Prenatal Mechanisms of Brain Injury

There is growing recognition that the brain is abnormal at birth in the majority of neonates with cCHD. Fetal and postnatal magnetic resonance imaging (MRI) studies have identified brain immaturity at birth and a surprisingly high incidence of white matter injury (WMI), stroke, and hemmorhage. MRI and echocardiographic studies have confirmed abnormalities of cerebral vascular resistance (CVR), fetal blood flow, and reduced substrate delivery leading to immaturity of the developing brain. In addition, there is an increased incidence of congenital structural CNS abnormalities in association with cCHD, suggestive of shared (heart, brain) genetic abnormalities. In combination, these functional and anatomic abnormalities seen in the newborn with cCHD might best be considered coexisting congenital brain disease , and appear to be present in nearly 50% of these neonates.

Fetal Cerebrovascular Physiology, Oxygen Delivery, and the Placenta

Ultrasound studies in the fetus have revealed that CVR is altered in fetuses with cCHD. Fetuses with left-sided obstructive lesions (e.g., HLHS) have been shown to have decreased CVR compared to normal fetuses. In patients with aortic atresia, the combined fetal cardiac output from the right ventricle must travel through the ductus arteriosus and deliver flow cephalad (in a retrograde fashion) to the brain, as well as caudad to the viscera and low resistance placenta. In left-sided cCHD, it is speculated that CVR must therefore be lower than normal to allow adequate fetal blood flow cephalad to the developing brain. In contrast, fetuses with right-sided obstructive lesions (e.g., tetralogy of Fallot [TOF]), where the combined fetal cardiac output leaves the left heart and passes cephalad, through the ascending aorta, to the brain prior to reaching the placenta, have been shown to have increased fetal CVR. The altered CVR, whether higher or lower than normal, most likely has an effect on the developing brain. The changes in cerebral blood low that occur immediately after birth, when pulmonary vascular resistance abruptly falls, are incompletely understood; however, studies of cerebral blood flow in the first days of life suggest that cerebral blood flow and oxygen delivery is low, and continues to fall during this critical time period.

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 the most desaturated blood to the placenta. When significant structural disease exists within the heart, these beneficial patterns are likely to be altered. Recently confirmed by fetal MRI measurements, fetuses with d-transposition of the great arteries (d-TGA) have the blood with the lowest oxygen saturation returning to the ascending aorta and brain, while blood with the highest oxygen saturation returns 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 more than 50 years, and has been offered as an explanation for the increased incidence of relative microcephaly and long-term developmental challenges seen so often in children with d-TGA. Complete mixing with a dual-distribution circulation (see Chapter 70 ), as seen in those with functionally univentricular hearts, and limitations on compensatory lowering of CVR, produce reduced fetal cerebral oxygen delivery. The contribution of the placenta adds complexity to the issue as it has been noted that placental weights are much lower than normal, and placental vascularity is abnormal in fetuses with cCHD. Furthermore, MRI measurements of umbilical vein oxygen saturations are significantly lower than expected, suggesting placental dysfunction (see also Chapters 7 and 11 ).

It has long been recognized that the neurologic status of newborns with cCHD is frequently abnormal prior to newborn heart surgery, including abnormalities in muscle tone, weak cry, and poor coordination of suck, swallow, and breathing. Following birth, cerebral blood flow may be significantly lower than normal in some patients due to abnormal cardiac physiology and frequently a “steal” of systemic cardiac output through the patent ductus arteriosus into the pulmonary arteries. In some lesions, such as total anomalous pulmonary venous return with obstruction and d-TGA with an intact atrial and ventricular septum, profound hypoxemia and acidosis may result immediately after birth. Certain procedures, such as balloon atrial septostomy, may be associated with an increased risk of stroke, although the data are conflicting in this regard. Genetic syndromes are present in approximately 25% of neonates with cCHD. Recent studies have suggested that genetic abnormalities may play a role in the abnormalities of brain structure, developmental delay, neurodevelopmental disability, as well as contribute to the risk of developing cCHD itself (see later). Finally, all patients with right to left shunting have the potential for air or thromboembolic material reaching the brain from intravenous catheters prior to, during, or after surgery. Hypoxemia, low cardiac output, and cardiac arrest in patients with uncorrected cCHD may contribute to CNS ischemia, injury, developmental delay, and neurodevelopmental disability, adding to the abnormalities that may be present at birth.

