Neuropsychologic impairment has been widely recognized as a major complication after open-heart surgery. Several studies have demonstrated both short-term and long-term neurological and neuropsychological deficits cardiac surgery. These include verbal memory, attention and psychomotor deficits among others. These changes constitute an overall decline in cognitive function known as postoperative cognitive dysfunction (POCD) which occurs for weeks or months after surgery. Psychological disturbances have also been observed in patients who underwent cardiac surgery. Recent data indicate a high prevalence of psychiatric morbidities in cardiac patients which include posttraumatic stress disorder, dysthymic disorder, agoraphobia and major depression. Changes in psychological functioning in pediatric cardiac surgery patients have also been demonstrated. These are characterized by anxiety, depression, behavioral problems, spatial skill deficits, social isolation, and symptoms of depression. Several risk factors of POCD have been identified. The advanced age of the patient and the occurrence of early cognitive decline were shown to have significant correlation with long-term cognitive decline.
The possibility of genetic predisposition to POCD has also been investigated. It was shown that there is a significant association between the occurrence of postoperative cognitive decline and the finding of the apolipoprotein E4 (apoE) allele, a gene known to play role in cholesterol and triglyceride metabolism and is strongly associated with aortic atherosclerosis. However, the exact pathogenesis of POCD remains unclear. Several studies have shown that cerebral hypoperfusion, systemic infections, metabolic abnormalities, medications, and a possible vascular pathology may be correlated with neurocognitive decline following cardiac surgery. Cerebral hypoperfusion secondary to a possible transient impairment of the auto-regulatory mechanisms of cerebral blood flow (CBV) were demonstrated in patients after heart surgery. It was suggested that a vasculopathy caused by microdilatations of the arterioles in the brain after coronary artery bypass may lead to POCD. Whatever the cause of POCD may be, the subtle nature on the neuropsychological effects of heart surgery necessitates an emphasis on its clinical features. Health care providers and relatives of cardiac patients should at least be aware of these postoperative changes so that they will be able to detect their existence and appropriate measures can be taken to address the problem. These changes include memory impairment, which is identified by reduction in the ability of the patient to learn or recall information; disturbances in executive functioning, exemplified by decline in planning, organizing, and abstracting; disturbance in attention or impairment of information processing in perceptual-motor abilities and impairment in language abilities such as written and verbal comprehension and word finding.
The aim of this review is to provide information from different published literature related to the investigation of postoperative neuropsychological effects of open-heart surgery. The risk factors and possible causes of postoperative cognitive decline (POCD after heart surgery as well as the different methods of assessment of cognitive decline will be assayed based on the studies provided. Still, more research is needed to identify the causes of cognitive decline in heart surgery as this will lead to better overall treatment outcome in patients undergoing heart surgery.
Neuropsycholgical Effects Of Heart Surgery
Neuropsychologic impairment has been widely recognized as a major complication after open-heart surgery. With the increasingly routine performance of various open-heart procedures such as coronary artery bypass grafting (CABG) and heart valve replacement, neurologic and neuropsychologic dysfunction following surgery presents a clinical dilemma in achieving a favorable long term treatment outcome. Despite the advances in surgical and anesthesia techniques which significantly improved the overall safety of cardiac surgeries, cerebral and neurocognitive impairment are of profound clinical significance since it may lead to increased mortality rate, prolonged confinement in the intensive care unit and extended hospital length of stay (Roach, 1999). Furthermore, aside from the financial implications, the necessity of long term rehabilitation secondary to neurologic dysfunction will like affect the patient’s quality of life following surgery.
Various studies have demonstrated the neurological and neuropsychological deficits following cardiac surgery. The incidence, severity, and duration of the subclinical congnitive deficit were not observed in other major thoracic surgery (Shaw et al; Smith et al as cited Tonera et al, 1998). Cerebral injury after open-heart surgery has been related to stroke, transient ischemic attack, and coma. The more subtle neurocognitive functional impairment were associated with attention, concentration, shot-term memory, fine motor finction, and speed of mental and motor responses (Zamvar, 2002). While no question can be raised regarding the clinical significance of cerebral injury following cardiac surgery, a justifiable objection was made on the use of adjectives such as “subtle”, “transient”, and “subclinical” to describe the neurocognitive decline that occur after open-heart surgery as it tends to minimalize the significance of its implications to the patients and their relatives (Newman et al, 2001). Studies have shown that cognitive impairment not only presents early during the postoperative period but it also persists after 5 years following surgery. Accordingly, it is indeed difficult to trivialize this complication to the patient when he has to deal with it even after several years following surgery.
Several tests have been described to assess the neurocognitive decline in patients who underwent open-heart surgery. Major clinical studies have employed a battery of standardized neuropsychological tests to identify the decline in neurocognitive function.
These tests are performed preoperatively in order to establish a baseline for each patient after surgery, they are performed again during predetermined postoperative days in order to extract a pattern in cognitive brain function and then compare them to the baseline. The statement of consensus on the assessment of neurobehavioral outcomes after cardiac surgery has been the guideline for most of these studies in selecting the tests to be used in the study (Newman et al, 2001; van Dijk et al, 2004). This includes the Rey auditory verbal learning test (word list learning test), the Trail making test (cognitive achievement at speed), and the Grooved pegboard (manipulative dexterity test) (Murkin, et al, 1995; Rickertand, 1998; Selami et al, 2002). However, new approaches were included in some studies to objective assess the cerebral injury following heart surgery which includes biochemical markers and diagnostic devices (Selami et al, 2002) (Tonera et al,1998) (Talpahewa et al, 2004).
