Prior to the early 1980s, it was uncommon for children with complex congenitally malformed hearts to survive into later childhood. The nearly simultaneous advances in congenital cardiac surgery, echocardiography, and intensive care were coupled with the availability of prostaglandins and the developing discipline of interventional cardiology. Together, these factors resulted in a dramatic fall in surgical mortality, with complex repairs taking place at increasingly younger ages. At many large centers, palliative surgery followed by later repair was replaced by primary repair in infancy, while staged reconstructive surgery for various forms of functionally univentricular heart, including those with hypoplastic left heart syndrome, was improving with steadily falling rates of surgical mortality. 1-4 As a result, the early part of the 21st century has seen an increasing number of children entering primary and secondary schooling. Research into their academic and behavioural outcomes has revealed some sobering realisations about the outcomes in these survivors of paediatric cardiac surgery.
For the purposes of this chapter, complex congenital cardiac disease will refer to morphological abnormalities significant enough to require surgical or catheter intervention as neonates or young infants. As a group, patients with such malformations have a significantly higher incidence of academic difficulties, behavioural abnormalities, fine and gross motor delays, problems with visual motor integration and executive planning, speech delays, inattention, and hyperactivity. 5–17 Abnormalities of the central nervous system in infants with congenital cardiac disease is characterised by abnormalities of tone, difficulties with feeding, delays in major motor milestones, and speech deficits. 5,8,18,19 In children with congenital cardiac disease, the need for special services in school is significantly increased compared to the general population. 6,11,13,20 As children progress through school, low scores in terms of academic achievement, learning disabilities, behavioural problems, difficulties with social cognition and attention deficit/hyperactivity disorder may result in academic failure, development of poor skills in both the classroom and socially, low self-esteem, behavioural disinhibition, and ultimate delinqunecy. 21–23 Recent reports have also shown that quality of life is affected in children with complex malformations. 24
Dependent upon a number of factors, including the underlying congenital lesion and the associated surgical management, genetic contributions, additional perinatal events such as profound hypoxia-ischaemia from a delayed diagnosis, 25 or post-operative events such as low cardiac output syndrome, 26 the incidence of abnormalities may range from infrequent to ubiquitous. For example, in studies of children with transposition, a small fraction may have severe developmental impairment, perhaps one-half are normal in all respects, and nearly one-half will have a combination of speech, motor, behaviour or learning issues. 6,27 Compared to children with transposition, the proportion of children with other forms of complex disease, such as obstructed totally anomalous pulmonary venous connection, hypoplastic left heart syndrome, or interruption of the aortic arch who are developmentally normal is significantly decreased, with perhaps only one-third of those tested having no dysfunction in any domain. 11,12 While most of these abnormalities are relatively mild, and may only be determined by formal testing, they result in a so-called high-prevalence, low-severity developmental signature. A schematic representation is shown in Figure 64-1 .
Importantly, the combined outcomes of developmental delay, academic difficulties, and behavioural abnormalities represent the single most common morbidity affecting the quality of life in surviving patients with congenital cardiac disease when they reach school age. This complication is more common than late mortality, severe exercise impairment, unplanned reoperations, bacterial endocarditis, or significant arrhythmias. The later implications of these findings through adulthood are uncertain, and must continue to be a robust area of research. Our current understanding of the aetiology of these findings is discussed below.
SCOPE OF THE PROBLEM IN ADULTS WITH CONGENITAL CARDIAC DISEASE
Surprisingly, although the current number of adults with congenital cardiac disease is at least as many as the number of children with congenital cardiac disease, there is a paucity of studies investigating outcomes relating to the central nervous system, particularly with regard to behaviour and cognition. In contrast, there is an increasing number of investigations evaluating employment, physical activity, insurability, and quality of life in these adults, which complement nicely the recent data on younger children. The results of these studies in adults are mixed. Some suggest over-achievement in life-related activities, employment, and quality of life, while others describe deficits in social functioning, lifetime earnings, and health-related quality of life. 28–32 These mixed results are most likely due to the heterogeneous nature of congenital cardiac malformations, as well as the multiple non-cardiac reasons for suboptimal outcomes. As patients are further removed from surgery, it is likely that the social and environmental milieu are more responsible for shaping long-term outcomes, compared to the underlying structure of the brain, or the effects of hypoxaemia, low cardiac output, and cardiac surgery.