Microcephaly

Head circumference at birth is a surrogate for growth of the brain in the fetus, and in neonates without cCHD, microcephaly is independently associated with later developmental delays and academic difficulties. The incidence of microcephaly at birth in neonates with cCHD is increased compared to heart-healthy neonates (approaching 25% of neonates in some reports), persists into later infancy, and is associated with later developmental abnormalities. While the causes are speculative, and most certainly multifactorial, Shillingford et al. reported on a series of children with HLHS where the median head circumference at birth was only at the 18th percentile. In this study, patients with microcephaly had a significantly smaller ascending aorta than those without microcephaly, suggesting that reduced flow to the brain from the left ventricle secondary to anatomic hypoplasia of the ascending aorta may result in diminished brain growth.

Decreased Central Nervous Maturity

Microcephaly, structural and biochemical immaturity of the white matter, and delay in cortical folding and white matter myelination have led researchers to delve into investigations of fetal brain development. Limperopoulos et al. have shown striking differences in brain growth in fetuses with and without cCHD, with brain growth diverging from normal in the fetuses with cCHD at the beginning of the third trimester of pregnancy. Fetuses with hypoplasia of the aortic arch fared the worst, with the most reduced brain growth during the final trimester of gestation. Wu et al also showed that measures of fetal cortical complexity similarly diverged from normal during the third trimester.

Periventricular Leukomalacia/White Matter Injury

WMI, in the form of periventricular leukomalacia (PVL), is a common finding in premature infants. Although WMI has been increasingly recognized in full-term neonates with cCHD, some feel strongly that the term PVL should be reserved for the premature infant. Importantly, while there may be no differences in the MRI appearance of the punctate WMI in the two populations, the WMI in the cCHD population never becomes cystic like PVL in the preterm. In premature infants, severe degrees of PVL have been associated with cerebral palsy, while mild degrees of injury have been associated with developmental delay, motor difficulties, and behavioral disorders. The developmental “phenotype” in children who were born prematurely is remarkably similar to that seen in school-age children with cCHD. Preoperative factors and patient-specific factors including the specific heart diagnosis, postnatal age at surgery, prenatal diagnosis, and genetic factors have been shown to be associated with WMI in neonates with cCHD. Ongoing research examining the relationship between cerebral vascular reactivity and autoregulation, cerebral perfusion, and the identification of sensitive and specific brain injury biomarkers may allow for real-time intraoperative and postoperative brain injury monitoring and intervention to reduce brain injury. Miller, McQuillen, and others first demonstrated alterations in white matter structure and maturation using diffusion tensor MRI. Thereafter, Licht used an MRI-based observational metric called the Total Maturation Scale, that demonstrated brain maturation in full-term presurgical infants with cCHD was equivalent, on average, to the expected brain maturation of a 35-week premature infant. Others have since shown that the Total Maturation Scale predicted not only the risk for preoperative and postoperative WMI but also abnormalities on neurodevelopmental outcome in childhood and adolescence. In a fetal lamb model, exposure of the fetal brain to low levels of oxygen delivery in the third trimester, results in a developmental arrest in oligodendrocytes resulting in populations of vulnerable premyelinating oligodendrocytes. Similarly, in infants with cCHD, during fetal development there is lower than normal oxygen delivery in the third trimester, which results in delayed brain maturation and abnormal integrity of the white matter at birth. In infants with cCHD, these changes result in their developmental vulnerability to WMI. Heart defect type, surgical strategy, and other exposures result in the injury. Lynch et al, using advanced optical techniques to quantify cerebral blood flow and oxygen saturations, showed that daily falls in cerebral oxygen saturations between birth and surgery increased the risk for postoperative WMI in babies with HLHS. In Lynch’s study, rising cerebral oxygen extraction was not compensated with increasing cerebral blood flow. It is theorized that WMI results from a combination of cellular vulnerability and limitations in cerebral oxygen delivery. Similarly, Petit et al found an increased risk for WMI in neonates with d-TGA, as the duration between birth and surgery increases. These studies, and others, have challenged the paradigm of the timing of neonatal surgery. At the current time, there are competing risks of waiting longer for surgery (from a brain perspective) compared to proceeding early with surgery (from a renal, pulmonary, and cardiac perspective). See Chapter 15 for a similar discussion in the premature infant with cCHD.