The implications of various open-heart procedures and the techniques used during cardiopulomary bypass (CPB) on the patient’s postoperative cognitive brain function have been the main focus in several studies. Extensive randomized controlled trials were commonly done were commonly done on the neurocognitive effects of CABG while the incidence of neuropsychologic dysfunction following heart valve replacements were also evaluated by some studies. The common application of CPB in most of these procedures also warranted the comparative investigation of on pump CPB with off pump coronary artery bypass. The benefits of thermal regulation during CPB on cognitive brain function were also assessed.
The purpose of this review is to provide information regarding the neurocognitive dysfunction following cardiac surgery and to discuss different published literature related to the investigation of postoperative neuropsychological effects of open-heart surgery.
Post-Operative Cognitive Dysfunction and Heart Surgery
Post-Operative Cognitive Dysfunction (POCD) has long been identified as a major complication following surgery. There have been common reports of patients feeling “not quite the same” post operatively (Selnes & McKhann, 2001; Lewis, et al., 2004). Studies have documented a constellation of post operative deficits involving memory, attention, concentration, psychomotor function, and speed of mental and motor responses which reliably described POCD (Symes et al. as cited by Lewis, et al., 2004; Zamvar, et al., 2002). Despite the several methods being employed in the assessment of cognitive function, the characteristics and severity of the cognitive decline has not been well defined. As a result, the incidence of POCD is highly varied and is largely influenced by the neuropsychological test being used. New approaches are being studied to objective demonstrate POCD. On the outset, it appears that the POCD is distinct from postoperative delirium (Lewis, et al., 2004) which might be secondary to the effects of anesthesia (Selnes & McKhann, 2001).
POCD in heart surgery been extensively studied. It seems that most studies on the deleterious effects of surgery on cognitive function have been related to heart surgery. Some investigators believed that while these neuropsychological changes may be present in other forms of major thoracic surgery, the severity and duration of the functional deficit were exclusively found in patients who underwent open-heart surgery (Shaw et al; Smith et al as cited Tonera et al, 1998). Further, these changes were not only observed early in the postoperative period of open-heart procedures but were also found to persist several years after the operation. While there are claims that the cognitive decline following heart surgery may be part of the outcome of the normal aging process, longitudinal studies looking into this possibility have proven otherwise. Neuropsychological impairments were also observed in children who underwent open-heart surgeries which further endorse the further endorses the idea that heart surgery may have a more direct involvement on the cognitive decline in patients after surgery.
Cognitive outcome after coronary artery bypass grafting
Coronary artery bypass grafting (CABG) comprises the majority of all open-heart surgeries in the U.S. In 2003, more than 70% of the total open-heart surgeries were cardiac revascularization involving CABG (AHA, 2006). Despite the growing preference for non-surgical procedures such as percutaneous transluminal coronary angioplasty (PTCA), CABG remains as an important treatment option for patients in the management of coronary artery disease. There is no doubt that CABG has prolonged the life expectancy of most patients with various cardiac diseases. With the increasingly rare operative mortality of the procedure as a result of the sophistication in surgery and anesthesia techniques over the past few decades, medical attention have shifted beyond immediate patient survival to perioperative morbitites and patient’s quality of life after surgery.
Early cognitive decline after CABG. In a multicenter study on the association between the cognitive outcome after CABG in the first operative week and that at 3 months (Van Dijk et al 2004), it was shown that 50 to 60% of patients had early cognitive decline in the first postoperative week after CABG. It was also determined that the early cognitive decline was a significant predictor of the cognitive outcome after 3 months. This association was shown using a series of univariate and multivariate analysis in which other possible predictors of cognitive decline were also accounted for. These included age, sex, diabetes, peripheral vascular disease, history of stroke or transient ischemic attack, the number of diseased vessels, the perioperative use of aortic side clamps and the use of off-pump and on-pump bypass techniques. After univariate analysis, only the use of aortic side clamps and off-pump and on-pump bypass treatment were the predictors other than early cognitive decline that were weakly associated with cognitive decline after 3 months. However, on multivariate analysis combining all 3 variables, only early cognitive decline remained as a significant predictor of cognitive decline after 3 months.
Previous studies have also demonstrated similar deficit in cognitive functioning early after CABG. A major clinical study reported that cerebral functional deficit was found in 48% of patients 1 week after surgery and in 34% at 2 months after surgery. The deficit was shown not only through neuropsychological testing but also on quantitative electroreencephalographic (EEG) assessment (Toner, Taylora, Newmanb & Smitha, 1998). The investigators added that while patients demonstrated deficits on both testing modalities 1 week after surgery, both neuropsychological and EEG deficits were associated only at 2 months after surgery. It was also shown that neuropsychological deficit at 1 week after surgery was a significant predictor of EEG deficit at 2 months after surgery as patients who failed in most test neuropsychological tests also showed greater EEG deficit at 2 months, but not 1 week, after surgery. Another study have also shown early cognitive decline in patients who underwent CABG, using quantitative tools aside from standard psychometric tests. It was reported that cognitive P300 evoked potentials were prolonged at 1 week and even at 4 months after CABG as compared to measurements before surgery (Grimm, Czernya, Baumera, Kiloa, Madlb, & Kramerb et al, 2000).. However, on psychometric tests, patients in all study groups scored normal throughout the whole study period which indicated that all patients did not demonstrate overt clinically significant cognitive decline. From the study, it demonstrated the use of cognitive P300 auditory-evoked potential measurements as a useful tool in detecting subclinical deficit in cognitive brain functioning that standard psychometric tests failed to detect.