At this point, it must be emphasised that it is ill-advised to suggest that the current findings in adults are applicable to current children, or will be predictive of later dysfunction in the next generation of patients with congenital cardiac disease. The diagnostic capabilities, surgical techniques, and importantly, interventional philosophy were quite different when current adults with congenital cardiac disease were children. For example, a child born in the 1960s or 1970s with tetralogy of Fallot would most likely have been managed with one or more systemic-to-pulmonary arterial shunts prior to a complete repair in later childhood. The outcomes 30 years on in these patients are likely to be different than those for a child born in the current era who undergoes a single-stage correction in early infancy.
We believe, nonetheless, that the recent reports of adverse outcomes in children currently of school age, such as behavioural and academic difficulties, deficits in motor function, social cognition and social interactions, set the stage for functional difficulties seen later in adult life. One model that has been proposed for analysis of outcomes in patients with cancer is that the ultimate outcome of interest results from a combination of environmental influences in the susceptible host. In patients with congenital cardiac disease, environmental influences include, but are not limited to, the effects of cardiac surgery in general and cardiopulmonary bypass in particular, hypoxaemia, low cardiac output, hospital complications, social class, psychosocial interactions, and the implications of chronic disease on the family unit. Host, or patient-related, factors similarly include, but are not limited to, birth weight, the physiology caused by the underlying cardiac malformation, genetic abnormalities including recognised syndromes and allele polymorphisms, and additional congenital anomalies, especially in the brain, which affect long-term outcomes.
CONGENITAL CEREBRAL DISEASE
Given that the central nervous and cardiovascular systems form nearly simultaneously in early gestation, it is not surprising that there is an increased incidence of structural abnormalities of the brain in children with co-existing structural abnormalities of the heart. Many children with multiple congenital anomalies or chromosomal abnormalities, many of whom have co-existing congenital cardiac disease, will have developmental delay and behavioural issues as a significant component of late morbidity. In addition to genetic factors which may affect both systems from a macroscopic perspective, congenital cardiac disease may alter cerebral blood flow, delivery of oxygen, or both, and result in secondary effects of the vulnerable fetal central nervous system.
The brain of the full-term neonate with congenital cardiac disease structurally resembles that of a preterm neonate, 32 and interestingly, survivors of complex cardiac surgery, when they reach school age, have developmental findings which are very similar to survivors of premature birth, suggesting a similar pathological response to injury. Serial studies of the fetal brain, using ultrasound and magnetic resonance imaging, are currently underway, and are increasing our understanding of the interactions between the abnormal fetal cardiovascular system and cerebral development.
