (6) what long-term neuropsychological changes were registered in the cardiac surgery patient cohorts. The reviewed literature data were summarized, and neural correlates of cognitive dysfunction after cardiac surgery were outlined.
2. Common postoperative brain alterations in cardiac surgery patients Neuroimaging studies consistently documented characteristic global and regional changes in brain structure and functioning early post cardiac surgery (Table 1). Brain swelling is commonly observed during the first 3 days after cardio-pulmonary bypass (CPB) and tends to disappear at the end of the first postoperative week [2,5,21]. Global brain metabolism decrease as measured by N-acetylaspartate/creatine ratio was also pronounced on the third postoperative day and significantly improved during the following 2 weeks in the study of Bendszus and colleagues [5]; whereas global decrease of cerebral glucose metabolism was still observed on the 8– 12th postoperative day by Jacobs and colleagues [23]. Three studies found new small ischemic lesions at diffusion-weighted MRI scans on the 4 – 5th postoperative day in more than 1/3 of cardiac surgery patients [5,28,49]; whereas T2-weighted MRI detected new ischemic lesions in 2 –6 week after surgery in 1/5 of patients [63,72]. Interestingly, two SPECT studies reported alterations in the left temporal region in patients which underwent CABG without gross neurological alterations [30,46]. Lee and colleagues [30] observed cerebral blood flow decrease in the left temporal and bilateral occipital and cerebellar lobes on the third day after surgery. Rasmussen and colleagues [46] reported significant decrease in benzodiazepine receptor density in left temporal and bilateral frontal cortex in 3 months after CABG. At the same time, Jacobs and colleagues [23] did not find asymmetry in postoperative regional glucose metabolism decrease between two hemispheres. However, authors stressed predominant impairment of cortical areas but not basal ganglia or infratentorial structures in their study. Spontaneous brain electric activity in 1 week after onpump surgery was characterized by excessive beta power in the study of Toner et al. [68]. In contrast, 2 months after surgery, the same patient sample demonstrated total power decrease most prominent in alpha and beta frequency bands. Similar data were reported by Vanninen and colleagues [72], who found global slowing of EEG total mean frequency in CABG patients in 3 months after surgery.
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Table 1 Postoperative brain alterations in cardiac surgery Brain alterations
Time of postsurgery
Recovery
Proportion of deteriorated patients (n)
Method
References
Brain swelling
1 – 3 days
7th day
71% (7), GM (10 – 35)
Diffusion-weighted MRI FLAIR MRI
Harris et al.; Anderson et al.; Bendszus et al. ([2,5,21])
Global and regional brain metabolism changes Decreased NAA/Cr ration Decreased global cerebral glucose metabolism Regional bilateral glucose metabolism changes Global cerebral blood flow increase New ischemic lesions
3rd day 8 – 12 days 8 – 12 days 6th day 4 – 5 day
10 – 14 days – – – –
GM (35) GM (18) GM (18) GM (12) 31 – 45% (13 – 35)
MRS PET PET CASL-P-MRI Diffusion-weighted MRI
2 – 6 weeks
–
18 – 21% (27 – 38)
T2-weighted MRI
3rd day
–
GM (30)
SPECT
Bendszus et al. [5] Jacobs et al. [23] Jacobs et al. [23] Floyd et al. [18] Bendszus et al.; Restrepo et al.; Knipp et al. ([5,28,49]) Vanninen et al.; Sylivris e al. ([63,72]) Lee et al. [30]
3 months
–
GM (15)
SPECT
Rasmussen et al. [46]
7th day 2 – 3 months
2 months –
GM (62) GM (38 – 62)
EEG EEG
7th day
2 months
GM (61)
Evoked EEG potentials
Toner et al. [68] Toner et al.; Vanninen et al. ([68,72]) Toner et al. [67]
7th day
2 – 4 months
Evoked EEG potentials
4 months
–
GM (61) GM (30 – 308) GM (30)
Brain perfusion decrease in bilateral occipital and cerebellar lobes and in left temporal lobe Benzodiazepine receptor density decrease in bilateral frontal and left temporal lobe Relative beta activity power increase Total power decrease most prominent in alpha/beta bands, slowing of the total mean frequency (1.46 – 20.02 Hz) Decreased amplitude of P300 component of auditory cognitive EP Prolonged latency of P300 component of auditory cognitive EP
Toner et al. [67] Kilo et al. [26] Zimpfer et al. [79]
Abbreviations: n, number of patients in studied cohort; GM, significant difference in group means at baseline and postoperative follow-up; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NAA/Cr ratio, N-acetylaspartate-creatine ratio; FLAIR MRI, fluid attenuated inversion recovery magnetic resonance imaging; PET, positron emission tomography; SPECT, single photon emission computer tomography; CASL-P-MRI, continuous arterial spin labeling perfusion MRI; EEG, electroencephalography; EP, evoked potentials.
