Rudolph's Pediatrics, 22nd Ed.

CHAPTER 483. Neonate and Infant with Cardiovascular Disease

David F. Teitel


OVERVIEW


Although there are over 7000 different congenital cardiac defects,1 there are only a very few ways that a newborn or infant presents with cardiac disease. Symptomatic heart disease occurs in about 40% of congenital lesions, so that many infants present without symptoms. For this reason, perhaps, many clinicians consider the presence of a murmur as the most definitive evidence of heart disease. Unfortunately, this is the source of a very large number of unnecessary referrals to the pediatric cardiologist—the vast majority of murmurs occur in patients with normal hearts, and most innocent murmurs are misdiag-nosed.2 Up to 50% of normal children present with an innocent murmur at some time, whereas only about 50% of newborns with symptomatic heart disease have murmurs on clinical presentation. Even assuming that all of the children without symptoms who have congenital heart disease have murmurs, this would make the presence of a murmur to be about 2% specific and 80% sensitive in the diagnosis of heart disease. There is no other sign in medicine that has such poor specificity and sensitivity yet is used with such certainty.

Rather than asymptomatic heart disease, it is of utmost importance for the pediatrician to be able to quickly diagnose symptomatic heart disease. The change from a fetal circulatory system to a transitional circulation occurs immediately at birth, and the mature circulation develops within weeks.3 Because of these dramatic alterations in blood flow and oxygen uptake patterns in the neonatal period, the fetus with a stable cardiovascular status can become a newborn with severe cardiovascular symptoms, potentially leading to death, soon after birth. On the other hand, advances over the last few decades have given the clinician the tools to rapidly stabilize these critically ill neonates, and subsequently correct or ameliorate even the most complex defects. Thus, it is essential that the pediatrician be able to recognize the infant with symptomatic heart disease quickly, so that the appropriate diagnostic and therapeutic interventions can be initiated as soon as possible. Many pediatricians are insecure in their ability to recognize symptoms of heart disease, and thus fall back on the murmur as their gold standard of diagnosis, which can lead to devastating consequences for those symptomatic infants without murmurs. It is possible to overcome this insecurity by recognizing that there are only 3 different, overlapping, modes of presentation of symptomatic heart disease in the newborn and infant, each very easy to recognize during a routine examination. These modes of presentation are cyanosis, decreased systemic perfusion (hypoperfusion), and respiratory distress/failure to thrive.

Prior to considering the modes of presentation of symptomatic heart disease in the newborn, it is worthwhile to review fetal physiology, to understand why symptomatic heart disease is rare in the fetus.

FETAL PHYSIOLOGY

Most of our knowledge of the fetal circulation presented in this section is derived from research in fetal sheep,4 but more recent studies in human fetuses using echocardiography and Doppler studies confirm those findings, with only modest differences in percentages of blood flow in the various vessels and chambers, primarily related to the significantly greater cerebral blood flow in the human.5 The fetal circulation is unlike the postnatal circulation because the 2 ventricles eject into the vascular beds that are not fully separated. Rather, there are three main connections, or shunts, between circulatory beds and cardiac chambers that allow for admixture of venous return to the ventricles and of their outputs to the arterial beds. These connections allow 1 ventricle to take over the work of the other when a congenital cardiac defect is present. Those shunts, along with the far lesser oxygen demand of the fetus compared to the newborn, are the main reasons that most forms of critical congenital heart disease do not present until after birth.

Although there is overlap in the function of the ventricles, they still primarily perform their postnatal tasks prior to birth. Postnatally, the right ventricle is the oxygen uptake ventricle, ejecting poorly oxygenated blood into the pulmonary circulation for oxygen uptake. The left ventricle is the oxygen delivery ventricle, ejecting highly oxygenated blood into the systemic circulation for oxygen utilization by the tissues. In order for the ventricles to perform these tasks in the fetus reasonably efficiently, the right ventricle should receive relatively deoxygenated blood and eject the majority of its output to the placenta, because that is the oxygen uptake organ, and the left ventricle should receive relatively highly oxygenated blood and eject the majority of its output to the most metabolically active tissues.

To understand how the fetal circulation supports the efficient function of the right and left ventricles, it is best to consider, in order, the components of venous return, the distribution of these components within the heart, and the various vascular beds into which the ventricles eject (Fig. 483-1). Because these venous and arterial components are not separated in the fetus, one cannot talk about “venous return” as representing systemic or pulmonary venous return, or “cardiac output” as representing pulmonary or systemic blood flow. The amount of blood that composes all of the venous components will be called the “combined venous return,” and the amount of blood that the ventricles together eject will be called the “combined ventricle output” (CVO). The latter is equivalent to 2 “cardiac outputs” of the normal postnatal circulation, as the sum of pulmonary and systemic blood flow.

There are 5 components of venous return in the fetus: the upper body systemic venous return via the superior vena cava (SVC); the lower body systemic venous return, via the inferior vena cava (IVC); the placental return, also via the IVC; the coronary venous return, primarily via the coronary sinus (CS); and the pulmonary venous return, via the pulmonary veins. The right atrium receives the vast majority of venous return in the fetus because the pulmonary venous circulation, the only one that drains directly into the left atrium, composes only about 8% of combined venous return (Fig. 483-2). Despite the fact that over 90% of combined venous return drains exclusively into the right atrium, flow patterns within the veins and the right atrium, in association with the foramen ovale, which shunts blood from the right atrium into the left, allow for the left ventricle to receive a large amount of relatively highly saturated blood and the right ventricle to receive primarily poorly oxygenated blood.