Microcephaly
The circumference of the head at birth is a surrogate for growth of the brain, and in neonates without congenital cardiac disease, microcephaly is independently associated with later developmental delays and academic difficulties. Multiple studies have shown the incidence of microcephaly at birth is increased in children with congenital cardiac disease, approaching one-fourth of children in some reports, 33–36 and persists into later infancy. 37,38 In a group of 318 neonates with various forms of congenital cardiac disease evaluated at our institution between 1992 and 1997, the incidence of congenital microcephaly, defined as a circumference of the head at or below the second percentile, was nearly 1 in 10. 34 More complex lesions have a higher incidence. In a series of consecutive neonatal autopsies at The Children’s Hospital of Philadelphia, approximately one-third of infants with hypoplastic left heart syndrome were noted to have congenital anomalies of the central nervous system and/or were microcephalic. 39 While the causes are speculative, and most certainly multi-factorial, a recent report in children with hypoplastic left heart syndrome, where the median circumference of the head at birth is only at the 18th percentile of that reported for normal neonates, revealed that patients with microcephaly had significantly smaller ascending aortas than those without, suggesting that reduced flow to the brain from the left ventricle secondary to anatomical hypoplasia of the ascending aorta may result in diminished brain growth. 33
The Open Operculum
The opercular region is that covering the so-called insulae Relie, and is made up of frontal, temporal, and parietal cortical convolutions. In magnetic resonance and computed tomographic imaging studies of neonates with complex congenital cardiac disease, underdevelopment of the operculum may be seen in nearly one-quarter of the patients, and is a marker for functional immaturity of the brain. 35,40 This may be a unilateral or bilateral finding, and has been termed underoperculinisation, or an open operculum ( Fig. 64-2 ). The operculum is thought to be related to oral motor coordination, taste, and speech, particularly to expressive language. In adults who develop a stroke in this area of the brain, the so-called Foix-Chavany-Marie syndrome, deficits include impairment of voluntary movements such as chewing and deglutition, dysarthria, and problems with taste. 41 In macaque monkeys, receptive fields on the tongue, lips and palate have been mapped to the operculum. 42 Giventhe high prevalence of problems with feeding, 36 delay with expressive language, and oral-motor apraxia in children with complex cardiac malformations, 5,12,27 as well as the increasing recognition of a high prevalence of an open operculum, we speculate that some patients with these developmental disabilities may have a structural underdevelopment of the operculum. We are currently pursuing this hypothesis.
Periventricular Leucomalacia
Injury to the white matter, a common finding in premature infants, has been increasingly recognised in full-term neonates with congenitally malformed hears. 40 It has also been suggested that decreased flow to the brain pre-operatively was significantly associated with lesions in the white matter, affecting slightly over one-quarter of neonates before surgery. 35 Periventricular leukomalacia was also found in slightly over half of a cohort of patients who underwent surgery for congenital cardiac disease as neonates, but was rarely detected in those who underwent surgery between 1 and 6 months of age. 43
All of these studies were carried out using populations of children who underwent cardiac surgery with deep hypothermic circulatory arrest. Because of concerns that the use of this technique during cardiac surgery is directly related to cerebral injury, many centres have adopted regional perfusion of the brain using low flow as an alternate strategy which decreases the period of cerebral ischaemia during cardiac surgery. Studies using magnetic resonance imaging of patients corrected with this technique 44 showed evidence of ischaemic lesions in one-quarter of the cohort prior to cardiac surgery, and in almost three-quarters after surgery. The majority of the ischaemic injury seen after surgery was in the form of periventricular leucomalacia, a proportion that is similar to those patients undergoing deep hypothermic circulatory arrest. 45 In another study, 46 injury to the white matter and/or stroke were identified in 22 infants pre-operatively, while another one-third of the survivors developed new evidence of brain injury on post-operative imaging. More sophisticated magnetic resonance imaging 32 has shown not only a high incidence of injury to the white matter, but also evidence of immature brain metabolism and microstructure, which are strikingly similar to findings seen in the premature population.
Periventricular leucomalacia is believed to arise from several factors, including the high susceptibility of the immature oligodendrocyte to hypoxic ischaemic injury, as well as the watershed distribution of flow of blood to this area between the small arteries that penetrate from the cortex and those that arise centrally and run radially outward. This watershed area is particularly prone to ischaemia during decreases in cerebral perfusion pressure. In premature infants, severe degrees of periventricular leucomalacia have been associated with cerebral palsy, while mild degrees of injury have been associated with developmental delay, 47 motor difficulties, and behavioural disorders, 48 a developmental signature remarkably similar to school-age children with congenital cardiac disease.