Long-term neurocognitive deficit after CABG. A conducted a longitudinal assessment of neurocognitive function after CABG has also reported the significance of early cognitive decline as a predictor of long-term function (Newman et al 2001). In the study, 261 patients who underwent CABG, were tested for neurocognitive function which were performed preoperatively, and then before discharge, then at six weeks, then at six months, and then five years after the surgery. Results from the study revealed a decline in cognitive function in 53 % of patients at discharge while 36 % and 24 % of patients had cognitive decline at six weeks and at six months, respectively. Five years after surgery, the incidence of cognitive decline was 42 %. The investigators determined which demographic and perioperative factors that may be associated with cognitive decline by identifying the suspected univariable predictors of cognitive decline, which included older age, lower level of education, and evidence of cognitive decline at discharge. These variables were then assessed using logistic regression anaylsis. From that analysis, the predictors that were found to be significant were included in a multivariable analysis. In the multivariable analysis, cognitive decline at discharge remained a significant predictor of long-term cognitive decline at five years.
A follow up longitudinal study was done to objectively measure long-term neurocognitive deficit in patients undergoing coronary artery bypass grafting and compare the findings with nonsurgical controls (Zimpfer et al, 2004). In the study, neurocognitive function in patients undergoing coronary artery bypass grafting (CABG) with cardiopulmonary bypass was prospectively measured. A cohort of age- and sex-matched patients served as nonsurgical controls. After CABG, neurocognitive function was serially reevaluated at 7-day, 4-month, and 3-year follow-up. Neurocognitive function was objectively measured by means of cognitive P300 evoked potentials. Additionally, standard psychometric tests were performed (Trailmaking Test A, Mini Mental State Examination). From the study, it was shown that compared to preoperative measures, cognitive P300 evoked potentials were prolonged at 7-day, 4-month, and 3-year follow-up. Trailmaking Test A was also abnormal, as compared to preoperative, at 3-year follow-up. Before the operation, surgical patients were fully comparable in P300 measures to nonsurgical controls. Most importantly, throughout the entire postoperative follow-up cognitive measures in surgical patients were prolonged as compared with controls. In stepwise multivariate regression analysis, neurocognitive deficit at 4-month follow-up were predictive for long-term neurocognitive deficit at 3-year follow-up. As shown by means of objective measures, and in comparison to nonsurgical controls, coronary artery bypass grafting with cardiopulmonary bypass grafting was shown to cause long-term neurocognitive deficit.
The significantly high incidence of short-term POCD may be due to the fact that the patients after open-heart surgery underwent a battery of test just days after undergoing a major surgical operation. The subsequent improvement in cognitive function of the patients after six weeks and six months could imply that other causal factors affecting the early cognitive decline may be present. It was suggested that some of the short-term changes may be due to anesthesia or nonspecific effects of surgery and that these changes may well be reversible if not superimposed with a possible gradually worsening effects secondary to initial injury from the CABG procedure itself (Selnes & McKhann, 2001). This might explain the strong statistical correlation between early cognitive decline and the delayed cognitive decline 5 years after the surgery, despite the relative improvement of cognitive function in between.
Neurocognitive and Psychological Effects of Pediatric Heart Surgery
According to Boucek et al. (1997), approximately 3,500 pediatric heart transplants have been performed worldwide since 1982, based on the first official pediatric report by the Registry of the International Society of Heart and Lung Transplantation. While recent data shows that medical improvements in heart transplantation have yielded overall 1-year survival rates of 78% to 86% (UNOS/ISHLT, 2006) and 3-year survival rates of 67% to 72% (UNOS/ISHLT, 2006) in children and adolescents, there is a increasing concern over the neurocognitive and psychological changes that occur following cardiac surgery. However, there are only few medical studies that investigate the postoperative effects of heart surgery on children with regard to their cognitive and psychologic function. Compared to the investigations in adults, these studies are often limited to smaller sample population. While most literature on adult heart surgery involve large prospective randomized studies, it may not be practical to correlate the results from those studies to those in pediatric heart surgery due to several factors that suggest that assessment of the effects of pediatric heart surgery should be studied separately. In adults, the most common indication for heart surgery is coronary artery disease is coronary artery disease secondary to artherosclerotic processes (AHA, 2006). In children and adolescents, however, the most common etiologies for coronary illness are congenital heart disease due to malformations of the cardiovascular system or cardiomyopathy (Baron, et al as cited by Todaro et al, 2000). In addition, neurologic and psychologic assessment in children entails a different approach than that in adults. While adults are able to give a more accurate response with regard to their mental state of mind, younger children may have a hard time assessing themselves and often require proxy assessors like a parent or a guardian. As a result, standardized assessment is necessary to increase the validity and reliability of the neuropsycholocal assessment which leaves out the benefits of a more comprehensive open interview that could provide more important information regarding cognitive functioning.
Cognitive Effects of Pediatric Heart Surgery. In a review conducted by Todaro, Fennell, Sears, Rodrigue, and Roche (2000), only few studies were found that extensively investigated the effects of heart transplantation on the neuropsychological functioning of children receiving heart transplantation. A previous major clinical study (Wray & Yacoub,1991 as cited by Todaro, 2000) compared the neuropsychological functioning of 52 children who received heart transplantation to 52 children who underwent alternative open-heart surgeries and to 48 normal, healthy peers. It was shown that children less than 5 years old who received heart transplantation performed within the average range on parameters of development based on the Ruth Griffiths Developmental Scales (RGDS; Griffiths, 1970 as cited by Todaro et al., 2000). From the study, the researchers noted that while the RGDS scores for children who had transplantation were within the normal range, they were significantly lower than those obtained by the healthy control group. They added that children older than 5 years old who had heart transplantation also demonstrated significantly lower developmental scores than the other 2 comparison groups, despite the scores being in the average range. Further, the investigators added that the children who received heart transplantation had lower grades at school and had significantly higher absentee rates than the other 2 comparison groups. However, the investigators suggested that the lower academic performance in transplant recipients might have been due to missing more time at school rather than the result of cognitive decline secondary to the heart transplantation (Wray & Yacoub, 1991 as cited by Todaro, 2000). It is interesting to note the investigators failed to elaborate on the better performance of the control group of children who received alternative open-heart procedures compared to the study group when presumably they too missed more time in school compared to the control group of healthy peers.