To understand this remarkable phenomenon, it is best to view blood flow patterns in Figure 483-3. The least saturated blood comes from the coronary and upper body circulations and preferentially flows to the right ventricle. The coronary sinus orifice is near the atrioventricular groove, just above the tricuspid valve, and below the foramen ovale. Thus, essentially all coronary venous return via the coronary sinus passes inferiorly via the tricuspid valve to the right ventricle. Similarly, the position of the eustachian valve and the superior vena cava ensures that well over 90% of SVC flow passes inferiorly and laterally, to the tricuspid valve and right ventricle. Unlike blood returning via the SVC and CS, that in the inferior vena cava is not well mixed just before it enters the right atrium but is composed of relatively separate streams of blood returning via the intrahepatic inferior vena cava, the ductus venosus, and the right and left hepatic veins. The intrahepatic inferior vena cava receives blood primarily from the lower limbs, the kidneys, and the adrenals, and that relatively poorly oxygenated blood is also directed laterally via the eustachian valve, across the tricuspid valve to the right ventricle. The 3 other venous streams have more complicated sources of blood flow, as shown in Figure 483-4. Umbilical venous blood first reaches the portal sinus, where the majority ascends via the ductus venosus to the medial aspect of the junction of the inferior vena cava and right atrium. This highly oxygenated ductus venosus blood primarily is directed through the foramen ovale, to the left atrium and ventricle. The remainder of the umbilical venous blood enters the left portal venous system, whereas the splanchnic venous blood, consisting of intestinal, stomach, and splenic venous return, goes via the portal sinus primarily to the right portal veins. The portal venous blood in each lobe mixes with a much smaller amount of hepatic arterial blood and returns to the inferior vena cava near the right atrium. The right hepatic veins, draining primarily the less oxygenated splanchnic blood, drain into the lateral wall of the inferior vena cava and flow, with the intrahepatic venous return, and pass primarily to the right ventricle, whereas the left hepatic venous blood, composed in large part of highly oxygenated umbilical venous blood, enters the medial aspect of the inferior vena cava and flows with the ductus venosus blood across the foramen ovale to the left atrium and ventricle.6 In the human, flow patterns in the central venous components and the atria lead to 55% of combined venous return entering the right ventricle, and 45% entering the left (Fig. 483-2). Although it has not been measured in the human, left ventricular blood is likely to be about 15% more saturated with oxygen than right ventricular blood, which would benefit its role as the oxygen delivery ventricle, and also has a higher glucose concentration, because it receives the vast majority of umbilical venous return, the source of substrate to the fetus. Thus, it is well set up to deliver oxygen and substrate to the highly metabolic tissues, as long as that is where its blood is delivered.

FIGURE 483-1. The fetal circulation, with direct communications existing between the right and left atria (foramen ovale), the aorta and pulmonary artery (ductus arteriosus), and the umbilical venous and systemic venous circulations (ductus venosus).

The organs that require the most nutrients, and thus blood flow, per gram are the heart, brain, and adrenal glands, though the latter are extremely small and thus are not of great consequence when considering blood flow distribution. The heart receives about 3% to 5% of CVO, and the brain receives about 32% of CVO (Fig. 483-2). Because both of these organs receive blood from vessels arising from the ascending aorta (Fig. 483-3), both receive blood entirely from the left ventricle in the normal fetus. Only a small amount of left ventricular blood, about 8% to 10% of CVO, is not delivered to the heart and upper body, but crosses the aortic arch and isthmus to the lower circulation (Fig. 483-2). About two thirds of the blood traveling down the descending aorta goes to the placenta for oxygen and substrate uptake, while the other third goes to the lower body of the fetus. Thus, only a small amount of left ventricular blood goes to the placenta. Conversely, the majority of right ventricular blood crosses the ductus arteriosus to the descending aorta, with only a minority going into the lungs, because of the high resistance in the pulmonary vascular bed. Over 80% of right ventricular output goes down the descending aorta, two thirds of which goes to the placenta. Thus, the majority of right ventricular blood indeed goes to the oxygen uptake circulation, whereas the majority of left ventricular blood goes to the highly metabolic tissues for oxygen and substrate utilization.

Although the ventricles perform their normal postnatal tasks relatively efficiently in the fetal environment, the intravascular and intracardiac shunts allow them to easily take over the other’s function in the presence of congenital cardiac defects, something that is not possible in the postnatal circulation. Alterations in gene expression in embryonic life alter cardiac and vascular structures, as described in the previous section, often leading to decreased blood flow through one ventricle or the other. These aberrations in structure lead to alterations in flow, which, although homeostasis is maintained, cause further changes in cardiac and vascular structures. The combination of primary molecular events and secondary flow events creates the specific congenital heart abnormality seen when the baby is born, but it is usual that we do not know which is the primary event and which is flow related.

FIGURE 483-2. The central components of the fetal circulation, with the percentages of combined venous return presented in circles and of combined ventricular output in squares. IVC, inferior vena cava; SVC, superior vena cava; RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle; MPA, main pulmonary artery; AAo, ascending aorta; DAo, descending aorta; PAs, branch pulmonary arteries.

TRANSITIONAL CIRCULATION

At birth, dramatic changes in blood flow and cardiac function unfold, leading to a circulation that is more efficient at the uptake and delivery of oxygen but that depends on a nearly normal heart and circulation. The most dramatic changes occur within seconds and minutes of birth, followed by gradual changes, which lead to a mature circulatory pattern within weeks of birth. These changes are required for the healthy survival of infants who underwent normal cardiovascular development, but are potentially lethal for those with congenital cardiovascular defects.

The 3 most important changes at birth are the dramatic decrease in pulmonary vascular resistance, the abolition of the central vascular and cardiac shunts, and the increase in output of the two ventricles.7 Of the 3, the driving force toward the achievement of the normal postnatal circulation is the dramatic and remarkable fall in pulmonary vascular resistance.