Additional Anatomical Findings at Birth
Congenital anatomical anomalies of the central nervous system are known to be coincident with malformations of the heart. 39,49–51 Cerebral abnormalities have been noted in one-quarter of a cohort of infants, with nearly half, such as holoprosencephaly and agenesis of the corpus callosum, present prior to any surgery. 52
Fetal Cerebrovascular Physiology and Delivery of Oxygen
Ultrasound studies in the fetus have revealed that cerebral vascular resistance is altered in the presence of congenital cardiac disease. Fetuses with left-sided disease, for example, hypoplastic left heart syndrome, were shown to have decreased cerebral vascular resistance compared to normal. 53,54 In patients with aortic atresia, the fetal cardiac output from the arterial duct must deliver flow cephalad to the brain as well as caudad to the low resistance placenta. It is speculated that cerebral vascular resistance must therefore be lower than normal to allow adequate blood flow to the developing brain. Fetuses with right-sided obstructive lesions, for example, tetralogy of Fallot, were also shown to have increased fetal cerebral vascular resistance. 53 In these children, it is speculated that the obstruction to flow into the pulmonary arteries changes the usual delivery from the patent arterial duct caudad to the placenta. In these cases, the left ventricle must contribute to placental blood flow antegrade from the ascending aorta, with a resultant increase in cerebral vascular resistance. The impact of these alterations in fetal cerebral vascular resistance is unclear, but almost certainly plays a role in subsequent neurological development.
In the normal fetus, the intracirculatory patterns created by the normal fetal connections result in preferential streaming of the most highly oxygenated fetal blood to the developing brain, and most desaturated blood to the placenta. When significant structural disease exists within the heart, these beneficial patterns are likely to be altered. Although not yet confirmed by fetal magnetic resonance spectroscopy, fetuses with transposition are likely to have the blood with the lowest saturation of oxygen returning to the ascending aorta and brain, while blood with the highest saturation will return to the abdominal organs and placenta. Speculation on the consequences of the transposed fetal circulation as an explanation for the high incidence of macrosomia in these infants dates back 40 years, 55 and has also been offered as an explanation for the increased incidence of relative microcephaly seen in transposition. 56 Complete mixing, as seen in those with functionally univentricular hearts, will produce intermediate values of fetal cerebral saturations of oxygen, but lower than those seen in the normal fetus ( Fig. 64-3 ).
PERI-OPERATIVE CONTRIBUTORS
Pre-operative Factors
Neonates with complex congenital cardiac disease frequently require hospitalisation immediately after birth, many to receive intravenous infusions of prostaglandin, some requiring intubation, mechanical ventilation, or invasive interventions such as balloon atrial septostomy. All of these interventions carry risks to the central nervous system, especially the potential for paradoxical embolus to the brain of air or particulate matter in children with intracardiac right-to-left shunts. These patients also have saturations of oxygen that are below normal, potentially compromising cerebral delivery of oxygen. In addition to diminished content of oxygen, neonates with critical congenital cardiac disease also have diminished flow of blood to the brain. 35 Such a finding of reduced flow to the brain, and abnormal vascular reactivity, has recently been confirmed in a neonatal piglet model of functionally univentricular physiology. 57
Intra-operative Factors
The conduct of cardiopulmonary bypass, and other support techniques used during open heart surgery, has received considerable attention, and has been the subject of active research. As opposed to all of the risk factors for abnormal neurological development discussed thus far, variation in intra-operative support, such as the conduct of cardiopulmonary bypass, is one of the few modifiable risk factors which may be altered to improve long-term neurological outcomes. Potential modifiable technical features of cardiopulmonary bypass are shown in Table 64-1 , and we pay particular attention to three of these.
