Abstract
Every year in the United States approximately 40,000 infants are born with congenital heart disease. Many of these infants require corrective or palliative surgery in the neonatal period. Mortality rates after cardiac surgery are highest among neonates and higher still in those born prematurely, of low birth weight, and with significant associated medical conditions or genetic syndromes. We will outline the immature organ systems that complicate care of the neonate—especially premature and low-birth-weight babies. We also describe three major noncardiac conditions that impose increased mortality risk when combined with congenital heart disease.
Key Words
low birth weight, cardiac surgery, prematurity, organ immaturity
The prevalence of congenital heart disease (CHD) ranges from 6 to 10 per 1000 live births, and CHD is the most common birth defect. Nearly 40,000 infants are born with CHD each year in the United States, and over 1 million babies are born every year worldwide. Many of these infants will require surgery to correct or palliate their heart defect during their lifetime, and some require surgery in the newborn period.
In North America between 2007 and 2010 the age distribution of the approximately 80,000 patients undergoing cardiac surgery for CHD across 96 centers is shown in Fig. 30.1 . Although neonates constituted only 25% of the total surgical volume, they accounted for more than 50% of all the deaths ( Fig. 30.2 ). Continual advances in surgical and cardiopulmonary bypass (CPB) techniques, as well as improved preoperative and postoperative management, have resulted in a general decline in operative mortality across all age-groups. However, neonates have the highest mortality risk. Multiple factors contribute to a mortality rate of approximately 10% after neonatal cardiac surgery.
Lesions requiring surgery in the neonatal period are often quite complex. Technical challenges include tissue fragility, cannulation, and maintenance of adequate CPB. The performance of intricate procedures in tiny hearts requires superior technical skill and years of experience for mastery.
Abnormal preoperative circulation and the effects of CPB on immature organ systems are additional factors that place neonates at greater risk for death after surgery. Premature birth and low birth weight (LBW) add substantial risk. Neonates born before 37 completed weeks of gestation are at greater risk of death after cardiac surgery than those born after 37 weeks. However, the risk of death after 37 weeks is not uniformly equivalent. Population and single-center studies have revealed this phenomenon both in babies born with CHD and in those without. There is an incremental decline in death rate from 37 to 40 weeks, with the nadir at 39 to 40 weeks. Death rates increase again if delivery is delayed beyond 41 weeks. Most babies with CHD are born before 39 to 40 weeks of gestation; this is often to allow better coordination of delivery, catheter intervention if necessary, and to avoid in utero demise. Extending pregnancy from 37 to 38 weeks to 39 to 40 weeks provides a significant survival benefit and reduces the risk of complications. Therefore elective delivery of babies before 39 completed weeks of gestation, absent any obstetric or fetal risk, should be discouraged.
Term gestation is actually delineated by statistical probability and ranges from 37 weeks to 42 weeks. Thirty-seven weeks is an entirely arbitrary beginning for term gestation, and the period between the two limits represents a continuum during which organ maturity continues. Therefore babies born in the “early term” period are physiologically less mature than babies born in “late term.” The exact physiologic immaturity that places early-term neonates at greater risk of mortality likely represents incomplete development of several organ systems. Even at birth, organ maturation is unlikely to be complete but is a gradual process that continues for several months and years after birth. Neonates are disadvantaged in comparison to infants and older children because of this multiorgan immaturity.
Immature Organ Systems
Cardiovascular
Postnatal Increase in Left Ventricular Output.
At birth the ratio of metabolic rate to oxygen consumption increases several-fold because of the additional demands imposed by heat conservation mechanisms and respiratory activity. Oxygen delivery increases in a similar proportion to maintain normal oxygen reserve capacity. Much of the increase in oxygen delivery is attributed to a substantial increase in left ventricular output after birth. Enhanced left ventricular output is caused by an increase in heart rate, an increase in left ventricular preload, and greater inotropic state. The exact mechanisms causing this postnatal increase in cardiac output are not completely known, but thyroid hormone is believed to play a role. Fetal lambs in which the thyroid gland was removed 2 weeks before delivery demonstrated low plasma levels of triiodothyronine (T 3 ) and failed to show the expected postnatal increase in T 3 levels and cardiac output. These same lambs had fewer beta-adrenergic receptors on the myocardial surface and exhibited a blunted response to beta-adrenergic stimulation. Elevation in cortisol levels, a catecholamine surge, and relief from ventricular constraint at delivery also contribute to the postnatal elevation in cardiac output.
