Perioperative Central Nervous System Injury or Dysfunction

Postoperative central nervous system (CNS) dysfunction includes emergence delirium, emergence agitation, POD, POCD, postoperative maladaptive behaviors, and postoperative stroke. These diagnoses share similar features but can be differentiated in part by their differential time courses ( Fig. 42.1 ). There is significant overlap in risk factors and suspected etiology between postoperative delirium and POCD, and delirium appears to affect the development of both early postoperative cognitive dysfunction and longer-term cognitive decline.

One of the principal distinctions between postoperative (Post-Op) delirium and postoperative cognitive dysfunction (POCD) is the time frame in which they are found. Emergence delirium occurs in the operating room (OR) or immediately after in the postanesthesia care unit (PACU) . Postoperative delirium occurs 24 to 72 hours after surgery. POCD is measured at weeks to months after surgery and anesthesia. Pre-Op, Preoperative.

(Reprinted with permission from Silverstein JH, Timberger M, Reich DL et al. Central nervous system dysfunction after noncardiac surgery and anesthesia in the elderly. Anesthesiology 2007;106(3):622–628.)

Postoperative Delirium

Delirium is a disturbance in attention and awareness that represents a change from baseline, accompanied by disturbed cognition, and not caused by a preexisting disorder or occurring in context of a severely reduced arousal level. Postoperative delirium rates range from 14% to greater than or equal to 50%, perhaps reflecting differing levels of delirium risk factors (e.g., older versus younger patients, and others). Delirium rates are likely underreported in routine clinical care.

Postoperative Cognitive Dysfunction in Cardiac Surgery

Many studies have used preoperative and postoperative neuropsychologic testing to assess POCD after surgery, with varying testing deficit thresholds used to define POCD. POCD at 1 to 3 months after cardiac surgery and noncardiac surgery shows a wide range of reported incidence. Most studies show postoperative cognitive dysfunction rates decrease over time from 3 months to 1 year after surgery. A number of factors are important for interpreting these studies. First, with most neuropsychological testing, scores improve with repeat testing during short intervals (learning effect). These issues can be partly mitigated by including multiple individual tests to assess each cognitive domain and by using methods such as factor analysis to create overall cognitive domain scores. Thus, an optimal cognitive test battery includes assessments that span different cognitive domains and cognitive ability ranges. Also, postoperative cognitive changes in older adults occur superimposed on normal age-related neurocognitive/ neurophysiologic changes, including preexisting neurodegenerative pathology. Since Alzheimer’s disease-associated pathology begins decades prior to observable cognitive deficits (such as memory impairment), many older patients may have clinically silent Alzheimer’s disease-associated neuropathology; these patients are at increased risk of postoperative delirium and POCD. Many statistical or clinical thresholds have been used to define cognitive dysfunction after surgery. Some thresholds incorporate changes in one or two tests, some rely on changes in larger cognitive domains, such as attention and verbal memory, and others measure global change across an entire cognitive test battery. Depending on the statistical thresholds and rules used to define it, POCD may represent either a single-domain or multidomain deficit in memory, executive function, or other affected areas. It is unclear how long-term cognitive trajectories differ in more detailed domain specific (memory versus executive function) analysis. It is also important to consider the timing of preoperative and postoperative testing. Cognitive dysfunction early after surgery is likely to be influenced by postoperative pain, medications like opioids, and acute postoperative recovery. Global cognitive dysfunction 1 year after coronary artery bypass graft (CABG), for example, was directly correlated with worsened quality of life measures, and global cognitive dysfunction and worsened quality of life 1 year after CABG were associated with increased self-reported depressive symptoms (but not increased anxiety symptoms). A continued correlation between overall cognitive dysfunction and quality of life was also seen more than 5 years after cardiac surgery, with a similar association between both measures and self-reported depressive symptoms. This correlation between POCD and quality of life was present across the full range of cognitive dysfunction severity at 1 and 5 years after surgery; even relatively minor postoperative cognitive deficits were associated with reduced quality of life. Thus cognitive dysfunction should be considered a syndrome with a severity distribution. The idea that “subthreshold” postoperative cognitive deficits may be significant for patients is consistent with the emerging view in medicine that many disease processes represent a continuous spectrum rather than dichotomous traits.