| Air or particulate embolus |
| Rate and depth of core cooling (if utilized) |
| Deep hypothermic circulatory arrest (if utilized) |
| pH management during cardiopulmonary bypass |
| Hematocrit management during cardiopulmonary bypass |
| Reperfusion injury and inflammation |
| Rate of core rewarming/hyperthermia |
| Postoperative delivery of oxygen |
| Hypoglycaemia |
| Hyperoxia/hypoxaemia |
pH Management
In one very important trial at Children’s Hospital, Boston, developmental and neurological outcomes were evaluated in infants undergoing repair of a variety of cardiac defects at less than nine months of age who were randomised to either alpha-stat or pH-stat management during deep hypothermic cardiopulmonary bypass. Eligibility was limited to children undergoing various forms of biventricular repair in the first 9 months of life. Although there were some benefits reported with the use of pH-stat management for outcomes in the immediate peri-operative period, 58 the use of either strategy was not consistently related to either improved or impaired neurodevelopmental outcomes at one to four years of age. 59 On the Bayley Scales of Infant Development, there was no effect of treatment on the Psychomotor Development Index. The Mental Developmental Index, in contrast, varied significantly depending on the underlying anatomical diagnosis. For patients with transposition and tetralogy of Fallot, use of pH-stat resulted in a slightly higher mental developmental index, although the difference was not statistically significant. In patients with a ventricular septal defect, the effect was opposite, with use of alpha-stat management resulting in significantly improved scores. There was a significant effect of cardiac diagnosis on outcomes. Both scores of the Bayley examinations were significantly higher in those with transposition compared to the other cardiac defects. Despite the equivocal data in this early report, with no longer-term follow-up yet available, many centers are currently utilising pH-stat management exclusively in all operations on neonates and infants. 60–62 Further research in this area, based upon additional potential modifiers, for example, cardiac diagnosis, age, pre-operative hypoxaemia, or presence of major systemic-to-pulmonary collateral arteries, should continue.
Deep Hypothermic Circulatory Arrest
Much has been written on the potentially deleterious effects of prolonged circulatory arrest with profound hypothermia in cardiac surgery for neonates and infants. It is generally agreed that very prolonged periods of uninterrupted circulatory arrest may have adverse neurological outcomes. Close inspection of the data shows that the effects of short durations of circulatory arrest are inconsistently related to adverse outcomes, and that the effect of circulatory arrest is not a linear phenomenon. 63,64 The effects are most likely modified by other pre-operative and post-operative factors related to the patient. Some reports, most in an earlier era of cardiac surgery demonstrate a detrimental effect of circulatory arrest on a variety of outcomes relating to the central nervous system, 7,9,65–68 while some demonstrate either an inconsistent effect or no effect. 12,37,69,70 Some have taken the stance that, since the majority of studies suggest a negative effect of circulatory arrest, it should be avoided at all costs. Innovative and challenging strategies have been designed to provide continuous cerebral perfusion during reconstruction of the aortic arch or intracardiac repair. The avoidance of circulatory arrest, however, by necessity requires an increased duration of cardiopulmonary bypass. 71 This has consistently been shown to have an adverse effect on outcomes in both the short and longer term. 72,73 A randomised trial comparing circulatory arrest to continuous cerebral perfusion has recently been completed at the University of Michigan. 74 This demonstrated no improvement in developmental scores at one year of age. Similar findings were reported in a contemporaneous but non-randomised study at Children’s Hospital of Boston. 75
It seems imprudent to change practice based upon studies with only short-term developmental assessment. Developmental studies in infants have very limited predictive validity for long-term outcomes, either for patients with 6,76 or without 77 congenital cardiac disease. Perhaps the best conducted study in this regard, which emphasises this point, is the Boston Circulatory Arrest Study. 5,6,63,76,78–81 In this study, a cohort of children with transposition undergoing an arterial switch were randomly assigned to intra-operative support predominantly by deep hypothermic circulatory arrest or predominantly by cardiopulmonary bypass at low flow. Earlier reports suggested that the group as a whole was performing below expectations in many aspects of evaluation, with worse outcomes for the those undergoing circulatory arrest in the areas of post-operative seizures, 80 motor skills at 1 year of age, 79 as well as behaviour, speech, and language at the age of 4 years. 5 Mean intelligence quotient at the age of 4 was lower than expected at 93, with no difference according to assignment. Many centers began avoiding even short periods of circulatory arrest based upon these and other reports.