Developmental Differences in Myocardial Structure and Excitation-Contraction Coupling.
Generation of myocardial contractile force increases with maturation. Developmental differences in contractility are mostly caused by age-related differences in myocardial structure ( Fig. 30.3 ).
The immature myocyte is smaller and has greater intracellular spatial disorganization than its mature counterpart. Also, a large proportion of the immature myocyte is inhabited by noncontractile organelles that do not contribute to force generation. The small, spherical structure of the immature myocyte and the central location of noncontractile elements impose a biophysical disadvantage to shortening.
Immature myofibrils assume a random arrangement rather than the parallel arrangement seen in adult myocytes. There are also far fewer myofilaments—the fundamental units of cross-bridge formation. An increased number of myofilaments correlates with an increase in myocardial force generation. Isoform switching of myofibrillar proteins with development also contributes to improved contractile efficiency with age.
The calcium-handling mechanism in the neonate is both underdeveloped and inefficient. The cytosolic calcium concentration is primarily dependent on transsarcolemmal flux of calcium because T-tubules and sarcoplasmic reticulum are scarce and intracellular calcium regulatory proteins are functionally immature. Neonatal myocardium is more sensitive to changes in extracellular ionized calcium and relies more on glucose metabolism. Thus there is a greater risk for myocardial dysfunction given the neonates’ decreased stores of calcium, inadequate glycogen stores, and impaired gluconeogenesis.
Adult myocardium is densely innervated by a plexus of sympathetic nerves. However, sympathetic innervation in neonatal myocardium is incomplete. Parasympathetic tone predominates, and hypotensive episodes are easily evoked.
Cardiac stores of norepinephrine, a reflection of sympathetic innervation, is lowest in late-term fetuses but approaches adult levels by 4 weeks of age. This is despite no significant quantitative difference between neonatal and adult beta-adrenergic receptors on the myocardial cell surface. Functional uncoupling of beta-receptor–G protein–adenylate cyclase complex in the newborn limits the effectiveness of catecholamine-modulated contractility in this age-group.
Neonatal Ventricular Performance.
Circulatory adaptation at birth is vital to meeting the increased metabolic demands of extrauterine life. An acute increase in heart rate, pulmonary venous return, and contractile state contributes to the postnatal enhancement in cardiac output. High resting inotropism limits contractile reserve in newborns, and immature hearts exhibit a blunted response to exogenous catecholamines compared with mature hearts. Rate-dependent mechanisms to improve cardiac output are thus favored in neonates.
The immature heart has less recruitable preload reserve and demonstrates only a modest Frank-Starling relationship compared to the adult mature heart ( Fig. 30.4 ).
This limited response to volume loading is partly due to the decreased compliance of immature hearts. With age, maturational changes in cytoskeleton and extracellular matrix improve myocardial compliance.
Volume or pressure loading of one ventricle can impact filling of the contralateral ventricle to a greater extent in immature hearts than in more mature ones. This restrictive effect is particularly evident in neonates who have endured an unfavorable postnatal transition and exhibit persistent fetal circulation. The pressure-loaded right ventricle (RV) alters septal dynamics and limits left ventricular filling and left ventricular stroke volume.
Increases in afterload profoundly diminish ventricular performance in the fetus and neonate. When exposed to similar afterloads, the immature myocyte shortens to a lesser extent and more slowly than a mature myocyte. Developmental changes in myocyte architecture permit the adult heart to counteract afterload stressors more effectively ( Fig. 30.5 ).
Congenital Heart Disease and Postnatal Circulation.
Most babies with structural heart disease experience an unremarkable transition to postpartum conditions. In neonates with ductal dependent circulations, symptoms will emerge with constriction of the ductus arteriosus. However, abnormal circulatory patterns in some forms of CHD may impose hemodynamic challenges immediately at birth:
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Babies with hypoplastic left heart syndrome with a restrictive atrial communication
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d-Transposition of the great vessels with intact ventricular septum and restrictive foramen ovale
In some forms of CHD the inherent limitations of the neonatal myocardial mechanics are also exposed:
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Severe aortic stenosis
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There is limited ability to increase myocardial performance in the face of increased afterload.