POCD Associated with Noncardiac Surgery

POCD, an accepted complication of cardiac surgery, has been, until the last 20 years, less appreciated or defined after noncardiac surgery. In 1998, the International Study of Postoperative Cognitive Dysfunction (ISPOCD-1) evaluated cognitive decline in 1218 elderly patients who underwent major noncardiac surgery and found that cognitive dysfunction was present in 25% of patients 1 week after surgery and in 10% of patients 3 months after surgery.

To investigate further POCD after noncardiac surgery, Monk et al. completed a prospective assessment of 1064 patients undergoing elective noncardiac surgery. This assessment was divided among young (18–39 years of age), middle-aged (40–59 years of age), and elderly (60 years and older) patients. A group of 210 primary family members were used as controls to provide a change score similar to that used in the ISPOCD. The patients completed a battery of cognitive tests at baseline (preoperatively) and at both 1 week and 3 months postoperatively. Fig. 42.2 shows the incidence of POCD at the hospital discharge and 3-month postoperatively based on neuropsychological evaluations. At hospital discharge, the incidence of POCD was 36% in the young, 30.4% in the middle-aged, and 41.4% in the elderly patients. The incidence of cognitive decline was significantly lower in middle-aged patients compared with elderly patients ( P = 0.01), but was not different for young versus elderly or young versus middle-aged patients. The incidence of cognitive decline was similar for control subjects of all age groups at the first postoperative testing session: 4.1% in young, 2.8% in middle-aged, and 5.1% in elderly patients. However, the differences in cognitive decline between age-matched controls and patients were significant for all age groups ( P < 0.001). At 3 months after surgery, POCD was identified in 5.7% of young, 5.6% of middle-aged, and 12.7% of elderly patients. POCD was significantly higher in elderly compared to young or middle-aged patients ( P = 0.001). There was no difference in the incidence of POCD between age-matched control subjects and patients in the young and middle-aged groups. However, elderly patients exhibited a significantly greater incidence of cognitive decline at 3 months after surgery compared with elderly control subjects ( P < 0.001). Of the significant univariate predictive factors for POCD at 3 months after surgery, only increasing age, lower educational level, and POCD at hospital discharge remained significant in the multiple logistic regression analysis. The results of this trial indicate that postoperative cognitive dysfunction is common in all age groups at 1 week. However, at 3 months after surgery it is more common in the elderly with lower educational achievement. Monk et al. not only reported on the incidence of POCD, but also reevaluated patients at 1 year to collect mortality data. They found an increase in 3-month mortality associated with POCD at discharge compared with those without POCD at discharge ( P = 0.02). They also found that patients with POCD at both discharge and 3 months have a significantly higher 1-year mortality rate than any other group ( Fig. 42.3 ).

Incidence of postoperative cognitive dysfunction (POCD) in adult patients after noncardiac surgery: Z score definition.

(Modified from Monk TG, Weldon BC, Garvan CW, et al. Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology . 2008;108(1):18–30.)

Relation between the presence of postoperative cognitive dysfunction (POCD) and the percentage of patients who died in the first year after surgery. This figure includes only patients who survived to test at the 3-month (late) test time. The figure includes the following four groups: none (patients who did not experience POCD at either of the testing times), hospital discharge (patients who had POCD only at hospital discharge), 3 months (patients who had POCD only at the late [3 months postoperative] testing session), and hospital discharge + 3 months (patients who had POCD at both hospital discharge and the late testing sessions). Hospital discharge + 3 months group was significantly different from the other 3 groups, P =0.02*.

(Reprinted with permission from Monk TG, Weldon BC, Garvan CW, et al. Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology . 2008;108(1):18–30.)

Pathophysiology of Neurocognitive Dysfunction after Surgery

In general, POCD is probably multifactorial. The risk factors and mechanism contributing to postoperative delirium and postoperative cognitive dysfunction can be categorized in several ways. Patient risk factors are clearly defined by those present before surgery and those present during and after surgery and anesthesia (such as cardiopulmonary bypass or anesthetic dosage) ( Table 42.1 ). These divisions are useful because they help define targets for prediction or prevention of POCD at a given time during perioperative care. It is also important to recognize that some proposed risk factors and mechanisms may be modifiable while some may not be. Another way to categorize etiology is by potential pathophysiologic processes, such as inflammation, neuronal damage, vascular damage/embolism, cerebral autoregulation and oxygen delivery, neurodegenerative disease pathology, and brain network dysfunction. These factors are clearly overlapping and are discussed in the following sections.