In 2003, assessments of quality of life, 82 and detailed standardised testing 6 were reported. Neurodevelopmental analyses when the patients were aged 8 years revealed that the intelligence quotients for the cohort as a whole are now closer to normal, at 98 versus the population mean of 100. The patients did demonstrate significant deficits in visual-spatial and visual-memory skills, as well as in components of executive functioning such as working memory, hypothesis generation, sustained attention, and higher-order language skills. In other words, the children had difficulty coordinating skills in order to perform complex operations. Those repaired using circulatory arrest scored worse on motor and speech functioning, while those undergoing bypass at low flow demonstrated worse scores for impulsivity and behaviour. When compared to a normative sample, parents of the entire cohort reported significantly higher frequencies of attention problems, developmental delay, and problems with learning and speech. More than one-third of the population required remedial services at school, and one in ten had repeated a grade. Thus, in this population of patients who underwent the arterial switch operation between 1988 and 1992, there appears to be a correlation between congenital cardiac disease and its surgical repair, with difficulties occurring later with speech and language, behavioural difficulties, and execution planning in childhood. 6,16,63,82 Whether current modifications of techniques will improve the outcomes in the long term remains the subject of ongoing study.
This well-designed trial, with superb follow-up, enrolled neonates who were planned to undergo an arterial switch operation between 1988 and 1992. Hence, the results reflect the peri-operative and surgical care delivered in that era, and thus may not be generalisable to the current era, or to other congenital cardiac lesions. For example, some features of routine post-operative care, including extension of the anaesthetic period for at least 48 hours, 83 active rewarming in the intensive care unit after surgery, and hyperventilation to reduce the risk of pulmonary hypertension, may each independently and adversely affect neurodevelopmental outcomes. In addition, those patients randomised to predominantly continuous bypass did undergo a brief period of circulatory arrest. Thus, the study does not compare use of circulatory arrest to no circulatory arrest. The results, nonetheless, serve to show the multiple factors which influence developmental outcome at school age, and show that factors related to poorer outcome, such as deep hypothermic circulatory arrest, which seem apparent and significant on early testing, may be attenuated or even abolished during longer-term follow-up, as other factors assume a more important role.
Haematocrit During Bypass
During cardiopulmonary bypass, haemodilution has been widely applied based upon the notion that increased viscosity would be detrimental during periods of profound or even moderate hypothermia. Work in animals suggesting that higher levels for the haematocrit confirmed better cerebral protection 84 was recently investigated in two randomised clinical trials. 85 The results of these trials indicated that levels for the haematocrit up to 24% were associated with increasing scores in the psychomotor development index, although the improvement was not linear at levels greater than 24%. In addition, lower levels were associated with higher fluid balance and higher levels of lactate in the serum. 61,85,86
Post-operative Factors
It has long been recognised that systemic flow is reduced in the first 24 to 48 hours following cardiac surgery, typically reaching a nadir in the first post-operative night. 73,87,88 At this time, the central nervous system may be especially vulnerable to secondary insults of decreased delivery of oxygen, particularly after circulatory arrest. To minimise the potential effects of low cardiac output following intra-operative ischaemia and reperfusion, the routine use of extracorporeal membrane oxygenation has been proposed for neonates at particularly high risk, such as those with hypoplastic left heart syndrome. 89 Post-operative mechanical support, however, has the potential to produce multiple deleterious effects, and the relative risks and benefits of this approach, as well as short- and long-term outcomes, are currently under investigation by those who performed the initial study. 89 Currently, close attention to cardiac output, and delivery and consumption of oxygen, seems warranted from the stance of the central nervous system, albeit that techniques for quantitative assessment of these parameters at the bedside is limited, particularly if there are residual intracardiac shunts.
Following cardiopulmonary bypass, with or without circulatory arrest, autoregulation of cerebral flow may be impaired, making the neonate and infant particularly vulnerable to periods of low cardiac output and/or hypoxaemia. 90 Although many studies in laboratory animals demonstrated various factors that adversely affect cerebral flow following cardiopulmonary bypass, it has previously been difficult to reproduce these studies in post-operative neonates and infants. Recently, transcranial Doppler and cerebral near-infrared spectroscopy techniques have been used to study cerebral flow in the cardiac intensive care unit following biventricular repair. 91 Approximately one in six of the patients studied demonstrated abnormalities of cerebrovascular pressure autoregulation, with risk factors including hypercapnia and higher mean arterial pressure during the time of the measurements. To date, the potentially deleterious effects of significant hypocapnia, which decreases total flow to the brain, and hypotension, the latter for ethical reasons, have not been studied in post-operative neonates. Further research is needed to determine the combined effects of cardiac output, mechanical ventilation, and cerebral flow, especially in the immediate post-operative period.