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Lesions with left-to-right shunts
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Recruitment of the Frank-Starling mechanism and increasing the inotropic state accomplish much of the increased stroke work required to maintain adequate systemic flow. However, large shunts may overwhelm the limited preload and contractile reserve of the newborn heart. Babies with hypoplastic left heart syndrome are particularly vulnerable. In these neonates, excessive pulmonary blood flow can limit systemic flow. Right ventricular output must increase several-fold to maintain systemic flow, and the right ventricular functional reserves may be insufficient to maintain systemic flow.
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Other Immature Organ Systems
Other organ systems may also be incompletely developed, especially in premature and LBW babies, but even in the infant born at term. A brief summation of critical systems is provided.
Respiratory
Fetal lungs achieve drastic maturation at the end of gestation. In preterm neonates this last surge of lung maturity is absent, resulting in significantly impaired alveolarization and dysmorphic vasculogenesis. As a result, functional residual capacity is reduced and has an adverse impact on respiratory function. Surfactant deficiency is common and leads to respiratory distress syndrome if untreated.
Chest wall structure and limited diaphragmatic apposition introduces mechanical inefficiencies in ventilation. The neonatal lung and chest wall possess variable compliances—the lungs are less compliant, whereas the chest wall is extremely compliant. This uncoupling predisposes the chest wall to deformational forces, and much of the respiratory energy is expended in counteracting these forces. Compensation is with a higher resting respiratory rate than that seen in older children and adults.
Renal and Gastrointestinal
Nephrogenesis is completed at 35 weeks of gestation; however, structural and functional growth of the kidney continues for several months after birth. The biggest limitation in renal function in the neonate is the rate of glomerular filtration, which, in the first few days of life, is one-third that seen in adults. Tubular and medullary renal function limit the maximal urine-concentrating ability of the newborn infant to half that of an adult. These functional limitations make the neonate more vulnerable to fluid overload or depletion.
Premature infants are at increased risk for necrotizing enterocolitis. The main risk factors are poor systemic perfusion (particularly if the cardiac anomaly causes substantial aortic runoff to the lungs) and higher dosage of prostaglandins. Jaundice is more severe, particularly in LBW or very LBW infants because of reduced blood cell survival and liver immaturity.
Temperature Regulation
Newborn infants, particularly those born prematurely, are susceptible to hypothermia. Their large surface area in relation to body weight permits greater heat loss than in older children. Neonates have only a modest ability to conserve heat in the presence of cold stressors. Shivering thermogenesis is limited in the first few weeks to months of life. Nonshivering mechanisms such as brown fat metabolism are recruited for heat production in neonates, but this increases oxygen consumption. Therefore neonates benefit from care in a thermoneutral environment—the temperature at which normal core temperature is maintained with minimal energy expenditure.
Immune System
Neonatal skin and mucosa are ineffective barriers, and thus they are susceptible to infections. Immature cellular and humoral systems limit their ability to mount an effective immune response. Particularly at risk are premature infants with long-standing indwelling venous catheters.
Low Birth Weight, Very Low Birth Weight, and Prematurity
LBW related to prematurity or small for gestational age is present in 8% to 18% of infants born with CHD. Among LBW (<2.5 kg) and very LBW (<1.5 kg) neonates, CHD accounts for approximately a quarter of all deaths. Approximately one-third of LBW neonates with CHD will have an associated noncardiac abnormality. LBW and prematurity are two separate variables; however, they are intimately related, and we will consider them together rather than apart.
Clinical manifestations of immature organs in LBW and premature neonates requiring cardiac surgery are typically seen in the respiratory, gastrointestinal, and neurologic systems.
Respiratory
Premature lungs are immature in structure and function. A deficiency in surfactant may require exogenous surfactant replacement, oxygen supplementation, and, in severe cases, mechanical ventilation. A variety of lung insults result in bronchopulmonary dysplasia, dependency on mechanical ventilation can cause significant barotrauma and interstitial emphysema, and long-standing intubation can cause airway stenosis. Any parenchymal lung disease, fluid, or air accumulation in the pleural space quickly exposes the diminished respiratory reserves of the neonate.
Gastrointestinal
Premature neonates have high insensible water losses and are prone to dehydration and electrolyte abnormalities. Gut immaturity often prevents establishment of enteral feedings, and parenteral nutrition is required for prolonged periods. Postnatal closure of the ductus arteriosus is unusual in extremely LBW infants. Wide patency not only causes congestive cardiac failure but also can lead to renal failure and necrotizing enterocolitis.