In 1 week after CPB, decreased amplitude and/or prolongation of latency of P300 component of evoked cognitive potentials were consistently reported in three studies [26,67,79]. The same research groups observed normalization of P300 in 2 –4 months after surgery in a considerable proportion of patients. Nevertheless, patients with prolonged CPB or aortic valve replacement were still characterized by increased P300 latency in 4 months after surgery [26,79]. In summary, during the first week after cardiac surgery, brain structure and functions are globally affected. This early postoperative period is characterized by global brain swelling, global decrease of brain metabolism, increased fast (beta) activity in EEG and slowing and weakening of brain electric potentials, which are generated at cognitive stimuli. Fortunately, most of these global changes rapidly reverse. However, the considerable proportion of patients demonstrated persisting small ischemic lesions after on-pump interventions. EEG studies also found significant slowing of brain electric activity in several months after surgery. Few neuroimaging data evidence that some brain regions (left temporal cortex) are especially prone to the postoperative alterations.
3. Selective effects of intraoperative microemboli on memory functions Significant association between the number of intraoperative microemboli and early and/or delayed postoperative decline of summarized neuropsychological indexes was consistently shown by several studies [11,16, 20,51,60,63]. Unfortunately, very few reports addressed the microemboli effects on performance on separate neuropsychological tests. In the study of Fearn and colleagues [17], number of intraoperative embolic signals at the middle cerebral artery significantly affected accuracy on the Digit Span paradigm test. These authors stressed the selectiveness of the microemboli effects on memory functions. In the study of Borger et al. [10], the number of perfusionist interventions during surgery was significantly associated with the postoperative performance on the Digit Span, Visual Span and RAVLT, but not with the TMT, Grooved Pegboard or Verbal Fluency tests. Importantly, the same authors showed that the majority of cerebral microemboli during CABG were caused by the injection of air into the venous side of the CPB circuit (i.e., by the perfusionist interventions) [66].
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Selnes and colleagues [52] found the significant association between the degree of aortic atherosclerosis (degree of surgeon’s difficulty in selecting a cross-clamp site) and the postoperative deterioration of short-term memory (sum of the scores on the Digit Span and RAVLT immediate recall). The former intraoperative factor did not correlate with the postoperative decline in performance on Grooved Pegboard, Digit Symbol or Stroop tests. In turn, the speed/time of performance on the latter test paradigms was associated with the diabetes mellitus, blood urea nitrogen level and/or serum creatinine level at discharge. Mora and colleagues [37] also found selective positive effect of intraoperative hypothermia on the postoperative performance on Digit Span, but not on Digit Symbol or Grooved Pegboard tests. Authors referred to the results of animal studies, which showed that mild hypothermia ameliorated cerebral ischemic damage. Lee and colleagues [30] observed slight left-sided predominance of intraoperative microemboli in both onpump and off-pump patient groups. As it might be expected, the number of microemboli was significantly higher in on-pump patients, and only this group demonstrated significant reduction of brain perfusion to the left temporal lobe early after surgery. Moreover, the on-pump patients did not show practice effect on RAVLT which was prominent in the off-pump cohort in 2 weeks and 1 year after surgery. The authors concluded that intraoperative microembolic damage of left temporal region might underlie the relative impairment of verbal memory in their on-pump patient cohort. Hence, the results of several prospective studies evidenced that intraoperative embolic load selectively affected memory (especially verbal short-term memory) functions in comparison to psychomotor speed or verbal fluency. Two research groups directly pointed to the association between intraoperative embolic load and postoperative decline in verbal short-term memory.