There have been recent reports following cardiac surgery in adults, as well in critically ill children with non-cardiac disease, suggesting that hyperglycemia is associated with adverse outcomes. These reports had stimulated some centers to develop protocols to control glycaemia, including continuous infusions of insulin, following congenital cardiac surgery in neonates and infants. However, recent reports have shown that hyperglycaemia is not a risk factor for adverse neurological or non-neurological outcomes in children after cardiac surgery. 92,93 In fact, hypoglycaemia may be more detrimental to the neonatal myocardium and brain. Thus, the treatment may be worse than the disease. This emphasises the point that extrapolation of research and management from patients without congenital cardiac disease to the neonatal and infant population following cardiac surgery should be undertaken with great care, skepticism, and after well-designed specific research.
Seizures have been reported to occur in the immediate post-operative period in up to one-fifth of neonates, depending upon the method used for detection. Clinical seizures are significantly less prevalent than those detected on continuous electroencephalographic monitoring. 78,94 The aetiology is most likely multi-factorial, but likely to be more prevalent in younger patients, those with prolonged periods of circulatory arrest, or those with co-existing abnormalities of the central nervous system. Peri-operative seizures are a marker for early injury, and have previously been reported to be associated with worse scores on developmental testing in children with transposition studied in the Boston Circulatory Arrest Trial, 5,79 although more recent data may show less of an impact than previously identified. 95
In addition to the identified factors above, the immediate post-operative period typically requires invasive monitoring, mechanical ventilation and significant medical support, especially in the neonate and young infant. 4 While these therapies have resulted in significant improvements in mortality, 96 they increase the risk factors which may adversely affect the central nervous system, including paradoxical embolus of air or particulate matter from peripheral or central intravenous access, fever, hypoglycaemia and swings in cerebral flow brought on by acute changes in mechanical ventilation. As was previously reported in a group of children who underwent the Fontan procedure, 9 longer stay in hospital and in the intensive care unit in the neonatal period was associated with worse developmental outcomes at the age of 8 years. 81 These effects were significant, even when controlling for other factors known to adversely affect long-term outcome, such as seizures, intra-operative support duration, reoperations and other post-operative events. Children with transposition whose length of stay was in the fourth quartile had mean intelligence quotients 7.6 points lower than those in the first quartile. Further investigation into the multiple potential mechanisms of injury to the central nervous system in the intensive care environment must continue.
There has been increasing interest in monitoring of the central nervous system in the intensive care unit, with interventions aimed at improving short-term cardiac outcomes, as well as longer-term neurodevelopmental outcomes. 96,97 In particular, the increasing use of cerebral near infrared spectroscopy holds great promise in this regard. 98,99 The benefits and risks of near-infrared spectroscopy, as well as the longer-term predictive validity of lower scores has not yet been studied in detail. Nonetheless, this technology is currently in use in a large number of centres caring for neonates and infants with critical congenital cardiac disease. 100
Continuous recording of the electroencephalogram, either with multiple channels or in an integrated fashion, also holds promise for peri-operative monitoring of the central nervous system. Abnormalities of the background electroencephalogram have been shown to be significantly related to other morbidities in the cardiac intensive care unit, such as the duration of mechanical ventilation, a longer length of stay in the hospital, and the need for supplemental tube feedings at hospital discharge. 101 These surrogate markers of injury are likely to be predictive of later neurological and developmental abnormalities.