In a later study by Wray, Pot-Mees, Zeitlin, Radley-Smith, and Yacoub (1994 as cited by Todaro, 2000), 65 children diagnosed with various coronary anomalies were examined for the effects of heart and heart-lung transplantation on their development, cognitive functioning, and behavioral status in. Their performance was later compared to 52 children who received other corrective heart procedures and 45 healthy children. From the study, children under 4.5 years who received transplantation performed within the normal range on the RGDS, though these recipients performed significantly lower than the healthy control group on all of the developmental subscales. Interestingly, the transplant group and the alternative open-heart surgery group did not differ on any of the measures of development. This illustrates the influence of deep hypothermic arrest procedures and the long exposure on cardiopulmonary bypass being used by both groups on the cognitive and development outcome of children receiving open-heart surgeries. For children with ages between 4.6 to 16 years, children in the transplant group showed lower mean IQ scores than both of the two reference groups, however, the performance on specific academic abilities, including arithmetic and reading, were not statistically different from either reference group Wray et al (1994, as cited by Todaro, 2000).
Psychological Functioning in Pediatric Heart Transplantation. The quality of life of pediatric heart recipients were studied by Lawrence & Fricker (1987, as cited by Todaro et al 2000). They described psychosocial functioning of seven children between the ages of 6 and 15 years old. The investigators reported that all children in this small sample were able to return to their normal lifestyles and were well adjusted to the stress of transplantation. They specified that all children were reportedly able to attend to self-care, return to school, and maintain pretransplant academic performance. In addition, six out of eight children were able to develop age-appropriate relationships after surgery. Psychiatric outcomes were also investigated in 9 pediatric heart transplant recipients. While the investigators did not specify the average time of post-transplant assessment, results from the study found that five out of nine recipients experienced post-transplant adjustment difficulties which was characterized by anxiety, depression, and/or behavior problems (Shapiro and Kornfeld ,1989 as cited by todaro et al 200) . However, the remaining four recipients reported no major adjustment difficulties.
In, 2000, Baum, Freier, Freeman, and Chinnock reported the developmental outcome of infant and child heart transplant recipients. They concluded that infant heart transplant recipients demonstrated IQ and achievement levels that were within the normal range. However there was a significant amount of variability as a higher number of children scored in the lower ranges than would be expected. Children with heart transplantation were at risk of developing visual spatial skill deficits. Demographic variability in age also contributed as young children were shown to be risk for social isolation while symptoms of depression were noted in older children. As pediatric heart transplantation has become a mainstay in the management of infants and children with end-stage heart disease, these postoperative effects should be considered in parent counseling to prepare to identify these effects so that appropriate medical attention will be provided for pediatric cardiac patients.
POCD and Cardiopulmonary Bypass
The use of cardiopulmonary bypass (CPB) has been considered standard practice during open-heart surgery. CPB provides an unobstructed view of a bloodless and motionless field to the surgeon during cardiac manipulation while maintaining pulmonary and hemodynamic stability. The purpose of the heart-lung machine in CPB is to provide adequate flow to maintain sufficient cardiac index for tissue perfusion (Caldarone & Abouassaly, 2002)). However, early primitive techniques in CPB have resulted in significant morbidity and mortality (McKenzie, Andropulos, DiBardino, & Fraser, 2005). Kirklin et al popularized the use of deep hypothermic circulatory arrest (DHCA) during CPB which successfully allowed precise cardiac repair while at the same time avoided the inherent morbidity and mortality associated will prolonged exposure to CPB (as cited by McKenzie et al, 2005). As a result, hypothermic CPB was previously considered as mandatory as it has been taught by the pioneers of heart surgery (McKenzie et al, 2005). However, studies have reported a strong correlation between POCD and the use of CPB. Investigators believed that the post operative decline in cognitive function is largely due to the use of cardiopulmonary bypass (on-pump procedures) in open-heart surgery. To investigate the causality of CPB in POCD, several studies compared the cognitive outcome of patients who underwent open-heart procedures with CPB to those who had surgery without CPB. Cognitive outcome after hypothermic CPB were also compared to those after normothermic CPB.
On-pump Versus Off-pump CABG
Zamvar et al. (2002) compared the neurocognitive impairment of sixty patients undergoing CABG for triple vessel disease who were prospectively randomized to the off-pump and on-pump techniques. Both groups were found to be similar in age, sex, angina class, left ventricualr function, and extent of coronary artery disease. Nine standard neuropsychometric tests were administered preoperatively and at 1 and 10 weeks postoperatively. From the study, the on-pump group showed a significant deterioration in scores at 1 week and 10 weeks postoperatively compared to the off-pump group. At 1 week after surgery, 63% of the on-pump group had neurocognitive impairment while only 27% of the off-pump group had impairment. Ten weeks postoperatively, 40% of the on-pump group, compared to 10% of the off-pump group, had neurocognitive impairment. The on-pump group also showed a significantly higher incidence of major deterioration in the grooved pegboard test using the dominant hand both 1 week and 10 weeks postoperatively. The study showed that off-pump coronary artery bypass graft surgery results in less neurocognitive impairment than the on-pump technique. However, there were several limitations in the study. One limitation was that the anaesthetic management used was different for both groups. Ninety percent of patients in the on-pump group received total intravenous anaesthesia which included high dose opioids while 54% of patients in the off-pump group received thoracic epidural anaesthesia. Another limitation of the study was that, apart from the relatively small sample size, only one surgeon performed all the operation in a single hospital. The investigators believed that while this allowed for reproducibility of the results, generalisability might have been affected. They suggested that this should be eliminated in a multicenter study with different surgeons and hospitals. The study also did not conform to the Statement of Consensus on Assessment of Neurobehavioral Outcomes after Cardiac Surgery (Murkin et al, 1995) and the assessment at 10 weeks postoperatively may not reflect long term cognitive outcomes.