Pulmonary vascular resistance is extremely high in the fetus, allowing only about 8% of combined ventricle output to enter the lungs until near term. The intense vasoconstriction occurs in the distal pulmonary arteries, which have a thick medial smooth muscle layer. Pulmonary vascular resistance actually begins to decrease substantially before birth, as a result of a large increase in vessels in late gestation, increasing the cross-sectional area of the vascular bed. They remain vasoconstricted, however, largely due to their hypoxic environment, the lack of vasodilating substances such as prostaglandins E2and I2, and the presence of vasoconstrictors such as the leukotrienes. Endogenous nitric oxide (NO), an important dilator of these vessels, is thought to be present in low concentrations. Immediately at birth, there is an abrupt and large decrease in pulmonary vascular resistance, which leads to an enormous increase in pulmonary blood flow of 10-fold to 20-fold. Although increased oxygenation is thought to be a major contributor to this fall in resistance, ventilation with fetal gases has been shown to be capable of causing up to two-thirds of the fall that is seen, so that other mechanisms must be in play. The decrease in pulmonary vascular resistance induced by ventilation alone may in part be caused by a direct effect, as changes in surface tension at the alveolar air–liquid interface reduce perivascular tissue pressures, but likely is also caused by an increase in PGI2 induced by gaseous distension, and by an increase in endogenous NO, which may also mediate the oxygen responsiveness of the pulmonary arteries.8

The large increase in pulmonary blood flow is essential to the second major component of the transitional circulation, the abolition of the central shunts.9 These shunts are the foramen ovale, between the left and right atrium; the ductus arteriosus, between the main pulmonary artery and descending aorta; and the ductus venosus, between the portal sinus and inferior vena cava. In fetal life, the foramen ovale is like a windsock, directing blood from the ductus venosus and left hepatic veins toward the left atrium, and remains open because of the far greater right atrial venous return than that of the left. As pulmonary vascular resistance falls immediately at birth, pulmonary venous return to the left atrium increases dramatically, often exceeding that of the right atrium as the shunt through the ductus arteriosus reverses its direction, now going from the descending aorta to the main pulmonary artery. Once left atrial venous return and pressure exceed that of the right, the flap of the foramen, which is in the left atrium, presses against the floor of the fossa ovalis, abolishing the foraminal shunt. The shunt through the ductus venosus is maintained primarily by umbilical venous return from the placenta, which is just under 50% of combined venous return. This source of blood is instantly abolished when the umbilical cord is cut. Even before this, however, umbilical flow almost entirely ceases, due to the vasoconstrictor effects of oxygen and mechanical stretch on the umbilical artery. Ductus venosus flow ceases completely within 3 to 7 days after birth, likely due to the passive effects of diminished blood flow, although it has been shown to vasodilate with elevations in PGE1.

The shunt through the ductus arteriosus is reversed as pulmonary vascular resistance falls, as mentioned above. The ductus arteriosus has a large amount of medial smooth muscle and thus is a very reactive vessel. In the fetus, its patency is maintained in part by high levels of PGE2, which are about 4-fold higher than those after birth, but it is uncertain whether it is the circulating levels or local levels that exert the greater control. Use of nonsteroidal anti-inflammatory drugs by the mother before birth has been shown to lead to ductal constriction, which in turn can lead to progressive pulmonary hypertension and possible right ventricular failure, with hydrops. After birth, the ductus arteriosus is functionally closed in most term infants within 10 to 15 hours, and permanent closure, caused by thrombosis, intimal proliferation, and fibrosis, is seen usually within 3 weeks. The functional closure is likely caused by the elevated levels of oxygen seen at birth, and the decrease in levels of PGE2. Persistent patency of the ductus arteriosus in preterm infants is common and is likely caused by a lower responsiveness of the immature ductus to oxygen, and perhaps to persistently elevated PGE2 levels.

FIGURE 483-3. Blood flow distribution in the fetal circulation demonstrating the preferential flow of the less-saturated blood via the right ventricle to the placenta for oxygen uptake and of the more highly saturated blood via the left ventricle to the highly metabolic organs, the heart and brain. UV, umbilical vein; DV, ductus venosus; CS, coronary sinus; UA, umbilical artery; see Figure 483-2 for other abbreviations.

Last, there is a large, nearly 3-fold, increase in ventricular output at birth. The increase in left ventricular output exceeds that in the right because the right ventricle ejects more blood than the left in fetal life, whereas they eject the same amount (or the left may eject a little more than the right because of the early left-to-right shunt through the ductus arteriosus). This increase in output is driven by a similarly large increase in oxygen consumption, which has been shown to increase 3-fold in newborn lambs. The increase in oxygen consumption is likely driven by the need of the newborn to maintain thermoregulation and to breathe, neither of which consumes much oxygen in the fetal environment.


SYMPTOMATIC HEART DISEASE IN THE NEWBORN AND INFANT


Most patients who eventually present with symptomatic heart disease do so during the neonatal period or early infancy, when there is a dramatic transition from the fetal to the transitional circulation (during the first days of life), a slower transition to the mature circulation as pulmonary vascular resistance continues to fall over the subsequent 6 weeks, and a period of physiologic anemia that occurs during the second and third months of life.

Symptomatic heart disease in the newborn and infant presents either primarily with cyanosis, inadequate systemic perfusion, or respiratory distress/failure to thrive (from excessive pulmonary blood flow, without either cyanosis or hypoperfusion). Cyanosis can be appreciated by careful visual inspection, hypoperfusion by examination of the extremities, and respiratory distress/failure to thrive by observing the respiratory rate and pattern, and by plotting the infant on the appropriate growth chart. A simple evaluation of the infant at each examination will undoubtedly uncover the possibility of congenital heart disease, and a thoughtful and rational approach will lead to the appropriate differential diagnosis and plan. Admittedly, this approach is imperfect; some lesions are complex with overlapping manifestations (eg, an infant with truncus arteriosus may present with cyanosis in the first hours of life as pulmonary vascular resistance is high, but becomes tachypneic without cyanosis over the next few hours and days). In addition, the differential diagnosis includes noncardiac disease, so that the initial evaluation points only to the possibility of heart disease, not to its definite presence. However, by focusing on these few signs of congenital heart disease and evaluating each infant throughout infancy, the pediatrician will not miss the diagnosis and will ensure that each infant is treated appropriately.