Following discharge from hospital, some neonates remain at risk for ongoing injury to the central nervous system. Chronic hypoxaemia, as a result of ongoing palliation and/or residual intracardiac right-to-left shunting, may result in neurodevelopmental impairment. In children with transposition, older age at repair, as a surrogate for duration of hypoxaemia, has been associated with worse outcomes during follow-up. 102 Studies, many from a much earlier era of cardiac surgery when delayed repair was common, consistently show lower scores in children with cyanotic as opposed to acyanotic lesions. 103–113 Simple comparisons of defects with and without associated hypoxaemia, however, are confounded by the multiple factors present in children with cyanotic disease, including earlier age at repair and exposure to bypass, more complex surgical procedures, abnormal fetal patterns of flow, and many of the factors mentioned in this review. In children with structurally normal hearts and hypoxaemia from other causes, such as chronic lung disease, sleep disordered breathing, or high altitude, chronic or intermittent hypoxaemia has been associated with adverse effects on development, behaviour, and academic achievement. 114 The presence of hypoxaemia undoubtedly plays some role in patients with congenital cardiac disease, but is most likely modified by other factors, as it is difficult to measure the effect of hypoxaemia in isolation. The most recent studies comparing neurodevelopmental outcomes following repair of tetralogy of Fallot with those following isolated ventricular septal defect, support the potential impact of chronic hypoxaemia in these children. 27,115–117
GENETIC AND ENVIRONMENTAL FACTORS
Socioeconomic state is perhaps the strongest predictor of eventual neurodevelopmental outcome, and is a reflection of both the environment and the genetic factors for development inherited from the parents. Multiple studies have shown the relationship between socioeconomic state and/or parental intelligence and outcome in children with congenital cardiac disease. 6,7,9,117,118 In adolescents and young adults who have undergone the Fontan procedure, socioeconomic state accounted for one-sixth of the variability in scores for intelligence quotient, whereas the percent variability explained by circulatory arrest and all other surgical variables accounted for only just over one-twentieth. 119 Curiously, this effect was not seen in a small cohort of teenagers with hypoplastic left heart syndrome. 69
Children with identified genetic syndromes with known chromosomal abnormalities, such as Down, Williams, and DiGeorge syndromes and trisomy 13 and 18, as well as multiple associations of congenital anomalies, such as the CHARGE and VACTERL associations, frequently have co-existing congenital cardiac disease. In total perhaps one-third of all children with complex congenital cardiac disease have additional abnormalities besides their cardiac disease. Subchromosomal genetic abnormalities are being discovered with increasing frequency in this population, and most studies report worse outcome in children with associated congenital anomalies compared to children with the same lesion without additional anomalies.
Trisomy 21 is universally associated with mental retardation and other neurological impairments, 120,121 and is associated with a variety of cardiac defects, some associated with hypoxaemia, and many which require cardiopulmonary bypass for repair. Microdeletion of the 22nd chromosome has been shown to result in the phenotype of DiGeorge or velo-cardio-facial syndrome, with many of these children having abnormalities of the ventricular outflow tracts, such as tetralogy of Fallot, interruption of the aortic arch, and common arterial trunk, isolated ventricular septal defects, or abnormalities of branching of the aortic arch. 122 While some of the developmental delay and behavioural problems seen in these patients may be related to the underlying congenital cardiac disease and/or its treatment, as discussed above, and some of the speech delay may be related to the associated palatal abnormalities, recent reports suggest that there is an increased incidence of abnormalities in the white matter, 123 as well as a predisposition to psychiatric abnormalities. 124,125 Studies are currently underway to determine the relationship of these findings to the haploinsufficiency of genes on chromosome 22q11. 126
Apolipoprotein E is also known to be important in the regulation of cholesterol metabolism, and is thought to effect neurological recovery following a variety of injuries to the central nervous system. Genetic polymorphisms of apolipoprotein E are related to abnormal neurological development, with a significantly smaller head circumference found in children aged 1 year who underwent open heart surgery as neonates or young infants. 127 The effect of the genotype was independent of ethnicity, socioeconomic state, cardiac defect, and the use of deep hypothermic circulatory arrest.
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