Stroobant, Nooten, , Belleghem, and Vingerhoets (2002) conducted a longer term neurocognitive follow up at 6 months in patients who underwent on-pump and off-pump CABG. Short-term outcomes were also assessed at 1 week after surgery and were compared with preoperative performance. In contrast to the study by Zamvar et al. (2002), results from this study showed that there were no significant differences between the on-pump and the off-pump groups in post-operative neuropsychological assessment soon after surgery. However, both groups revealed significant evidence of early cognitive impairment after CABG. Post-operative cognitive decline was seen in 61% of all the patients, 57% from the on-pump group and 63% from the off-pump group. At 6 months after surgery, a significant difference between the post-operative neuropsychological performances of the two surgical groups was noticed, with more favorable results being observed from the off-pump group. The investigators added that 11% of the all the patients in the study had persistent patient cognitive sequelae at follow-up and all of them were from the on-pump group. The study showed that off-pump coronary artery bypass have favorable long term cognitive outcomes compared to the conventional use of CPB in CABG. However, the investigators stressed that selection bias might have influenced the study since in patients with multiple vessel disease, surgeons preferred on-pump technique relative to off-pump surgery to avoid hemodynamic instability caused by prolonged tilting of the heart. The inclusion of more patients with a higher number of grafts in the on-pump group also resulted in increased operation time although the neuropsychological deficits in the study did not correlate with operative variables (Stroobant et al, 2002). A study by Van Dijk et al (2002), however, showed that the benefit of avoiding CPB was smaller than was anticipated. In a randomized controlled trial conducted on 281 CABG surgery patients, only 21% in the off-pump group had cognitive decline compared to 29% in the on-pump group. Moreover, at 12 months, Van Dijk et al (2002) obeserved that the small differences between the groups had become negligible.
Hypothermic and normothermic cardiopulmonary bypass
Hypothermic and normothermic cardiopulmonary bypass (CPB) has resulted in apparently contradictionary cardiac and neurologic outcome. While the rationale for hypothermic CPB was to reduce the metabolic rate of the brain to cushion the effects of cerebral hypoperfusion during CPB, some suggest that inducing hypothermia may have a direct effect on cognitive function. With recent reports of the potential benefits of normothermic CPB, this practice has challenged the hypothermic CPB as the prefered technique during coronay artery bypass. However, cerebrovascular risk and cognitive dysfunction associated with normothermic CPB still remain uncertain. A prospective randomized study was conducted to measure the effects of mildly hypothermic (32°C) vs. normothermic (37°C) CPB on cognitive brain function. All patients received elective coronary artery bypass grafting. Cognitive brain function was objectively measured by cognitive P300 auditory-evoked potentials before surgery, 1 week and 4 months after surgery, respectively. Additionally, standard psychometric tests were performed and clinical outcome was monitored. From the study, patients operated with mild hypothermia showed a marked impairment of cognitive brain function. As compared with before surgery, P300 evoked potentials were prolonged at 1 week and even at 4 months after surgery. In contrast, patients operated with normothermic CPB, did not show an impairment of P300 peak latencies. Group comparison revealed a trend towards prolonged P300 peak latencies in the patient group undergoing mildly hypothermic CPB. 1 week after surgery. However, 4 months postoperatively, no difference between the two groups could be shown. Further, Trailmaking test A and mini mental state test failed to discriminate any difference. From the results, it was shown that objective cognitive P300 auditory evoked potential measurements indicated that subclinical impairment of cognitive brain function was more pronounced in patients undergoing mildly hypothermic CPB as compared with normothermic CPB for CABG.
Possible causes of cognitive decline after heart surgery
The incidence of cognitive declineafter heart surgery has been extensively studied. Several large prospective randomized trials have documented the strong association between heart surgery and postoperative cognitive decline. Longitudinal studies have demonstrated significant statistical evidence of long term cognitive changes following open-heart surgery. In addition, investigators have established that early poor cognitive outcome was a significant predictor of patient’s risk of long term cognitive decline after cardiac surgery. However, despite the overwhelming evidence, the definitive etiology of cognitive decline following heart surgery remains elusive. While investigators have offered several suggestions to explain the neuropsychologic effects of heart surgery, only few follow up studies have been conducted to investigate possible pathogenesis of the decline in cognitive function.
Oppenheimer and Lima (1998) listed several possible causes that could lead cognitive changes following heart surgery. These include cerebral hypoperfusion, systemic infections, metabolic abnormalities, medications, and a possible vascular pathology that is specific for cardiac surgery. Oppenheimer and Lima (1998) suggested that the “aetiopathological phenomena” might be the result of “focal microdilatations of arterioles” based on a study by Moody et al which identified such intracerebral arteriolar dilatations in the brains of patients who died during or shortly after coronary artery bypass. They added that the microdilatations could have been caused by “air of fat microembolisation after the release of aortic cross clampig” (Oppenheimer and Lima, 1998).