Inflammation

Inflammation associated with surgery and anesthesia are thought to play a major role in delirium and postoperative cognitive dysfunction. Tissue trauma during surgery leads to the release of injury-associated chemokines and cytokines. These mediators result in a systemic inflammatory response which leads to further release of interleukins IL-1 and IL-6, tumor necrosis factor (TNF)-α, and damage-associated molecular pattern molecules such as high mobility group box-1 and S100 calcium binding proteins ( Fig. 42.4 ). Systemic inflammatory mediators may also enter the brain as a result of postsurgical breakdown of the blood–brain barrier. Blood–brain barrier dysfunction is frequently seen in older adults (even in the absence of surgery), and has been seen in ~ 50% of patients after cardiac surgery. Furthermore, postoperative blood–brain barrier breakdown correlates with the degree of cognitive dysfunction after cardiac surgery. Neuroinflammation has detrimental effects that are sufficient to cause deficits in cognition, memory, and behavior, and has been implicated in conditions ranging from mood disorders to neurodegenerative disease and postoperative cognitive dysfunction. Supporting the role of neuroinflammation in postoperative cognitive dysfunction are studies demonstrating that genetic polymorphisms that modulate inflammation (e.g., in the genes CRP, SELP, GPIIIA, and iNOS) are associated with postoperative cognitive dysfunction risk. Inflammation in cardiac surgery is exacerbated by blood contact with foreign surfaces of the cardiopulmonary bypass (CPB) circuit causing significant peripheral inflammation, including multiple-fold elevations of the proinflammatory cytokines interleukins 6 and 8 (IL-6, IL-8) also seen during noncardiac surgery. The classic complement cascade can also be activated by heparin-protamine complexes after CPB. Sternotomy and surgical incision also increases proinflammatory cytokine levels in rats, and possibly in humans, although some studies have not replicated these findings. Lastly, anesthetic drugs themselves, both in cardiac and noncardiac surgery can modulate inflammation. Inhaled anesthetics have proinflammatory effects on microglia and opioids and heparin can also modulate inflammation and monocyte function in vitro. Thus drugs given during surgery may have significant effects on the overall balance of pro- and anti-inflammatory cytokine levels and on patient outcomes. Taken together, these findings suggest that exposure to anesthetics and other drugs during surgery, together with the effects of surgical trauma or other factors such as the incision, median sternotomy, tissue damage, and ischemia reperfusion injury, may contribute to neuroinflammation and ensuing postoperative delirium and postoperative cognitive dysfunction. In rodent models, cardiac surgery causes more prolonged neuroinflammation and a wider spectrum of behavioral impairments than abdominal surgery, although both surgery types reduced hippocampal neurogenesis rates and neurotrophic factor levels (such as brain-derived neurotrophic factor). Terrando found similar neuroinflammation and subsequent behavioral changes after orthopedic surgery in mice, suggesting that common mechanisms involving decreased hippocampal neurogenesis, spinal pain signaling, and central neuroinflammation may lead to memory dysfunction after both orthopedic and cardiac surgery. Blocking neuroinflammation and microglial activation reduced postoperative memory deficits in mouse models, although these interventions have yet to be tested in humans. Several anti-inflammatory drug trials have failed to prevent delirium or cognitive dysfunction after cardiac surgery, including lidocaine, magnesium, complement cascade inhibitors, and postoperative acetylcholinesterase treatment. Intraoperative high-dose steroids were also ineffective, perhaps because steroids can also cause delirium and hallucinations that may counterbalance their theorized cognitive improving antineuroinflammatory effects. Intraoperative ketamine treatment reduced delirium and cognitive dysfunction after cardiac surgery in small pilot studies, but did not reduce delirium in a large multicenter randomized trial (which included approximately both cardiac and noncardiac surgery patients). Dexmedetomidine also had no effect on delirium incidence after cardiac surgery in a recent multicenter randomized trial, although it had mixed effects on delirium after noncardiac surgery; these divergent results may be caused by differing dexmedetomidine infusion rates and durations between these studies. The large predominance of negative study findings may reflect the complexity of delirium and postoperative cognitive dysfunction, which may also underlie the relatively greater success of multimodal interventions. Alternative strategies to more specifically target postoperative inflammation may better prevent postoperative delirium and postoperative cognitive dysfunction.