4. Divergent dynamics of cognitive performance during the first months after surgery We analyzed the postoperative group mean changes of the performance on 12 neuropsychological test paradigms, which were used in the assessment of cardiac surgery outcomes most often (Table 2). As original test paradigms are often being modified and used under various names, we referred to the Compendium of Neuropsychological Tests by Spreen and Strauss [57] in order to determine the identity of a reported neuropsychological tool. Hence, names of the discussed tests designate original paradigms rather than primary versions of tests. Overall, data on dynamics of cognitive performance were extracted from 40 prospective studies of on-pump patient cohorts. As might be seen from figures in the Table 2, tests measuring speed/time of performance demonstrated prom-
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inently high sensitivity to the early POCD. All 13 patient groups (10 studies) which performed Pegboard test during the first postoperative week demonstrated significant group mean worsening. At the same time, only one of 20 patient groups showed decline on Grooved Pegboard in 1 – 3 months postoperatively. Similar dynamics was characteristic for Digit Symbol test. Thirteen from fifteen patient cohorts significantly worsened on this psychomotor speed test paradigm early after surgery. In contrast, only one from 20 groups performed this test poorly in 1– 3 months after CPB. Fewer data are available on computer reaction time tasks, Stroop word/color and Letter Cancellation tests. Nevertheless, most examined cardiac surgery cohorts demonstrated significant decline on these speed/time paradigms during the first postoperative week, and none patient group was significantly ‘‘impaired’’ in 1 – 3 months after surgery. It should be noted, that part A of the Trail Making Test (TMT A) was the only test paradigm of this type, which did not demonstrate consistent group mean changes early after surgery. However, TMT A is too easy to perform (trailing numbers from 1 to 25 in forward order), and this may explain its low sensitivity in the context of cardiac surgery outcomes research. Hence, speed of cognitive performance is commonly impaired early after cardiac surgery, but fortunately, this brain functional deficit rapidly recovers during the first months after CPB in the majority of patients. Delayed recall of learned words (RAVLT was used in most studies) was also impaired early after CPB in most (10 from 12) tested patient groups. In contrast to the speed/time tasks, delayed recall did not recover in four from nine (44%) patient cohorts in 1– 3 months after cardiac surgery. Immediate recall in word list learning tests or Digit Span test showed less sensitivity to the early POCD, i.e., only 1– 2 thirds of patient groups significantly declined on these tasks at discharge. Again, at delayed follow-up, somewhat larger proportion of patient groups (10 – 12%) demonstrated significant impairment on these cognitive tests in comparison to speed/time paradigms. Hence, the speed of cognitive performance is commonly impaired early after surgery and rapidly recovers during the first postoperative weeks. Decline of verbal short-term memory represents a rarer postoperative event in comparison to psychomotor slowing. However, a considerable proportion of on-pump patients showed persistent deficits in verbal short-term memory in several months after surgery.
5. Possible mechanisms of localized perioperative ischemic brain damage The cited data of SPECT and neuropsychological studies give serious grounds to suggest that cardiac surgery is associated with predominant suffering of the left temporal
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Table 2 Dynamics of cognitive performance after cardiac surgery
Speed of performance Pegboard test Digit symbol test Reaction time tasks Stroop test Letter cancellation TMT, part B TMT, part A Accuracy of performance Word list learning (delayed recall) Word list learning (immediate recall) Digit span WMS nonverbal memory subtests Verbal fluency test Benton VRT Block design
Proportion of studies with significant mean group decline
Incidence of POCD (1 SD criterion)a
1 week follow-up
6 – 30 months follow-up
1 week follow-up
0% 0% 30% 0% 0% 0% 0%
18% (n 6% (n – 8% (n 11% (n 25% (n 13% (n
100% (n = 13) 87% (n = 15) 80% (n = 5) 75% (n = 4) 73% (n = 11) 69% (n = 13) 13% (n = 15)
1 – 3 months follow-up 5% 5% 0% 0% 0% 4% 0%
(n (n (n (n (n (n (n
= = = = = = =
20) 20) 11) 3) 9) 26) 17)
83% (n = 12)
44% (n = 9)
58% (n = 12)
10% (n = 21)
31% (n = 13) 22% (n = 9) 33% (n = 9) 33% (n = 3) 25% (n = 4)
(n (n (n (n (n (n (n
= = = = = = =
7) 7) 3) 5) 3) 9) 8)
–
= 6) = 9) = 1) = 1) = 2) = 5)
References (in alphabetic order)
1 – 3 months follow-up 6% 0% 7% 1% 9% 9% 7%
(n (n (n (n (n (n (n
= = = = = = =
5) 5) 6) 3) 2) 3) 4)
24% (n = 2)
16% (n = 3)
0% (n = 5)
28% (n = 2)
7% (n = 3)
12% (n = 17) 20% (n = 5)
0% (n = 5) –
11% (n = 5) 8% (n = 2)
7% (n = 3) 20% (n = 2)
0% (n = 9) 0% (n = 2) 0% (n = 2)
50% (n = 2) 30% (n = 3) 0% (n = 2)
15% (n = 2) 41% (n = 2) –
10% (n = 1) – –
Ahlgren et al. [1]; Bendszus et al. [5]; Borger et al. [10]; Brækken et al. [11]; Browne et al. [13]; Bruggemans et al. [15]; Fearn[17]; Grieco et al. [19]; Jacobs et al. [23]; Kilo et al. [26]; Kneebone et al. [27]; Knipp et al. [28]; Lee et al. [30]; Lloyd et al. [32]; Mahanna et al. [34]; McKhann et al. [35]; Millar et al. [36]; Mora et al. [37]; Mu¨llges et al. [38]; Nagels et al. [40]; Neville et al. [41]; Reents et al. [47]; Regragui et al. [48]; Robson et al. [50]; Selnes et al. [54]; Silbert et al. [55]; Steed et al. [58]; Stygall et al. [60]; Sugiyama et al. [61]; Taggart et al. [64]; Taggart et al. [65]; Toner et al. [68]; Uebelhack et al. [69]; Van Dijk et al. [71]; Vanninen et al. [72]; Vingerhoets et al. [73]; Wang et al. [74]; Westaby et al. [77]; Zamvar et al. [78]; Zimpfer et al. [79]
Abbreviations: n, number of patient groups; POCD, postoperative cognitive decline; SD, standard deviation; TMT, trail making test; VRT, visual retention test; WMS, Wechsler memory scale. a Incidence of decline on individual tests is presented as medians of the cited data.