Cognitive impairment has been associated with the reduction in cerebral blood flow during heart surgery. A study by Talpahewa et al (2004) investigated the changes in cerebral oxygenation during CABG with normothermic CPB using near infrared spectroscopy (NIRS). Measurements of cerebral cortical oxygenation were performed on 19 patients who were receiving normothermic CPB. These measeurements included oxygenated hemoglobin (O2Hb, changes in the redox status of the cytochrome c oxidase (Cyt-Ox), cerebral blood volume (CBV) as expressed by tissue hemoglobin index (THI). Results from the study showed a marked reduction in O2Hb and CBV during the entire CPB duration when compared to baseline measurements. These changes were seen at their worst level 40 minutes after initiation of CPB. It was also shown that the while the deterioration of O2Hb was recovered by the end of the surgery, the changes in CBV persisted. The investigators suggested that among other factors, the findings might be due to a transient impairment of the auto-regulatory mechanisms of cerebral blood flow. Various authors have also indicated that cerebral autoregulation is indeed disturbed during open heart surgery. Oppenheimer ; Lima (1998), however, suggested that it is most likely that the reduction in the cerebral metabolic rate for oxygen as a result of CPB that might have caused the concurrent physiological decrease in cerebral blood flow. Talpahewa et al (2004) denoted that this was the case in their study since it was found that there was no disturbance observed in intracellular respiration and the oxygen supply to the brain was adequate based on the minimal changes observed in Cyt-Ox levels. These changes did not reach significant levels indicating an adequate supply of oxygen at the mitochondrial level. Talpahewa et al (2004) added that despite the marked reduction in cortical cerebral oxygenation and the persistent reduction of CBV, none of the patients in their study sufferd any major neurological events during hospitalization. Unfortunately, the study did not involve any assessment of subtle cognitive dysfunction which the investigators accepted as a major limitation to their study.
Other factors have been suggested to contribute to the occurrence of cognitive dysfunction after cardiac surgery. Whereas it was shown that adequate mitochodrial oxygenation was achieved despite the reduction in cortical cerebral oxygenation (Talpahewa et al 2004), other studies have shown different mechanisms in which hypoxia can lead to cognitive dysfunction. A study on the association of Alzheimer’s disease (AD) and post-operative cognitive dysfunction (Xie & Tanzi, 2006) suggested that hypoxia can decrease the processing of amyloidogenic ß-amyloid precursor protein (APP), a protein implicated in the neuropathogenesis of AD (Glenner & Wong, 1984 as cited by Xie & Tanzi, 2006). Further hypoxia has been shown to cause AD-type molecular abnormalities via increased Aß formation and reactive oxygen species generation. Animal studies have indicated the increased vulnerability to brain injury after reperfusion to hypoperfused brain. In addition, hypoxia can induce apoptosis [(Daval et al., 2004; Namura et al., 1998; Northington et al., 2001 as cited by Xie & Tanzi, 2006) which has been shown to be also involved in neuropathognesis of AD. These findings suggest that hypoxia may cause POCD by triggering AD neuropathogenesis.
The vigurous inflammatory response provoked during cardiac surgery has also been implicated in the development of cognitive dysfunction after surgery. As it has been known to contribute to the pathogenesis of acute pulmonary, cardiovascular, neurologic, splanchnic, hematologic and immune system dysfunction following cardiac surgery, uncontrolled inflammatory reaction, in response to surgical stress, may also be responsible for the neurologic complications after heart surgery (Kálmána et al., 2006). To confirm this hypothesis, Kálmána et al (2006) evaluated the changes in the levels of inflammatory biomarkers in the cerebrospinal fluid after off-pump CABG (OP-CABG). CSF levels of interleukins (IL-4 and IL-6) were assessed at baseline, 1 week and 6 months after surgery. Results showed that during and immediately after OP-CABG, increased concentrations of IL-6, a mainly pro-inflammatory cytokine, were present in the CSF. However, on evaluation at 6 months post-operatively revealed a normalized level of IL-6 while the concentration of the anti-inflammatory IL-4 showed marked elevation in the CSF. The investigators suggested that a regulated immune response may participate in the development of adverse neurologic events and complications following cardiac interventions, and that inflammatory cytokines in the cerebrospinal fluid may serve as predictors of cognitive decline after coronary surgery. Oddly, the study did not include any postoperative cognitive assessment so it is improbable to correlate the levels of these inflammatory biomakers to cognitive dysfunction.
Transient intracerebral platelet activation
Transient intracerebral platelet activation after removal of the aortic cross-clamp is also associated with post-CPB neurocognitive injury. A previous study conducted Herrmann, Eberta, Toberb, Hannb & Huth (1999) investigated the association between neurobiochemical markers of brain damage and the neurobehavioral outcome in patients undergoing either valve replacement (VR) or isolated coronary artery bypass surgery (CABG). This was based on previous reports that patients with neurological complications, such as stroke or seizures exhibited highly elevated concentrations of protein S-100B and neuron-specific enolase (NSE). However, the investigators concluded that no significant correlation were found between NSE release and decline in neuropsychological performance (Herrmann, et alh (1999).
Newman et al. (2001) investigated the role of genetic factors in the neurologic and neurocognitive outcome after cardiac surgery with CPB. As genetic factors have been shown to be involved in the progression of conditions related to aging such as stroke and congnitive decline, the investigators suggested that genetic predisposition of patients may have a significant influence cognitive outcome after open-heart surgery. In a multivariate analysis of patients with and without cognitive decline, there was significant association between the occurrence of postoperative cognitive decline and the finding of the apolipoprotein E4 (apoE) allele. confirmed that apoE alters cognitive function after CABG.