Pathophysiologic mechanisms that may play a role in postoperative cognitive dysfunction (POCD) and/or delirium. Starting from the top, in clockwise order, the pullout boxes represent cellular/molecular and synaptic mechanisms (such as Alzheimer’s disease-related pathology), cerebral oximetry monitoring, anesthetic dosage, resolution of inflammation, vascular mechanisms (such as emboli), and blood–brain barrier dysfunction, which may be involved in POCD and delirium. Additional physiologic variables that may be involved in POCD and delirium are described in the text. APP , amyloid precursor protein; CNS , central nervous system; RBC , red blood cell.

(Reprinted with permission from Berger M, Terrando N, Smith SK et al. Neurocognitive function after cardiac surgery: from phenotypes to mechanisms. Anesthesiology. 2018;129(4): 829–851.)

Embolic Load

Embolic load may also play a role in neurocognitive dysfunction after cardiac and noncardiac surgery. Direct manipulation of the aorta during cardiac surgery often disrupts atheromatous plaques. Increased intraoperative atheroma burden has been seen in patients with postoperative cognitive dysfunction (versus those without postoperative cognitive dysfunction) at 1 week, but not at 3 or 12 weeks, after cardiac surgery. Current guidelines recommend epiaortic ultrasound evaluation of aortic plaque in patients with increased stroke risk, including those with a vascular disease history and those with other evidence of aortic atherosclerosis or calcification. Aortic plaque disruption can liberate microemboli that can travel to the brain. These microemboli can be detected by transcranial Doppler ultrasound, although the majority of transcranial Doppler signals actually represent small gas emboli.

Gaseous microemboli occur frequently in open chamber cardiac valve cases, which has led many centers to flood the open cardiac chamber with carbon dioxide, because carbon dioxide is more soluble than air and thus promotes the resorption of gas emboli. However, a randomized trial found that field flooding with carbon dioxide versus medical air had no effect on cognitive function 6 weeks after surgery.

Microemboli can also be detected by postoperative diffusion-weighted magnetic resonance imaging (MRI) although preoperative MRI scans are needed to differentiate new microemboli from prior lesions. The percentage of cardiac surgery patients with detectable microemboli vastly outnumber the percentage with clear postoperative stroke(s). Many experts refer to these emboli and diffusion-weighted MRI abnormalities as “clinically covert strokes,” because they are not associated with neurologic abnormalities detectable in routine clinical examination. Although it seems intuitive that embolic load to the brain and resulting T2-weighted MRI white matter hyperintensities would have detrimental neurocognitive effects, correlations between embolic load and postoperative cognitive changes have been inconsistent. This is complex and observational studies have found that these “clinically covert strokes” are associated with future risk of stroke, cognitive decline, and Alzheimer’s disease. Interaction between embolic load, central neuroinflammation, and other variables that may interact in synergistic ways to produce postoperative neurocognitive dysfunction.

Cerebral Blood Flow, Autoregulation, and Oxygen Delivery

Since the inception of CPB with nonpulsatile blood flow, low perfusion pressure has been blamed for both stroke and POCD. Further, an increasing percentage of our elderly surgery patients (cardiac and noncardiac) have hypertension, which can shift the normal autoregulatory range of cerebral blood flow (classically thought to be 60 to 160 mmHg) and thus increase risk of hypoperfusion. The actual autoregulation range for any given patient is unknown and the lower limit of autoregulation during CPB may vary from 45 to 80 mmHg. Newman et al. found significant cerebral autoregulation impairments in 215 patients during cardiac surgery, but no correlation with postoperative cognitive dysfunction. Similarly, Joshi et al. found that up to 20% of cardiac surgery patients have impaired autoregulation and these patients with “pressure passive” cerebral blood flow had increased perioperative stroke rates. Further, intraoperative cerebral autoregulation can dynamically change in response to intraoperative physiologic changes, suggesting the need for real-time cerebral autoregulation measurement.

Studies examining the relationship between mean arterial pressure (MAP) management and postoperative cognitive change have shown varying results. For example, maintaining intraoperative MAP within 80 to 90 mmHg, rather than 60 to 70 mmHg, was associated with less postoperative delirium and a smaller postoperative decrease in mini mental status examination scores. Gold et al. found that higher MAP targets (i.e., 80 to 100 mmHg versus 50 to 60 mmHg) were associated with lower cardiac and neurologic complication rates (i.e., stroke): however, they found no difference in postoperative cognition between groups. Much of this variation, especially in stroke rate, was later defined to be primarily associated with the degree of aortic atheroma with pressure only being of substantial effect in those patients with severe aortic atherosclerosis. Postoperative MAP values below the lower limit of autoregulation have also been associated with increased levels of the glial injury biomarker glial fibrillary acidic protein, emphasizing the importance of maintaining MAP within the autoregulatory range. However, observational studies have found that maintaining blood pressure above the upper limit of cerebral autoregulation is associated with increased postoperative delirium rates, suggesting that it may be important to avoid MAPs above, as well as below, each patient’s autoregulatory range.