While there are no prospective longitudinal studies to directly link the WMI seen in the newborn after heart surgery, with long-term (10-year outcomes or longer) neurodevelopmental outcomes or specific functional deficits, there is growing evidence that suggests that abnormal white matter is in fact at the core of these deficits. Brain MRIs obtained as part of the 16-year follow-up of the Boston Circulatory Arrest Study demonstrated that the white matter in the CHD subjects showed regions of decreased fractional anisotropy (a marker of WMI) compared to age-matched controls. Further investigations revealed that some of these areas of reduced fractional anisotropy were correlated with worse performance on the Conners 3 attention deficit–hyperactivity ADHD index, the Wechsler Individual Achievement Test mathematics composite, and visual spatial testing (visual closure). In this same cohort of adolescents with d-TGA, Panigrahy and colleagues used MRI analysis techniques, which allow testing the intactness of networks of white matter (whole-brain functional connectivity of resting state networks). The work demonstrated that worse neurocognitive function was mediated by global differences in white matter network topology, suggesting that disruptions of large-scale networks drive neurocognitive dysfunction. Interestingly, some of these large-scale networks may be abnormal even before the newborn has heart surgery.

Cardiopulmonary Bypass Strategy

When continuous CPB is utilized, perfusion to the body and brain is maintained. When DHCA is utilized, there is a period of obligate global cerebral ischemia followed by reperfusion. The use of DHCA provides a bloodless surgical field, which facilitates faster and easier completion of the cardiac repair or palliation and decreases the duration of blood exposure to the bypass circuit; however, it is used at the cost of a period of global cerebral/systemic ischemia. Continuous CPB—either in the typical manner or via regional cerebral perfusion techniques—maintains perfusion to the brain and body but increases the duration of blood exposure to the bypass circuit, which may increase the severity of the inflammatory response and its potential negative consequences. The use of continuous CPB avoids the period of global cerebral ischemia but results in a greater increase in inflammation, total body water, and potentially more severe dysfunction and/or possible injury to other organs such as the heart, lungs, brain, and kidneys.

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 more prolonged periods of uninterrupted circulatory arrest will result in an increased risk of adverse neurologic outcomes. However, closer inspection of the data suggest 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. As mentioned previously, the effects are most likely modified by other preoperative and postoperative 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 CNS, while some demonstrate either an inconsistent effect or no effect. Some have taken the stance that, since the majority of studies suggest a negative effect of circulatory arrest, DHCA 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. However, the avoidance of DHCA by necessity requires an increased duration of CPB, which has been consistently shown to have an adverse effect on both short- and long-term outcomes. A randomized trial comparing circulatory arrest to continuous cerebral perfusion completed at the University of Michigan demonstrated no improvement in developmental scores at 1 year of age. Similar findings were reported in a contemporaneous but nonrandomized study at Boston Children’s Hospital. Given the current widespread adoption of regional cerebral perfusion, it seems important to investigate the long-term neurodevelopmental outcomes following this widespread change in clinical practice. However, these studies, thus far, are absent. While there are some shorter-term follow-up studies suggesting noninferiority of regional cerebral perfusion, developmental studies in infants have very limited predictive validity for long-term outcomes, and research must continue in this regard.