Nature of the cardiac surgery
The nature of the cardiac surgery has been correlated with the likelihood of a neurological complication: Cernaianu et al suggested that the lowest stroke rate occurred with aortic valve replacements (0.9%). Interestingly, severe aortic atherosclerosis with calcinosis was identified in 43% of patients who developed neurological complications, but in only 5% of patients who did not. This would suggest embolisation of atherocalcareous debris in the aetiology of strokes in these patients. About 14% of patients who developed perioperative cerebral infarction had also had a previous stroke. The aortic cross clamping time was almost twice as long in patients with postoperative stroke compared with those who remained neurologically pristine. Bypass time was also about one third longer. Surgery for congenital heart conditions, whether in children or in adults, has been associated with a comparatively low incidence of neurological sequelae: Litasova et al found an incidence of 3.5% in 3141 patients. Application of Luria’s tests identified cognitive abnormalities in 15% of patients. These neurological complications were not associated with the time of circulatory arrest, but rather fluctuations in blood pressure. However, the patients in this study underwent perfusionless deep hypothermia, and therefore it may not be possible to extrapolate these findings to the general population of patients undergoing cardiac surgery. Kuroda et al found that the incidence of neurological complications was higher in patients with coronary artery bypass grafting (11%) than in patients who underwent valve surgery (7%). The factors predictive of CNS complications included: previous stroke and the length of time on bypass. However, patients undergoing coronary artery bypass grafting were older and had a significantly greater incidence of hypertension, diabetes, and previous stroke.
For patients who are at a possible risk for late cognitive decline, several attempts have been made to slow down the aggravation of the neurocognitive deficit by diet, medication, and lifestyle modification (Selnes ; McKhann, 2001). However, more focus has been directed on neuroprotection against early cognitive decline after heart surgery. This stimulated the interest on different pharmacological agents that may render neuroprotection against injury to the brain during heart surgery. However studies related to this approach have yielded conflicting results to provide
Assessment of neurocognitive function
Several approaches have been employed in assessing the neuropsychologic outcome after heart surgery. These involve either subjective or objective parameters or a combination of both. Van Dijk et al utilized a battery of six neuropsychological tests to establish the early cognitive outcome of patients who underwent CABG (2004). These tests were used to evaluate the motor skills, verbal memory capacity and attention of the patients in accordance with the statement of consensus for assessment of neurobehavioral outcomes after cardiac surgery (Murkin et al, 1995). In order to establish a comparison of neurocognitive decline, the patients were asked to perform the tests a day prior to surgery and four days after surgery. Seven main variables were taken for each test for analyses. The investigators defined “cognitive decline” as the decrease of a person’s performance by at least 20% from the baseline performance preoperatively. This decrease should be in at least 2 of the 7 main variables that were taken. However, patients who had had stroke were automatically considered to have cognitive decline.
Van Dijk et al identified certain limitations in the method that they used for their study. Among them was the comparison between preoperative and postoperative test performance to define the cognitive decline wherein the subject acted as his own control (2004). This will likely introduce a bias when a patient performs well preoperatively as he is likely to repeatedly meet the criteria of cognitive decline if he does not do well postoperatively. This disadvantage may also be compounded by the possible influence of postoperative discomfort on the person’s cognitive performance. Conversely, when a patient initially obtains a poor preoperative performance, he may misleadingly pass the cognitive decline criteria despite a poor postoperative performance. A previous study by Roach et al has remedied this limitation by comparing the test results from nonsurgical patients matched for age and education (1999). However it was uncertain from the study whether there was no significant difference between the preoperative performance of surgical and nonsurgical patients.
With all the variations in the mode of evaluation of POCD, an accepted guideline of the assessment of neurocognitive function is necessary. While the statement of consensus for assessment of neurobehavioral outcomes after cardiac surgery developed by Murkin et al (1995) has already provided for the subjective neuropsychological test that can be used, newer objective tests such as electroreencephalographic (EEG) assessment as used by Toner, Taylora, Newmanb ; Smitha (1998) and near infrared spectroscopy (NIRS) (Talpahewa et al, 2004) should also be intergrated to improve the documentation and monitoring of POCS after heart surgery. The possible correlation of biologic markers (Herrmann, et al.1999; Xie ; Tanzi, 2006) and genetic factors (Newman et al. 2001) with POCD should also be established to further enhance the diagnosis and management of POCD. The goal is to have a reliable set of test that can be consistently used to screen, diagnose and monitor the development of POCD. This will help greatly in identifying the risk and aggravating factors that leads to POCD so that measures can be developed to protect patients undergoing heart surgery.
After reviewing the literature investigating the neuropsychological effects of heart surgery, it is undeniable that a significant percentage of patients who underwent cardiac surgery have experienced neurocognitive and psychological changes. These changes do not include those which are attributable to the occurence of other neurologic and cognitive complications such as stroke and postoperative delirium. (Selnes ; McKhann, 2001). Prospective studies have shown that stroke,which is considered as the most serious of these complications, has an incidence rate of 1.5 to 5.2 percent (McKhann, Goldsborough, Borowicz, Mellits, Brookmeyer, Quaskey et al.1997). Postoperative delirium after CABG was found to be present in about 10 to 30 percent of patients and was partly correlated to the adverse effects of anesthesia (Selnes ; McKhann, 2001). A previous study suggested it is likely that patients who had delirium after CABG had a history of stroke (Rolfson, McElhaney, Rockwood, Finnegan, Entwistle, Wong, ; Suarez-Almazor 1999). The presence of psychological disturbances also compound the comlications endured by patients who underwent cardiac surgery. Aside from the changes in psychological functioning found in pediatric cardiac surgery patients as observed in the review conducted Todaro et al. (2000), more recent data also indicate a high prevalence of psychiatric morbidities in adult cardiac patients which include posttraumatic stress disorder, dysthymic disorder, agoraphobia and major depression (Rothenhausler, Grieser, Nollert, Reichart, Schelling ; Kapfhammer, 2005).
