surgery, probably is due in part to genetic polymorphisms Common genetic variants, often due to single nucleotide substitutions, occur with a frequency of greater than 1% For a child with cCHD, environmental factors include cardiac surgery, use and/or duration of deep hypothermic circulatory arrest (DHCA), inflammatory response to blood exposure to synthetic surfaces during bypass, the need for repeated operations, the response to pressor or sedating medications, and socioeconomic status (SES) The role of genetic polymorphisms in determining the susceptibility to CNS injury in children with CHD is not known Recent studies suggest that polymorphisms of apolipoprotein e (ε2 polymorphism) may be predictors of adverse neurodevelopmental sequelae following infant cardiac surgery,53,61–63 and this has been similarly reported in adults with the ε4 polymorphism.63–65 Antagonistic pleiotropy is the term that describes how a polymorphism may be beneficial early but harmful later in life.66 It is likely that multiple genes modulate the CNS response to cardiopulmonary bypass (CPB), DHCA, and other environmental factors modifying the risk and pattern of injury.67 Impact of Cardiac Diagnosis on Neurodevelopmental Outcome The underlying cardiac diagnosis may have a significant and independent impact on neurodevelopmental outcome, and may modulate the effects of neuroprotective strategies.61,68–70 In addition to more obvious factors, such as arch obstruction or the number of ventricles, even the presence of a coexisting ventricular septal defect (VSD) in patients with d-TGA has been shown to be an independent significant risk factor for poor neurodevelopmental outcome (though this finding was confounded by older age at surgery).68–70 Bellinger and colleagues assessed the effect of intraoperative pH management on developmental and neurologic outcomes in infants with d-TGA with or without VSD, TOF, isolated VSD, atrioventricular canal defect, truncus arteriosus, and total anomalous pulmonary venous return undergoing cardiac surgical repair during deep hypothermic CPB.71 In this trial the Psychomotor Developmental Index (PDI) and Mental Developmental Index (MDI) scores of the Bayley Scores of Infant Development were significantly higher in the d-TGA group compared with those noted for the other cardiac defects Effect of Cardiac Surgery on the Brain Although at present there is increasing evidence that congenital and acquired CNS injury occurs in a significant fraction of children with CHD before surgery, the initial focus of research was on intraoperative management as the most significant contributor to CNS injury This remains important because, as opposed to all of the risk factors for abnormal neurologic development discussed thus far, variation in intraoperative support is one of the more easily modifiable risk factors that may be altered to improve long-term neurologic outcomes A partial list of factors that may contribute to CNS injury during surgical repair are included in Box 76.2 These multiple facets of CPB have received considerable attention over the last 3 decades with the completion of multiple randomized clinical trials looking at important intraoperative variables related to vital organ support conduct of CPB (see Box 76.2) as potential independent risk factors for worse neurodevelopmental outcome.53,68–70,72 Thus far, with the exception of higher hematocrit during CPB, and possibly pH management, no intraoperative interventions or specific procedural modifications have shown to improve neurodevelopmental outcomes.68–70,73 Of the many potential modifiable technical features of intraoperative support mentioned above, there are three that been most extensively studied, particularly CPB perfusion strategy, pH management, and hematocrit on CPB Box 76.2 Factors That May Contribute to Central Nervous System Injury During Surgical Repair Hypoxemia Cerebral hypoperfusion Cerebral embolism (particulate and/or air) Mechanical support during surgery (DHCA or continuous CPB) Hemodilution