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Neuropsychological tests
L.A. Bokeriia et al. / Brain Research Reviews 50 (2005) 266 – 274
region, which serves verbal short-term memory processes. Few studies addressed the distribution pattern of major perioperative ischemic strokes, nevertheless, two of them also pointed to predominant left hemisphere damage during cardiac interventions. Both studies found preponderance of left hemisphere strokes (75% and 81.5%, respectively), which occurred within 1– 3 days since coronary artery bypass grafting [75] and percutaneous transluminal coronary angioplasty [31]. Several explanations for these findings may be suggested. First, medial temporal cortex which mediates verbal memory processing is supplied by the posterior circulation, which in turn was shown to be compromised during general anesthesia in a large subgroup of patients. Weintraub and Khoury [76] demonstrated that neck hyperextension during tracheal intubation induced reduction of blood flow in the basilar artery, which was especially prominent in patients with vertebral and/or carotid stenoses or occlusions. Kostylyov [29] also observed slowing of blood flow in occipital venous sinus along with increased intracranial pressure at tracheal intubation and general anesthesia in patients with chronic cerebrovascular disease. High risk of perioperative ischemic stroke in posterior circulation was also demonstrated in this subgroup of general anesthesia patients [7]. Hence, even when massive microemboli are lacking, the posterior circulation, including left medial temporal cortex, is especially prone to intraoperative ischemia in atherosclerotic patients. Second, in their neuropathological study, Brown and colleagues [12] showed that with increasing survival time the total embolic load along with percentage of large and medium emboli significantly declined in brain specimen of patients after CPB. Authors explained these findings by pumping of the lipid emboli through the brain and by breaking larger emboli into smaller globules as they pass through the capillary network. Clearly, the compromised posterior circulation may hamper these sanative processes in posterior brain structures in contrast to anterior brain. Finally, some anatomical characteristics of left temporal circulation or particular sensitivity of left temporal cortex to ischemic damage may predispose patients to the selective postoperative decline of verbal short-term memory. For instance, Fearn and colleagues [17] observed greater deteriorative effects of asymmetric delivery of microemboli to the left hemisphere in comparison to the right one. Thus, the cited data give serious grounds to suggest that the left temporal region, which serves verbal short-term memory, is especially prone to perioperative ischemia in cardiac surgery patients. Several reports pointed to prominent disturbances in posterior arterial and venous circulation during intubation and general anesthesia, which might considerably contribute to postoperative memory decline even when massive microemboli are lacking. Finally, some anatomical factors also may underlie the prominent sensi-
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tivity of left temporal cortex to perioperative ischemic damage.