CYANOTIC HEART DISEASE

The newborn or infant who presents with cyanosis without significant respiratory distress almost always has structural congenital heart disease. The general approach to the cyanotic infant is detailed in Chapter 49. Because cyanosis can be diagnosed by inspection only, it is the most common manifestation of symptomatic congenital heart disease and may be associated with critically decreased oxygen delivery; therefore, it is important for the pediatrician to be able to quickly and accurately exclude its presence. The presentation, however, may be difficult to appreciate for a variety of reasons: the presence of a ductus arteriosus immediately at birth, which may not close during the short period of time that a newborn is in the hospital, may maintain adequate levels of systemic arterial oxygen saturations so that cyanosis is difficult to detect clinically; cyanosis may be masked by a decrease in blood hemoglobin concentration because it is not determined directly by the level of arterial oxygen saturation but by the amount of reduced hemoglobin in the blood; many cyanotic lesions are not associated with heart murmurs which, unfortunately, leads some clinicians away from the possibility of congenital heart disease; and cyanotic heart disease is diagnosed clinically by the presence of central cyanosis, and the few vascular beds that do not have significant vasomotor tone and thus reflect central oxygen saturation are not easy to evaluate. Because of these considerations, various investigators have evaluated the usefulness of routine pulse oximetry as part of the newborn evaluation and have subsequently proposed its adoption,10,11though it has not been widely implemented as yet. Thus, the newborn with cyanotic heart disease may not be diagnosed prior to discharge from hospital, making it essential for the pediatrician to consider the possibility at each routine examination, at least through the first few months of life. Many infants have been diagnosed with complex cyanotic heart lesions several weeks after birth.

FIGURE 483-4. Venous return patterns demonstrate that the highly saturated blood from the placenta preferentially crosses via foramen ovale to the left atrium and left ventricle, and the less-saturated blood from the upper body, heart, lower body, and splanchnic bed preferentially flows across the tricuspid valve to the right ventricle. LPV, left portal vein; LHV, left hepatic vein; MPV, main portal vein; RPV, right portal vein; see Figures 483-2 and 483-3 for other abbreviations.

HEMODYNAMIC CATEGORIES

As with the other forms of symptomatic congenital heart disease, it is best not to memorize the various lesions associated with cyanosis, but rather to understand the pathophysiologic processes that lead to the finding; moreover, as with each, cyanosis can be divided into 2 processes. Infants present with cyanosis due to heart disease either because the amount of blood going through the pulmonary vascular bed is decreased (decreased pulmonary blood flow) or the amount is normal or even increased, but that systemic venous blood is abnormally directed via the ventricle across the aortic valve (D-transposition complexes). It is useful to consider these 2 hemodynamic categories of cyanotic lesions separately, because lesions within each category tend to have similar presentations, associated findings in the fetus and after birth, and therapeutic approaches.

Decreased Pulmonary Blood Flow

Most lesions with decreased pulmonary blood flow have obstruction either to the inflow of blood to the right ventricle, or the ejection of blood from it. A much smaller number of lesions, occurring with much less frequency, are associated not with obstruction but with insufficiency of one of the right-sided valves, either of the inflow (tricuspid valve) or outflow (pulmonary valve). All of these lesions can be considered sequentially, along lines of blood flow (Table 483-1), and the lesions, when presented in the text. Systemic venous blood arrives in the right atrium and from there, crosses the tricuspid valve to enter the right ventricle. Thus, the first level of obstruction occurs at the tricuspid valve, which may be totally absent (tricuspid atresia) or narrowed (tricuspid stenosis, or hypoplasia). The former is almost always associated with a ventricular septal defect, whereas the latter is associated with hypoplasia of the right ventricle and secondary pulmonary valve atresia. The most common cause of insufficiency of the tricuspid valve is Ebstein anomaly, in which the septal leaflet is displayed inferiorly, toward the apex of the right ventricle, preventing coaptation of the leaflets and leading to severe valve insufficiency. Because the right ventricle cannot generate much pressure in the presence of severe insufficiency, there may be acquired pulmonary valve atresia, though often this is just functional (evidence that the valve is patent but cannot be opened by the right ventricle is the presence of pulmonary insufficiency on color Doppler echocardiography).

Table 483-1. Congenital Cardiovascular Defects Presenting with Cyanosis Caused by Decreased Pulmonary Blood Flow

The next level of obstruction occurs within the right ventricle. Right ventricle hypoplasia, as mentioned above, is usually secondary to tricuspid valve hypoplasia and may include abnormalities in the volume of all 3 components of the right ventricle—the inflow, apex, and outflow. Outflow obstruction alone occurs most frequently when the outlet ventricular septum is malaligned anteriorly so that it does not meet the muscular and membranous septum, leading to an outlet ventricular septal defect. The association of anterior malalignment of the outlet ventricular septum, a ventricular septal defect, and outlet (infundibular) obstruction leading to a right-to-left shunt across the ventricular septal defect is called tetralogy of Fallot and is one of the most common forms of cyanotic congenital heart disease. Because tetralogy of Fallot involves abnormal embryonic movement of the outlet septum, it may be associated with a microdeletion of 22q11 (diGeorge syndrome, velocardiofacial syndrome, etc), which has many other manifestations thought primarily to be caused by abnormal migration of the cardiac neural crest tissue. This syndrome is particularly prevalent in tetralogy of Fallot when the aortic arch is right-sided, because this chromosomal abnormality affects arch development as well, causing other cardiovascular defects such as interrupted aortic arch. In the most severe form of tetralogy of Fallot, the pulmonary valve is atretic. In this situation, the branch pulmonary arteries may arise from a ductus arteriosus or may not form normally. If that occurs, the vascular segments of the lung are fed by major aortopulmonary collateral arteries, and surgical reconstitution of a normal vascular bed is very complex.

Outflow obstruction without a ventricular septal defect rarely can occur, leading to cyanosis. There are two primary causes of outflow obstruction without an associated ventricular septal defect. The course of the moderator band, between the body and outflow of the right ventricle, can be anomalous and partially obstruct the outflow tract. Because there are high-pressure and low-pressure components to the right ventricle in this lesion, it is called double-chamber right ventricle. However, it usually occurs later in life, often in patients with a ventricular septal defect (which may have since closed), so that it is not commonly considered in the differential diagnosis of cyanosis in the infant and newborn. More commonly, right ventricular outflow tract obstruction without a ventricular septal defect can occur in hypertrophic cardiomyopathy of the newborn, often associated with maternal diabetes. In some cases, the massive septal hypertrophy can preferentially obstruct the right ventricular outflow tract, leading to a right-to-left atrial shunt and cyanosis.