Temperature Management During Cardiac Surgery

The cerebral metabolic rate of oxygen (CMRO ₂ ) is closely associated with temperature, which led to the practice of lowering cerebral metabolic rate of oxygen utilization by inducing hypothermia, thus reducing brain oxygen deprivation and neurocognitive injury during reduced oxygen delivery period. Hypothermia reduces neurologic injury in animal models of focal cerebral ischemia and cardiopulmonary resuscitation. Alternatively, hyperthermia increases cerebral metabolic rate of oxygen utilization and is associated with worse neurocognitive outcomes and increased mortality risk in numerous clinical situations. Thus studies have examined whether lowering cerebral metabolic rate of oxygen utilization by inducing hypothermia during CPB would improve postoperative neurocognitive function. Early work showed that patients who underwent normothermic (i.e., “warm” or greater than 35°C) CPB had a threefold higher stroke incidence than those who underwent hypothermic (i.e., “cold” or less than 28°C) CPB. Yet one randomized trial found no benefit of hypothermia (i.e., 28°C to 30°C) versus normothermia (35.5°C to 36.5°C) during CPB on cognitive change from before cardiac surgery to 6 weeks after cardiac surgery. Nonetheless, the maximum postoperative temperature after cardiac surgery was associated with cognitive dysfunction severity 6 weeks after surgery, emphasizing the importance of avoiding postoperative hyperthermia. This concept may help explain data showing that rewarming to a lower temperature (34°C versus 37°C) was associated with lower cognitive dysfunction rates 1 week after surgery and improved performance on the grooved pegboard test (a manual dexterity and visuomotor processing speed task) at 3 months after surgery, although there was no overall cognitive benefit at 3 months after surgery. In essence, the early cognitive benefits of rewarming to a slightly lower target in this trial may have been a result of the prevention of postoperative hyperthermia. This group also found no neurocognitive difference among CABG patients randomized to undergo normothermic (37°C) CPB or hypothermic (34°C) CPB without operating room rewarming in either group; avoiding central hyperthermia during rewarming may therefore help optimize postoperative cognitive function. Similarly, another recent randomized trial found that achieving a lower core body temperature (via external head cooling) during CPB was associated with less cognitive dysfunction 10 days after cardiac surgery. Despite numerous studies, there is still debate about temperature management during cardiac surgery. Current clinical recommendations simply call for avoiding hyperthermia (arterial outlet blood temperature greater than or equal to 37°C) during cardiac surgery and for a rewarming rate less than or equal to 0.5°C/min once temperature exceeds 30°C. Slow rewarming may help avoid cerebral ischemia because rapid rewarming has been shown to cause cerebral metabolic rate of oxygen utilization increases prior to corresponding increases in CBF.

Glucose Homeostasis During Cardiac Surgery

Neurocognitive function is typically unaltered by glucose changes within normal physiologic limits. Because many surgical patients have diabetes and the surgical stress response can decrease peripheral insulin sensitivity and cause hyperglycemia, studies have investigated the relationship between intraoperative glucose management and postoperative neurocognitive outcomes. One retrospective study found that intraoperative hyperglycemia (i.e., glucose levels greater than 200 mg/dL) was associated with worsened postoperative cognitive function in nondiabetic patients, but not in diabetic patients. This is not surprising because diabetic patients are often exposed to hyperglycemia, which causes physiologic compensatory responses (such as glucose transporter downregulation on brain capillaries) to reduce excessive glucose influx into the brain. This adaptation helps explain why intraoperative hyperglycemia may be more detrimental to the brains of nondiabetic patients. However, this interpretation is challenged by the results of a large randomized trial ( n = 381) showing that intraoperative insulin infusion (up to 4 units/h) in nondiabetic patients did not improve neurocognitive outcomes. The idea that hyperglycemia is detrimental to the brain led to additional interventional studies examining whether tighter glucose control would improve postoperative cognition. Yet, tight intraoperative glucose control with a hyperinsulinemic–normoglycemic clamp (glucose target 80 to 110 mg/dL) versus standard therapy (glucose target less than 150 mg/dL) during cardiac surgery was associated with increased delirium rates, perhaps as a result of the increased hypoglycemia in the intensive glucose control arm of this study. Another study found that the use of glucose and insulin infusions to maintain serum glucose at ~ 64 to 110 mg/ dL preserved auditory learning and executive function after cardiac surgery, suggesting that avoiding hyperglycemia may result in improved postoperative cognitive function. These data suggest that it may be equally important to avoid hypoglycemia and hyperglycemia in order to avoid postoperative delirium and postoperative cognitive dysfunction. The physiologic adaptations to chronic hyperglycemia in diabetic patients suggest that intraoperative glycemic control should be individualized.