Neurologic
Premature babies have abnormally developed areas of the brain, such as the immature germinal matrix, which are susceptible to injury. These abnormalities are also found in full-term gestation neonates with CHD, probably caused by abnormal cerebral circulation in utero. Extremely premature babies are especially prone to intraventricular hemorrhage because of fragile cerebral vessels. Brain maturation is also considerably delayed in neonates with congenital heart defects and more so if associated with prematurity.
Preterm infants face multiple challenges that are compounded in the presence of CHD and require special attention in perioperative management.
Treatment Options in Low-Birth-Weight or Very Low-Birth-Weight Neonates With Congenital Heart Disease
The three main physiologic issues in neonates with CHD are volume overload, pressure overload, and cyanosis—from reduced blood flow or poor mixing. The goal of neonatal heart surgery is to either correct or palliate these conditions. It is essential to weigh the balance between the risks of waiting and the risk of surgery to achieve the best possible results.
Medical Therapy
Prostaglandin E 1 is used to keep the ductus arteriosus patent and maintain fetal circulation when required for certain types of CHD. However, the use of prostaglandins can be complicated by hypotension, apnea, fever, intraventricular hemorrhage, electrolyte disturbances, and increased fragility in ductal tissue. In LBW babies, duration of preoperative hospitalization significantly correlated with preoperative complication rates, and a longer waiting period caused worse complications, which impacts mortality and morbidity after cardiac surgery.
Effects of Cardiopulmonary Bypass on Neonates
The adverse effects of CPB, including hemodilution, systemic inflammation, and bleeding, are more pronounced in neonates than in older children and adults. The priming volume of the extracorporeal circuit may be as high as two or three times the circulating blood volume of the term neonate (approximately 80 mL/kg). This disparity between the circulating blood volume and bypass circuit size results in marked hemodilution, anemia, hypoproteinemia, and a reduction in coagulation factors. Significant hypoproteinemia leads to greater movement of fluid from the intravascular compartment into the extracellular space.
Surgical trauma and extracorporeal circulation trigger an extensive systemic inflammatory response involving neutrophil, contact, and complement activation; cytokine release; platelet aggregation; and coagulation cascade activation. Systemic inflammatory mediators can cause cellular and organ dysfunction. Release of C3a increases vascular permeability, tumor necrosis factor-α (TNF-α) and interleukin-1-β depress myocardial contractile function, and TNF-α increases vascular permeability and lung water content and decreases glomerular filtration. These adverse effects of global inflammation are more pronounced on the immature organ systems of neonates.
Palliative Surgery
Because of the insult of CPB during corrective cardiac surgery and the limitations of medical therapy, surgeries have been designed to palliate CHD and allow patient growth and organ system maturation before complete corrective repair. These surgeries include systemic-to-pulmonary shunts for patients with decreased pulmonary blood flow, pulmonary artery banding for patients with increased pulmonary blood flow, and surgical septectomy or catheter balloon septostomy for patients requiring mixing to maintain saturations.
These procedures can be performed without the use of CPB and are technically relatively simple; however, postoperative management is complex because it is very difficult to regulate the appropriate amount of pulmonary blood flow because neonatal pulmonary vascular resistance is very mercurial.
Difficulty in managing this abnormal physiology means there is a consistent amount of early postoperative morbidity, which in some institutions may be equivalent to the morbidity from early corrective surgery.
The palliated state also has implications for other organ systems, and palliative surgeries can also create adhesions and distort native tissue, such as the pulmonary artery, which may then require reconstruction at the time of complete repair.
When to Delay Surgery
The rate of complications is clearly related to length of time before corrective surgery. The strategy of “letting the child get bigger” on his or her own is not a good enough reason to delay surgery. One should aim to perform corrective surgery before the development of complications unless there are specific reasons not to operate. Conditions that generally preclude surgery include sepsis, specifically necrotizing enterocolitis, bacteremia, and bronchiolitis; end-organ dysfunction, predominantly respiratory, renal, and liver failure; active bleeding or bleeding tendency; and cerebral hemorrhage or stroke. These conditions should be corrected before surgery.