The next level of obstruction is at the pulmonary valve, which may be stenotic or atretic. The diagnosis of critical valvar pulmonary stenosis is made when the systemic arterial saturation is under 92% in the absence of a ductus arteriosus, and requires neonatal intervention. When the pulmonary valve is atretic in the presence of right ventricular hypoplasia, it is generally thought to be a secondary phenomenon, with the primary embryological event being hypoplasia of the tricuspid valve. When there is a well-developed, tripartite (inflow, body, and outflow) ventricle, it may caused by a later, fetal event, perhaps a valvulitis, causing fusion of the commissures. The presence of well-developed ventricle allows for a transcatheter perforation and dilation of the valve, obviating the need for a surgical shunt (see Chapter 499, “Interventional Cardiology”). Above the pulmonary valve, supravalvar pulmonary stenosis may occur, usually in association with branch pulmonary artery stenosis, which are seen together in Williams syndrome, a genetic defect of the elastin gene, which has been mapped to chromosome 7.12 However, the arterial obstruction in Williams syndrome usually occurs over time, is rarely severe, and rarely presents with cyanosis in infancy. Branch pulmonary artery stenosis is also seen in Alagille syndrome, in which there is an associated paucity of bile ducts in the liver, leading to liver dysfunction. It also has a defined genetic basis,13 as about 88% of patients show a mutation of the JAG1 gene.

Finally obstruction can occur at the pulmonary arteriolar level. This is not cyanotic congenital heart disease, but is pulmonary hypertension of the newborn, in which the arterioles do not dilate normally at birth. It is discussed in a separate chapter.

Findings determined by postnatal flow patterns help greatly with the clinical diagnosis and stabilization. In infants with decreased pulmonary blood flow, the decreased pressure and flow out the pulmonary valve implies that a ductal shunt, if present, must be left-to-right. Thus, upper- and lower-body pulse oximetry must be the same, whatever the lesion (Table 483-2). The presence of differential saturations excludes a lesion associated with decreased pulmonary blood flow, as does the presence of decreased lower body pulses, as mentioned above.

The time course of cyanosis can also lead the clinician to this category of lesions. In most lesions with decreased pulmonary blood flow, the ductus is widely patent at birth, supplying adequate flow for several hours or days. With the rapid fall in pulmonary vascular resistance, pulmonary blood flow may be 2 to 4 times systemic, causing saturations to be in the high 80s to low 90s, and preventing the appearance of cyanosis. Cyanosis may then progress gradually, over hours to days, or, as often happens, is first noticed when the newborn cries or is fed, both of which increase oxygen utilization and decrease pulmonary blood flow, by increasing pulmonary impedance in the former and decreasing systemic vascular resistance in the latter. This time course is very different than that seen in the transposition complexes, which will be presented below.

Last, blood flow patterns may also allow for the distinction of inflow lesions associated with decreased pulmonary blood flow and all other causes of cyanosis by simple physical findings. When the right ventricle does not fill appreciably, in tricuspid atresia or severe hypoplasia, with a hypoplastic right ventricle, it ejects a minimal amount of blood, and thus does not generate a parasternal impulse. In all other causes of cyanosis (decreased pulmonary blood flow with outflow obstruction, transposition complexes, and pulmonary hypertension of the newborn), the right ventricle ejects a reasonable amount of blood under high pressure, and thus there is a normal to increased parasternal impulse. Thus, the careful physical examination can lead to the rapid diagnosis of cyanosis secondary to decreased pulmonary blood flow caused by inflow obstruction to the right ventricle, and a simple electrocardiogram can usually differentiate the 2 possible lesions (Fig. 483-5).

Table 483-2. Hemodynamic Categories in Cyanotic Newborns Related to Upper and Lower Body Pulse Oximetry

Because blood flow patterns are similar in the fetus and newborn with most lesions causing decreased pulmonary blood flow, the means to stabilize the patient prior to definitive diagnosis and cardiac interventions are similar as well. The atrial septum is rarely restrictive, so that there is rarely a need for a cardiologist to perform a balloon atrial septostomy. Because pulmonary blood flow is usually maintained adequately when the ductus arteriosus is widely patent, these infants can almost always be stabilized by giving PGE1, as long as the side effects of that drug are properly considered and avoided. The ductus arteriosus may close even more rapidly than normal in these patients because it is often long and thin. Most importantly, care needs to be taken to ensure adequate ventilation, because apnea is a common occurrence, and the volume status and arterial perfusion pressure must be maintained, because PGE1 is also a potent systemic vasodilator.

D-Transposition of the Aorta

The second group of lesions associated with cyanosis in the newborn and infant can be considered together as defects in which the aorta is anteriorly and rightwardly displaced, committed to the systemic venous, or usually, right, ventricle. The aorta is transposed over the ventricular septum, and systemic venous rather than pulmonary venous blood preferentially flows across the valve to the body via the ascending aorta. Pulmonary blood flow may be normal, increased, or decreased in this group of lesions, depending on the associated lesions, but in most, is either normal or increased.

The classic and most common lesion in this group is d-transposition of the great arteries with intact ventricular septum, also called simple d-transposition of the great arteries. Details of the diagnosis and management of this lesion are provided in Chapter 484. In this lesion, the pulmonary artery is also malposed, sitting over the left ventricle. It is best to consider the various lesions in this group of patients along lines of flow as well, but in this group, that consideration relates to associated defects rather than the primary pathophysiology, which, in all lesions, is cyanosis due to preferential streaming of systemic venous flow across the aortic valve.