Perhaps the best conducted study that emphasizes the importance of follow-up into adolescence and adulthood is the Boston Circulatory Arrest Study. In this study, a cohort of children with d-TGA undergoing an arterial switch operation were randomly assigned to intraoperative support predominantly by DHCA or predominantly by CPB 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 DHCA in the areas of postoperative seizures, motor skills at 1 year of age, as well as behavior, speech, and language by the age of 4 years. For the group, the mean intelligence quotient at the age of 4 was lower than expected at 93, with no difference according to treatment assignment. When these studies were published, many centers began avoiding even short periods of DHCA. Continued follow-up of this cohort, when the patients were aged 8 years, revealed that the intelligence quotients for the cohort as a whole were now closer to normal at 98 versus the population mean of 100. Many of the patients demonstrated significant deficits in visual-spatial and visual-motor skills, as well as in components of executive functioning such as working memory, hypothesis generation, sustained attention, and higher-order language skills. Those repaired using DHCA scored worse on motor and speech functioning, while those undergoing low-flow CPB demonstrated worse scores for impulsivity and behavior. When compared to a normative sample, parents reported significantly higher frequencies of attention problems, developmental delay, and problems with learning and speech, irrespective of treatment assignment. More than one-third of the population required remedial services at school, and 1 in 10 had repeated a grade. Most importantly, at age 16, no significant impact was seen based on intraoperative perfusion management; the early negative effects of hypothermic DHCA were no longer seen, and in fact, some outcomes were worse in the arm randomized to low-flow CPB. However, additional concerns became apparent: executive dysfunction and social cognition abnormalities were prevalent ; patients were four times more likely to be taking psychotropic medications compared to cardiovascular medications, and the number who received behavioral therapies and/or additional help at school increased to 65%. One-third had brain abnormalities detected on MRI. Additional recent investigations confirm these abnormalities in multiple centers throughout the world.

Whether current modifications of CPB techniques will improve the outcomes in the long term remains the subject of ongoing study. The Boston Circulatory Arrest Study was an extremely well-designed trial, with superb follow-up, but only included the enrolled neonates who were planned to undergo an arterial switch operation, and took place between 1988 and 1992. Hence, the results reflect the perioperative and surgical care delivered in that era, and thus may not be generalizable to the current era, or to other congenital cardiac lesions. For example, many features of routine postoperative care in that era, including extension of the anesthetic period for at least 48 hours, active rewarming in the ICU after surgery, and hyperventilation to reduce the risk of pulmonary hypertension, may each independently and adversely affect neurodevelopmental outcomes. In addition, those patients randomized to predominantly continuous CPB also underwent a relatively brief period of circulatory arrest. Thus, the study does not compare the use of circulatory arrest to no circulatory arrest. Nonetheless, the results serve to show the multiple factors that influence developmental outcome at school age, and show that factors related to poorer outcome, such as DHCA, 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. More recently, pooled 2-year neurodevelopmental testing data from over 1700 patients from 22 international centers collected from 1996 to 2009 were analyzed. PDI and MDI (77.6 ± 18.8 and 88.2 ± 16.7, respectively) were lower than normative means, and after controlling for a variety of risks, MDI improved only 0.38 points/year, hardly a drastic effect from over a decade of modifying surgical and medical care strategies.

pH Management

As noted previously, investigators at Boston Children’s Hospital assessed the effect of intraoperative pH management on developmental and neurologic outcomes in infants with d-TGA with and without VSD, TOF, isolated VSD, atrioventricular canal defect, truncus arteriosus, and total anomalous pulmonary venous return undergoing cardiac surgical repair who were randomized to either alpha-stat or pH-stat blood gas management strategy during deep hypothermic CPB. There was no effect of the pH management treatment group on the PDI score of the Bayley Scores of Infant Development. However, the MDI score varied significantly depending on treatment group and diagnosis. For patients with TGA and TOF, the use of pH-stat resulted in a slightly higher MDI, although the difference was not statistically significant. In patients with VSD, the effect was the opposite, with the use of alpha-stat management resulting in significantly improved scores. Neither pH management strategy was associated with either improved or impaired neurodevelopmental outcomes in childhood. Despite the equivocal data in this early report, with no longer-term follow-up yet available nor confirmatory data from other randomized trials, many centers are currently utilizing pH-stat management—particularly during cooling on CPB—in all operations on neonates and infants. Further research in this area, based on additional potential modifiers (e.g., cardiac diagnosis, age, genetics, and severity of preoperative hypoxemia) should continue.