Some malformations do not impose a severe physiologic impact on the neonate and allow the neonate to grow appropriately, without mechanical ventilation or medication. Small atrial septal defects (ASDs) and ventricular septal defects (VSDs), transposition of the great arteries with VSD and pulmonary stenosis, tetralogy of Fallot without severe cyanosis, double-outlet RV with balanced circulation, and unobstructed total anomalous pulmonary venous return fit into this category. Traditionally, single-ventricle palliation, especially the Norwood procedure for hypoplastic left heart syndrome, has shown high mortality in LBW neonates, and management usually involved delayed surgery if stable hemodynamics can be maintained on prostaglandins; however, recent data from our own unit showed univentricular palliation was not a risk factor for mortality in the LBW group of patients. Technical limitations relate not only to surgical care but also anesthetic and intensive care management. Surgical limitations usually relate to cardiac size and tissue fragility, which predominantly affects those defects requiring intracardiac repair. The deleterious effects of prolonged CPB and myocardial ischemia on immature myocardium should also be taken into consideration before embarking on a prolonged procedure.
Although accurate surgery is requisite, perioperative management by neonatologists, anesthetists, and intensive care physicians is often more difficult. There is an inverse association between pediatric cardiac surgical volume and mortality that becomes increasingly important as case complexity increases. Although volume is not associated with mortality for low-complexity cases, high-volume programs outperform smaller programs as case complexity increases. This reflects not only surgical technique but experienced perioperative care from all treating teams.
Cardiac Surgery at Low Birth Weight and Very Low Birth Weight
The functional limitations of the premature baby must be recognized in the operating room and intensive care unit. Exposure to CPB may result in surfactant dysfunction, hemodilution, inflammation, and postoperative capillary leak syndrome. Ventilator strategies favorable to premature lungs and chest wall should be used. High peak inspiratory pressure and tidal volumes are particularly injurious to immature lungs. Positive end-expiratory pressure stabilizes the highly compliant chest wall and maintains functional residual capacity. The myocardial structural and functional limitations detailed earlier can be managed with inotropes; however, there are no clear data favoring one inotrope over another, and choice is usually driven by institutional practices.
The Society of Thoracic Surgeons database study from 2008 provides a modern data set to guide prognostication. Outcomes for 3000 patients (of which 517 were <2.5 kg) are described. Compared with infants weighing 2.5 to 4 kg, infants weighing less than 2.5 kg had a significantly higher mortality for the following operations: repair of coarctation of the aorta, repair of total anomalous pulmonary venous connection, arterial switch procedure, systemic-to-pulmonary-artery shunt, and the Norwood procedure. Lower infant weight remained strongly associated with mortality risk after stratifying the population by Risk Adjustment for Congenital Heart Surgery-1 levels 2 through 6 and Aristotle Basic Complexity levels 2 through 4.
Our own analysis of cardiac surgery in LBW babies also revealed a significantly higher mortality rate compared to babies weighing more than 2.5 kg (10.9% versus 4.8%; P = .0069). We also found that lower gestational age at birth was an independent risk factor for early mortality in neonates or infants weighing less than 2.5 kg at surgery. The rate of early unplanned reintervention was not significantly different between patients weighing less than 2.5 kg and more than 2.5 kg, suggesting that technical surgical factors that might occur in tiny neonates can be overcome and were not the primary cause of the greater mortality seen in the patients weighing less than 2.5 kg. Factors such as the STS–European Association for Cardio-Thoracic Surgery (EACTS) Congenital Heart Surgery (STAT) risk categories, surgeon, and bypass time were also not related to mortality or early reintervention. Several technically complex procedures, such as the arterial switch operation, interrupted aortic arch repair, or truncus arteriosus repair, were performed with no hospital mortality in the patients weighing less than 2.5 kg. The expertise of the surgical and perfusion teams in the management of CPB in low-weight neonates, with significant emphasis on fluid restriction such as priming volume reduction and a lack of postoperative bleeding to avoid blood product transfusion and the lack of a need for permanent pacemaker implantation, should not be underestimated.
Our analysis of “usual” versus “delayed” timing of surgery did not show greater risk for any of the outcomes in the low-weight population. This finding is consistent with a study from Toronto that showed that for neonates weighing less than 2.0 kg, imposed delays in intervention neither compromised nor improved survival. The risk of medical complications from delayed surgery and higher mortality risk in nondelayed surgery seem to be in balance.
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