Valuable to the clinician is the timing of cyanosis in this group of lesions. In simple d-transposition of the great arteries, there is little mixing of the systemic and pulmonary venous circulations after birth, just as in the normal newborn. Unlike the normal newborn, though, this separation of venous returns causes the desaturated systemic venous blood to cross the aortic valve to the ascending aorta, leading to significant, often intense, cyanosis, immediately after birth. This is in contrast to the infant with decreased pulmonary blood flow in most of whom the ductus arteriosus is widely patent at birth, maintaining normal or increased pulmonary blood flow initially. Although the ductus arteriosus may close rapidly in such patients, cyanosis is often not appreciated in the first few hours of life. The earlier and more severe the cyanosis, the more likely the neonate has d-transposition of the aorta rather than decreased pulmonary blood flow. In addition, the presence of a ductus arteriosus and modestly elevated pulmonary vascular resistance in the first hours after birth may lead to somewhat higher saturations in the lower body in such an infant, which cannot happen in neonates either with decreased pulmonary blood flow or with persistent pulmonary hypertension (Table 483-2).

FIGURE 483-5. An electrocardiogram in a patient with tricuspid atresia. Note that the axis is in the superior left quadrant (−40°), excluding pulmonary atresia with intact ventricular septum, in which the axis lies between 0 and 90°.

Although neonates with simple d-transposition of the great arteries tend to present immediately after birth with severe cyanosis, neonates with complex lesions may not present for days or even months. This is because those lesions are nearly always associated with a ventricular septal defect, which significantly increases pulmonary blood flow. Although the majority of the systolic shunt goes from the right ventricle to the left because systemic vascular resistance is higher than pulmonary vascular resistance, there can be a fairly large diastolic shunt from the left ventricle to the right because of the far higher venous return and filling pressures, increasing right ventricular and thus aortic saturation to levels that may not be easily detected by the clinician. This is particularly true if there is also an atrial septal defect with a large left-to-right atrial shunt promoted by the large increase in pulmonary blood flow caused by the VSD shunt. Whereas cyanosis with decreased pulmonary blood flow usually presents within a few hours or days of birth, d-transposition complexes may present earlier, right at birth, or significantly later.

The therapy to stabilize these infants prior to surgical intervention needs to take into account the fetal and postnatal physiologic findings discussed above. In simple d-transposition of the great arteries, this means that the foramen ovale is likely to close at birth and that the ductus, while still patent, will likely shunt from the aorta into the lungs. Administration of PGE1, maintains a ductal left-to-right shunt into the lungs, followed by balloon atrial septostomy to allow highly saturated blood to pass into the right atrium until an arterial switch procedure is performed within a few days of birth.

INADEQUATE SYSTEMIC PERFUSION

Inadequate systemic perfusion, or hypoperfusion, is the second most common presentation of the neonate with symptomatic heart disease and represents the most common cause of mortality. Unlike cyanosis, hypoperfusion is commonly caused by noncardiac diseases, particularly sepsis, so that heart disease is not always considered in a timely manner. This is particularly true when no murmur is present, because many clinicians consider that its absence excludes congenital heart disease. Unfortunately, some of the most common and lethal forms of cardiac disease that present in the newborn and infant are not associated with murmurs.

HEMODYNAMIC CATEGORIES

As with cyanosis, hypoperfusion on a cardiac basis can be divided into 2 pathophysiologic mechanisms that may overlap in an individual patient. Hypoperfusion may be caused by obstruction to the inflow of blood to, or the outflow from the left side (pulmonary venous side) of the heart, or it may be caused by decreased left ventricular function without obstruction. Most causes of hypoperfusion that are not on a primary cardiac basis exert their effects on systemic perfusion by a decrease in left ventricular function, but some do so by other means, most notably by severely decreasing systemic vascular resistance causing pooling of blood in various vascular beds, diminishing the circulating volume to a critical level. Only those causes of left ventricular dysfunction which are a form of congenital heart disease will be discussed in this section, although secondary causes are listed in Table 483-3.

Prior to discussing the individual congenital cardiac lesions that cause hypoperfusion, a few important issues should be considered. First, the transitional circulation is different than the mature circulation in that the upper and lower body still may be perfused by different ventricles, while the ductus arteriosus is patent. Thus, evaluation of the neonate for signs of hypoperfusion must be performed rigorously, with the appreciation that demonstrating normal upper body perfusion does not exclude hypoperfusion of the lower body, and vice versa. Second, all patients with hypoperfusion present with moderate to severe respiratory distress due to elevation of pulmonary venous pressures. Whether the left side of the heart is obstructed or the left ventricle is dysfunctional, the inflow of blood is impaired, and pulmonary venous pressures increase, causing pulmonary edema. Thus, it is important to carefully evaluate every neonate with significant respiratory distress for hypoperfusion, which may be subtle and limited to only the upper or lower body. In that way, for example, a newborn with a coarctation of the aorta who presents with respiratory distress may be diagnosed and treated appropriately before cardiovascular collapse. Further details regarding the diagnosis and management of various lesions is provided in Chapter 484.

Table 483-3. Causes of Decreased Systemic Perfusion without Obstruction

Left-Sided Obstruction

The left side of the heart may be obstructed at its inflow or outflow; many inflow lesions are associated with secondary outflow lesions because the reduced blood flow through the left heart structures in the fetus causes left-sided hypoplasia. The most proximal obstructive lesion is total anomalous pulmonary venous return with obstruction. The pulmonary venous confluence is not actually part of the primitive heart but is a coalescence of the pulmonary veins, arising from the primitive lung bud.15 The vessels coalesce with each other and the back of the primitive left atrium to form the posterior, pulmonary venous component of the left atrium. If they do not approach close enough to the left atrium, they connect to other vascular structures. Sometimes, they connect to the posterior cardinal veins and run inferiorly, below the diaphragm, and usually enter the portal sinus. After birth, as pulmonary blood flow increases dramatically and the ductus venosus closes, blood is trapped in the confluence, dramatically increasing pulmonary venous pressure and causing pulmonary edema and severe respiratory distress. More commonly, the veins connect to an ascending vein in the left mediastinum, part of the superior cardinal system, and drain into the innominate vein. This drainage may not be obstructed unless the vessel is trapped between the left pulmonary artery and the left bronchus, causing a “hemodynamic vise.” Other sites of drainage of the pulmonary veins, the coronary sinus, or the right superior vena cava are obstructed less than 30% of the time.