Hematocrit During Bypass

During CPB, hemodilution has been widely applied based on the notion that increased viscosity would be detrimental during periods of profound or even moderate hypothermia. Research in animals suggesting that higher hematocrit levels conferred better cerebral protection has been more extensively investigated in two human randomized clinical trials. The results of these trials indicated that hematocrit levels during CPB below 24% were associated with lower scores in the PDI of the Bayley Scales of Infant Development, although no further improvement was seen comparing hematocrit levels of 35% to 25%. In addition, lower hematocrit levels were associated with a more positive fluid balance after surgery and higher serum lactate levels. Pooled data from these two studies were analyzed and an inflection point at around 28% was noted. These findings have been confirmed by multiple authors, and higher hematocrits on CPB are utilized by most centers.

Effect of Anesthesia

There have been concerns raised on the effect of anesthetic on the developing brain. Animal studies have reported increased cellular death (apoptosis) after brief or sustained exposures to inhaled anesthetics, isoflurane in particular. In humans, retrospective studies have shown that there are reasons to be concerned about the detrimental long-term cognitive effects of volatile anesthetics. What is lacking are alternatives to inhaled anesthetics that are not toxic, as both barbiturates and benzodiazepams have been linked to similar animal and human effects.

However, good evidence shows that untreated pain and stress have an adverse effect on neurodevelopment; therefore providing effective analgesia, sedation, and anesthesia at this stage would seem to be more important than concern over neurotoxicity.

Hemodynamic Instability

Decreased cerebral oxygen delivery may result from decreased systemic cardiac output (Qs), severe hypoxemia, and/or severe anemia. Postoperative agitation, pain and/or hyperthermia may increase the metabolic needs of the brain, resulting in a diminished oxygen supply/demand ratio, decreased cerebral oxygen delivery, and worse CNS injury. In addition, postoperative cardiac arrest—with or without the need for mechanical circulatory support—may occur in as many as 20% of certain subgroups of newborns with cCHD, and may result in significant CNS injury. Following cardiac surgery with CPB with or without DHCA, cerebral autoregulation may be impaired, ultimately affecting neurodevelopmental outcomes.

Following surgery, especially in newborns and infants, there is a predictable and reproducible fall in cardiac output, which may ultimately affect neurodevelopmental outcomes. This period of decreased oxygen delivery, usually within the first 24 hours after surgery, represents a particularly vulnerable time for the brain, especially if associated with increased oxygen consumption. Postoperative hypotension has been shown to be related to new or worsened WMI, especially if combined with hyperventilation (which may further reduce cerebral blood flow). Despite theoretic concerns of adverse neurodevelopmental effects, postoperative hyperglycemia has not been shown to correlate with adverse longer-term neurodevelopmental outcomes.

Seizures

Postoperative seizures have been reported to occur in 1% to 21% of infants. As all reports thus far have been single-center studies, the risks for seizures are variable and possibly only relevant to the site of the study. Significantly, in the Boston Circulatory Arrest Study, postoperative seizures were identified as a major determinant of academic achievement and performance 16 years after surgery. Multiple studies agree that the majority of postoperative seizures (>85%) occur without clinical signs and can only be identified with an electroencephalogram. The largest report of postoperative seizures in neonates (~400 patients, single institution) with cCHD showed that seizures occur in about 8% of patients, with the major identified risk factors being younger gestational age at birth and longer duration of bypass.

Length of Stay

Compared to cardiac surgery at older ages, neonates with cCHD have longer stays in the ICU—averaging nearly 1 month in most reports—with a significant number of outliers considerably longer length of stay (LOS). Increased LOS has been associated with increased risks of medical error, costs, parental stress, reoperation, and other cardiac and noncardiac morbidity. In the Boston Circulatory Arrest Study, LOS was independently associated with worse cognitive function at 8 years of age, even after adjustment for factors related to the LOS (e.g., sepsis, low cardiac output) or cognitive outcomes (e.g., maternal education, SES). Virtually all studies reporting short- and longer-term neurodevelopmental outcomes have two consistent factors independently related to worse outcomes: increased LOS and lower SES. While some aspects of LOS may not be modifiable, many units are now actively investigating strategies to reduce LOS (e.g., timing of surgery, early extubation, minimizing elective delayed sternal closure) in hopes of improving longer-term outcomes. While SES is not modifiable, per se, children from disadvantaged families may be at highest risk, and particular attention must be given to neurodevelopmental care during hospitalization and after discharge.