6. Possible mechanisms of postoperative psychomotor slowing Slowing of speed/time of performance in a variety of neuropsychological test paradigms, which is commonly seen in cardiac surgery patients during the first postoperative week, does not seem to relate directly to the embolic load effects. Indeed, the rapid postoperative recovery of psychomotor speed is similar to the positive dynamics of postoperative brain swelling and global metabolism decrease, which were reported by neuroimaging studies. Hence, the acute psychomotor slowing after cardiac surgery may be better explained by diffuse brain biochemistry/metabolism disturbances rather than true postoperative Fbrain injury_. Interestingly, Bendszus and colleagues [4,5] reported similar global decrease of brain metabolism as measured by NAA/Cr ratio in acute alcohol withdrawal and cardiac surgery patient cohorts. Moreover, psychomotor slowing was also pronounced and significantly correlated with NAA/Cr decrease in both patient groups. Importantly, the symptoms dramatically improved in 2 –4 weeks in both alcoholics and cardiac surgery patients. The pronounced increase in spontaneous EEG beta activity early after cardiac surgery is also akin to the conditions with pronounced neurobiochemical imbalances as acute alcohol or heroin withdrawal is [44,45]. Moreover, strong correlation between psychomotor slowing as measured by performance on Digit Symbol and increased beta activity in spontaneous EEG is a well known phenomenon, demonstrated in many studies [24,33]. Probably, these acute postoperative disturbances in brain functioning represent stress/inflammatory response to a series of intraoperative traumatic events as surgical injury, CPB and general anesthesia are. Moreover, some postoperative factors may also contribute to this condition. For instance, Browne and colleagues [14] demonstrated direct association between composite cognitive index at the 5th postoperative day and the hypoxia (mean arterial oxygen tension) due to postoperative respiratory impairment. It seems very probable that patients with any complication would perform slower on psychomotor speed tests in comparison to patients with Fideal_ postoperative course. Many studies showed (Table 2) that 6– 9% of cardiac surgery patients continued to perform ‘‘speed’’ tests significantly slower in 1 –3 months after cardiac surgery. These findings might be very well explained in the context of the data of Selnes and colleagues [52], who showed that psychomotor slowing in 1 month and 1 year after CABG was significantly related to the conditions (diabetus mellitus and renal dysfunction) compromising brain metabolism.
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Hence, postoperative psychomotor slowing appears to represent prominent nevertheless reverse global brain metabolism changes rather than true ‘‘perioperative brain injury’’. Therefore, summarized indexes of postoperative cognitive decline which are commonly used in the research of cardiac surgery outcomes do not seem to represent an Fevidencebased_ approach. The literatures cited in the present review give strong grounds to recommend separate neuropsychological test analyses rather than summarized indexes for future research of cardiac surgery outcomes.
7. Long-term cognitive changes in cardiac surgery patients We compared the incidence of POCD (proportion of declined patients) at discharge to the incidence at 6 and more months after surgery in the same five patient cohorts [22,34,41,43] by paired t tests. As expected, the difference in incidence of POCD at discharge and at long-term follow-up was significant (54 T 12% vs. 16 T 12%, t = 9.89, P = 0.001). When similar analyses compared the incidence at 1– 3 months follow-up and the incidence at 6 and more months after cardiac surgery in 6 patient cohorts [30,34,41,43,71], no significant difference was found (23 T 8% vs. 21 T 9%, t = 0.64, P = 0.54). One study [43] reported the secondary increase of the incidence of POCD from 6 months (24% of patients) to 5 years (42% of patients) after cardiac surgery. Few data are available on long-term dynamics of performance on separate neuropsychological tests after cardiac surgery. Some reports consistently demonstrated secondary decline of cognitive performance in 6 and more months after on-pump interventions. In the study of Fearn and colleagues [17], CABG patients did not show any slowing of reaction time in 6 cognitive tests at 2 months follow-up, whereas the same patient group performed the same tests significantly slower in 6 months after surgery. McKhann and colleagues [35] reported secondary decline on Stroop test, Boston Naming test and Rey Complex Figure Test in 11 –24% of CABG patients, who performed these tests normally at 1 month follow-up and demonstrated 0.5 SD decline in 1 year after surgery. In the same patient population, Selnes and colleagues [53] found secondary decline of group means of performance on the latter three tests along with performance on Pegboard test from 1 year to 5 years after CABG. Indeed, the proportion of middle age healthy individuals, who declines on the Digit Symbol test (a change >1 SD) during the 5-year interval is rather high and constitutes about 35– 39% [62]. Hence, secondary cognitive decline after 6 months since cardiac surgery was consistently reported; nevertheless, no data indicated that this deterioration is related to cardiac surgery effects rather than aging or concomitant pathological processes.
8. Conclusion Cardiac surgery induces long-term localized brain ischemic lesions along with rapidly reversing global brain swelling and decreased metabolism. A range of studies evidenced that left temporal region is especially prone to perioperative ischemic injury, and these findings may explain persistent verbal short-term memory decline in a considerable proportion of cardiac surgery patients. Speed/ time of cognitive performance is commonly decreased early after on-pump surgery either. Nevertheless, no associations between slowing of psychomotor speed and intraoperative embolic load were found. The rapid recovery of the latter cognitive domain might be better explained by surgery related acute global brain metabolism changes rather than ischemic injury effects. Hence, analyses of performance on separate cognitive tests rather than summarized cognitive indexes are strongly recommended for future neuropsychological studies of cardiac surgery outcomes.
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