Whether the pulmonary venous confluence is obstructed or not, the left side of the heart does not receive pulmonary venous return directly, but from the right atrium, via the foramen ovale. Thus, the left side is quite small, but systemic blood flow is usually not critically decreased. Thus, the symptoms of respiratory distress in total anomalous pulmonary venous return with obstruction far exceed the signs of hypoperfusion. Because of this, and 2 other important facts—that the markedly elevated pulmonary venous pressures often cause secondary, severe pulmonary hypertension, and that there are no murmurs, this lesion is often misdiagnosed as pulmonary hypertension of the newborn. Every infant carrying the latter diagnosis must have a full cardiology evaluation including echocardiography, to exclude this diagnosis.

When the pulmonary venous confluence does connect to the left atrium but perhaps just barely, the connection may be restrictive. Because the connection between the pulmonary venous confluence and the primitive atrium is small, the left atrium appears to be separated into two, and thus the lesion is called cor triatriatum, or “heart with 3 atria.” This lesion may present in early infancy with similar findings to that of obstructive total anomalous venous connection, except that there is not significant systemic arterial desaturation, or the obstruction may be mild, presenting later with mild respiratory distress, failure to thrive, or without symptoms.

Obstruction within the left atrium may occur just above the mitral valve (supravalvar mitral web) or at the valve (valvar mitral stenosis). When the valve is critically obstructed, just like in the right heart, there is severe hypoplasia of the left ventricle, often with secondary aortic valve atresia. This lesion, hypoplastic left heart syndrome, is the most common obstructive lesion that presents in the neonatal period. When the mitral valve is stenotic with only 1 papillary muscle rather than 2 (parachute mitral valve), there is often associated subvalvar aortic stenosis and coarctation of the aorta, called Shone’s complex.

Outflow obstruction at the subvalvar level can occur because of septal hypertrophy, often in the presence of maternal diabetes, or because of membranous or fibromuscular subaortic stenosis. At the aortic valve, critical obstruction can occur because of a bicuspid or unicuspid aortic valve. Supravalvar aortic stenosis can occur in Williams syndrome, although it rarely causes symptoms in infancy. Interrupted aortic arch, type B, is frequently associated with microdeletions of 22q11,16 usually with a posteriorly malaligned ventricular septal defect and occasionally, with a right aortic arch. Coarctation of the aorta is a common cause of left-sided obstruction. It is usually associated with a bicuspid aortic valve, and frequently with a ventricular septal defect.

The level of the obstruction very much determines the timing and rapidity of progression of symptoms. The more proximal the obstruction, at equal levels of severity, the earlier the onset. Thus, critical obstruction of the pulmonary veins presents within minutes or hours after birth, as blood rapidly accumulates in the pulmonary venous confluence and increases pulmonary venous pressures. Hypoplastic left heart syndrome, the most common of the obstructive lesions, usually presents within the first hours or days of life, as the ductus arteriosus begins to close. Systemic blood flow is entirely dependent on ductal size, so as it begins to constrict, blood flow to the body decreases, and signs of hypoperfusion manifest. In the uncommon situation when the foramen ovale is restrictive, blood flow returning from the lungs becomes obstructed, and these infants present like infants with total anomalous pulmonary venous connection with obstruction, within minutes or a few hours of life, with severe respiratory distress. Critical aortic stenosis and interrupted aortic arch present in a similar time frame to hypoplastic left heart syndrome, but perhaps slightly later, because the small amount of forward flow across the aortic valve supplements that crossing the ductus arteriosus. However, coarctation of the aorta may present significantly later. The coarctation usually occurs in the region of the aorta across from the ductus arterious, at the distal end of the aortic isthmus (Fig. 483-6). The ductus arteriosus, when patent, assists in blood supply to the lower body, maintaining adequate perfusion. It starts to constrict within the first hours of life and is fully closed in most infants within 24 hours. However, ductal closure begins in the middle of the ductus and progresses toward the ends. The ductal ampulla, the distal end of the ductus at the connection with the descending aorta, may remain relatively large for a few weeks, as the ductus undergoes full anatomic closure. During that time, the region around the coarctation may be of reasonable size so that symptoms of hypoperfusion do not manifest. In addition, it is thought that many infants developed coarctation because of the extension of ductal muscle posteriorly around the descending aorta. This is called a ductal sling. As the ductal sling constricts, a posterior indentation develops and the coarctation manifests.

Most infants with a severe coarctation of the aorta present with signs of hypoperfusion at about 7 to 10 days of age, though decreased pulses usually can be appreciated well before this time, and some present as late as 2 to 3 weeks of age. Thus, it is essential for the clinician to do a careful physical examination including upper and lower body pulses to exclude coarctation of the aorta through the first month of life, and to consider obstructive heart disease when an infant presents with hypoperfusion during that time period.

FIGURE 483-6. Coarctation of the aorta in the newborn, demonstrating that the ductal ampulla frequently lies at the same level as the coarctation, so that the obstruction may not become severe until closure of the ductus arteriosus along its entire length occurs, usually within 7 to 10 days. Note that the transverse aortic arch (between the left carotid and left subclavian arteries) is quite small because very little blood flow crosses it in the fetus, primarily feeding the left subclavian artery.