However, the North American Diagnostic and Statistic Manual of Mental Disorders, Fourth Edition (DSM-IV) have no direct reference to these neuropsychologic changes secondary to cardiac surgery (Bekker ; Weeks, 2003). Rasmussen (2006), loosely defined postoperative cognitive dysfunction (POCD) as the changes which constitute an overall decline in cognitive function that occurs for weeks or months after surgery. These changes was suggested to include verbal memory, attention and psychomotor deficits among others. The subtle nature on the neuropsychological effects of heart surgery, nevertheless, necessitates a cleare definition and emphasis on its clinical features. This is of importance as there are common reports by patients of “not being the same” after surgery (Selnes ; McKhann, 2001). While the assessment of POCD is done by medical specialist, health care providers and relatives of cardiac patients should at least be aware of these postoperative changes so that they will be able to detect their existence and appropriate measures can be taken to address the problem. The diagnostic criteria suggested by Ramussen (1999) list several functional domains detectable in the presence of neurocognitive dysfunction (as cited by Bekker ; Weeks, 2003). These include memory impairment, which is identified by reduction in the ability of the patient to learn or recall information; disturbances in executive functioning, exemplified by decline in planning, organizing, and abstracting; disturbance in attention or impairment of information processing in perceptual-motor abilities and impairment in language abilities such as written and verbal comprehension and word finding.
Despite the overwhelming research involving the investigation of POCD, there are no available studies indicating that this condition can be successfully treated once it is diagnosed (Bekker ; Weeks, 2003). It is aimed that early recognition of the condition will allow for early therapy and initiation of supportive care and education of family members. Safety measures should also be initiated. A study on the driving performance of patients who underwent coronary artery bypass grafting showed that there are deteriorations in cognitive demanding parts like traffic behavior and attention in these patients (Ahlgren, Lundqvist, Nordlund, Aren, ; Rutberg, 2003). Since driving a car requires several complex cognitive skills, even subtle neuropsychological deficits occurring in POCD are of importance for the safety of the patient and of the public in general. As studies have shown that early cognitive decline is a significant predictor of long-term cognitive dysfunction, the early identification of POCD should warrant for aggressive intervention strategies to prevent the progression of late cognitive deterioration which were documented in these studies (Van Dijk et al. 2004; Newman, Kirchner et al. 2001). In addition to rehabilitation, when patients are identified to be at risk for late cognitive decline after heart surgery, vigorous attempts to slow the progress of vasculopathy by means of diet, medications, and changes in lifestyle should be indicated (Selnes ; McKhann, 2001).
It is evident from the literature gathered that most of the investigations on cognitive decline after cardiac surgery are centered on elucidating risk factors and predictors of POCD. This may be because the complexity of the condition requires a thorough understanding of its occurence. Through this approach, it is anticipated that the exact etiology and pathogenesis of POCD will be identified. This will guide future studies in developing meaningful treatment options for the condition. On top of the list of the risk factors of POCD is the increasing age of cardiac patients and type of surgery (Rasmussen, 2006). This should alert health care providers and relatives that if elderly patients who underwent major surgery should complain of changes in cognition postoperatively they should be taken seriously in order to provide them with appropriate management and rehabilitation. Investigators, however, emphasized the elderly patients should not be excluded from cardiac surgery exclusively on the basis of their age (Rasmussen, 2006). As advances in surgical techniques have allowed older patients with heart diseases to undergo open-heart procedures, it is likely that POCD, particularly the late cognitive decline, may in fact be a manifestation of aging of these patients (Selnes ; McKhann, 2001). While most studied showed that age-matched ‘normal’ controls did not have significant cognitive decline compared to cardiac patients who had surgery, a comparison between cardiac patients who underwent surgery against nonsurgical controls but with the same cardiovascular condition showed that the neuropsychological performance of surgical patients did not differ significantly with those nonsurgical group with the same morbidity (Selnes, Grega, Borowicz, Barry, Zeger, Baumgartner ; McKhann, 2005). It is then argued that POCD may not be specific to heart surgery after all. However, studies have demonstrated that although POCD have been verified to also exist after major non-cardiac surgery, theincidence, severity and duration of functional deficit were lower in other forms of major thoracic surgery (Toner, Taylor, Newman ; Smith, 1998; Rasmussen, 2006).
The neurological and neuropsychological effects following cardiac surgery have been demonstrated by several studies. Patients have been shown to manifest both short-term and long-term cognitive deficits postoperatively. While it is clear that heart surgery is a causative factor of POCD, it is also known that aside from improving the survival of patients with severe heart disease, heart surgery has also significantly improved the quality of life of patients after surgery. A 12-month follow-up study by Rothenhausler et al (2005) on psychiatric and psychosocial outcome of cardiac surgery showed that despite the cardiac surgery-related cognitive decline of cardiac surgical patients, the self-reported quality of these patients significantly improved compared to baseline quality of life taken preoperatively. This only shows that the benefits of cardiac surgery far outweigh its consequences. Still, more research is needed to identify the causes of cognitive decline after heart surgery as this will lead to better overall treatment outcome in patients undergoing heart surgery.
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