Genetic Factors

An intriguing development in the field of neuroprotection is in the area of genetic predisposition or susceptibility in surgery-associated cerebral injuries. The possibility that a person’s genetic makeup might alter cognitive outcome after cardiac surgery was first delineated in a 1997 study. In that study, the apolipoprotein E hypothesis was born, that is, that patients possessing the Apo E4 allele had worse cognitive outcomes after CPB. Although not all studies have replicated this finding, the consideration that postoperative cognitive dysfunction and delirium may involve mechanisms similar to those of Alzheimer’s disease has led to further studies. These studies have found conflicting results; overall it appears that ApoE4 carriers are not more likely to develop early postoperative delirium or postoperative cognitive dysfunction, but do have worse long-term cognitive trajectories after cardiac surgery. This finding could be related to the known long-term detrimental effects of the ApoE4 allele on cognition, and/or to the increased aortic arch atheroma burden seen in ApoE4 carriers and thus a possible increase in cerebral microemboli during cardiac surgery. Several other genetic polymorphisms have recently been found that are associated with Alzheimer’s disease risk, and it will be important to examine whether these Alzheimer’s disease risk polymorphisms are also associated with postoperative cognitive dysfunction or delirium risk after surgery.

To investigate further the possible role of inflammation and possible thrombus formation in POCD, Mathew et al. characterized the PlA2 polymorphism of the platelet integrin receptor GP IIb/IIIa, and examined its influence on cognitive outcome after cardiac surgery. A multivariate analysis revealed that the PlA2 genotype was significantly associated with greater decline on the Mini Mental State Examination ( P = 0.036). The mechanism may be related to an increased prothrombotic role, which has been shown in investigations of coronary artery thrombosis and myocardial infarction. Overall, the progression of genetic predictors of perioperative cognitive decline have mimicked the more general progression of genetic studies moving from the investigation of single candidate genes to multiple candidate genes and then to genome-wide scans as technology advances.

Mathew et al. also hypothesized that candidate gene polymorphisms in biological pathways regulating inflammation, cell matrix adhesion/interaction, coagulation-thrombosis, lipid metabolism, and vascular reactivity are associated with POCD. In a prospective cohort study of 513 patients (86% European-American) undergoing CABG surgery with cardiopulmonary bypass, a panel of 37 SNPs was genotyped by mass spectrometry. The association between these SNPs and cognitive deficit at 6 weeks after surgery was tested using multiple logistic regression accounting for age, level of education, baseline cognition, and population structure. Permutation analysis was used to account for multiple testing. Mathew found that in European-Americans ( n = 443), minor alleles of the CRP 1059G/C SNP (OR: 0.37; 95% CI: 0.16–0.78; P = 0.013) and the SELP 1087G/A SNP (OR: 0.51; 95% CI: 0.30–0.85; P = 0.011) were associated with a reduction in cognitive deficit. The absolute risk reduction in the observed incidence of POCD was 20.6% for carriers of the CRP 1059C allele and 15.2% for carriers of the SELP 1087A allele. This compared with a greater than 40% incidence of decline in those patients who did not possess either allele ( Fig. 42.5 ). Perioperative serum CRP and degree of platelet activation were also significantly lower in patients with a copy of the minor alleles, providing biologic support for the observed allelic association. These results suggest a contribution of P-selectin and CRP genes in modulating susceptibility to cognitive decline following cardiac surgery, with potential implications for identifying populations at risk who might benefit from targeted perioperative anti-inflammatory strategies. Identifying genetic and mechanistic factors associated with lower rates of injury and sequelae help us define pathways to protection and to provide the opportunity for preoperative genetic screening to identify patients who are at risk for cerebral injury and who will most likely benefit from interventional protective strategies.

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