The therapeutic approach to the infant with hypoperfusion and possible obstruction must be rapid and directed at the central problems of respiratory distress and decreased systemic blood flow. Early intubation and mechanical ventilation are essential. This not only drives the fluid from the alveoli, improving both oxygenation and ventilation, but also eliminates the metabolic demand of breathing, which, in the distressed infant, may represent up to 50% of oxygen consumption. The decrease in heart rate and catecholamine stimulation further decreases oxygen consumption, so that mechanical ventilation both dramatically increases oxygen uptake and decreases oxygen demand simultaneously. Maintenance of a neutral thermal environment will aid in the decrease in oxygen consumption. Improvement in systemic blood flow is the next consideration. Filling pressures are usually high, even on the systemic venous side of the circulation, as evidenced by hepatomegaly, so that volume infusion is rarely beneficial, though it is often used. Inotropic support may be beneficial. Stabilization of the metabolic status of the infant in the presence of metabolic acidosis is generally undertaken though it is not certain how beneficial this is. The newborn myocardium is quite resistant to the deleterious effects of acidosis on its function,17 and the volume load of the base may exacerbate the pulmonary edema. Prior to surgical or transcatheter relief of the obstruction of the lesion, PGE1 will relieve the obstruction at the ductus arteriosus and should be begun in all patients who have a presumptive diagnosis of left heart obstruction. In the past, the possibility of total anomalous pulmonary venous connection has led clinicians to hesitate using PGE1 in the newborn presenting early with obstructive disease. However, many of these infants have suprasystemic pulmonary arterial pressures, so that the ductal shunt will be right-to-left, supplementing systemic blood flow, and it has been suggested that PGE1 may dilate the ductus venosus, which would ameliorate the obstruction. Moreover, mechanical ventilation, if instituted immediately before PGE1 infusion, should mitigate the problem of increasing pulmonary edema. The potential benefits of PGE1infusion in all patients with presumptive obstruction far outweigh the potential risks, as long as the clinician is aware of and rapidly responds to the vasodilatory effects of the drug.

Ventricular Dysfunction

Ventricular dysfunction without obstruction presents similarly to the obstructed heart and may be difficult to differentiate on clinical examination. It may be caused by processes that directly impair cardiac function, such as arrhythmias, coronary flow disturbances, or myocardial infections, or by indirect mechanisms, such as metabolic derangements, systemic infections, or severe anemia or polycythemia (Table 483-3). Each of these processes is discussed in other chapters and is not detailed here. Rarely, but importantly, structural congenital disease may present with hypoperfusion despite the absence of obstruction. This occurs when blood from the left ventricle flows directly, in an obligatory manner, away from the systemic vascular bed. The most common and dramatic of the lesions is the vein of Galen aneurysm, or other cerebral arteriovenous malformations. More rarely, hepatic arteriovenous malformations, or sacrococcygeal teratomas, may present with systemic hypoperfusion. There is an obligatory shunt through the low-resistance bed, and if the bed is large enough, the left ventricle cannot direct adequate volume to the normal systemic beds. Heart failure may present in the fetus as a form of nonimmune hydrops, but more commonly, the infant presents at birth with hypoperfusion. Likely this is because the demands for left ventricular output by the systemic circulation increase greatly at birth, and because there is an addition of the low-resistance pulmonary vascular bed that the left ventricle sees in the hours after birth, due to patency of the ductus arteriosus during that time. This is one situation where, perhaps, the use of PGE1 may be deleterious. The diagnosis of a cerebral arteriovenous malformation is obvious if the clinician auscultates the head for bruits, which, if it is a regular part of the exam, will not be forgotten. Therapy is difficult because the bed is under low resistance and the shunt is obligatory. Intubation and mechanical ventilation are essential, for the reasons outlined above, and if an inotropic agent is used, it should also have vasodilatory actions so that blood is not further directed toward the malformation. Therefore, an agent such as milrinone is much more advantageous than dopamine, if ventricular dysfunction is present. However, the only way to resolve the hypoperfusion is to abolish the shunt. This is not offered in many patients because of the severe neurologic consequences of the malformation on the developing brain.

RESPIRATORY DISTRESS/FAILURE TO THRIVE

Newborns and infants with excessive pulmonary blood flow who are symptomatic present with respiratory distress or failure to thrive without overt cyanosis. This is the least common presentation of symptomatic heart disease in the neonatal period, but the most common in the subsequent months. The respiratory distress usually manifests during the period of the physiologic anemia of infancy, when cardiac output is highest. When pulmonary blood flow is very high, there may even be a pressure gradient between the pulmonary veins and the left atrium.

Often, the respiratory distress is subtle so that the primary symptom is failure to thrive. In the absence of a heart murmur, such as occurs in total anomalous pulmonary venous connection, the diagnosis of heart disease is often missed until a serendipitous event, such as a putative episode of bronchiolitis, leads to a chest x-ray or pulse oximetry, which alerts the clinician that the problem may be cardiac.

HEMODYNAMIC CATEGORIES AND OTHER CONSIDERATIONS

There is a very diverse group of congenital cardiac malformations that, despite their differences, have a common pathophysiologic process of increased pulmonary blood flow. The lesions can be divided into 2 hemodynamic groups, those lesions in which there is only a left-to-right shunt without a right-to-left shunt, and those lesions that have a large left-to-right shunt but in addition have a right-to-left shunt, so that the systemic arterial saturation is somewhat decreased (see Fig. 483-7A,B). Lesions in the latter group are often labeled as forms of cyanotic heart disease, but this label does not take into account the pathophysiology that determines both the symptoms and the therapeutic approach.

For example, truncus arteriosus is frequently labeled a form of cyanotic heart disease because pulse oximetry shows saturations in the 85% to 90% range. However, infants with saturations in that range are rarely appreciated as being cyanotic, and with normal systemic blood flow, this decrease in hemoglobin arterial oxygen saturation leads to only about an 8% to 10% decrease in systemic oxygen delivery. However, pulmonary blood flow is extremely high.

This is the same presentation as an acyanotic infant with a large ventricular septal defect. Thus, an infant with truncus arterious presents similarly to an infant with a large ventricular septal defect—without clinically appreciable or metabolically significant cyanosis, but breathing fast, and growing poorly. Thus, categorizing an infant with truncus arteriosus as “cyanotic heart disease” rather than as “respiratory distress/failure to thrive” makes no sense from a clinician’s standpoint. Infants with excessive pulmonary blood flow, whatever the lesion and whether they have normal or somewhat reduced systemic arterial saturation, should be considered together for diagnostic and therapeutic purposes.

Another consideration is the timing of presentation, which is very variable among the various lesions. As one might imagine, obligatory lesions will present symptomatically early if they are going to present at all. The best example is that of the arteriovenous malformation. Arteriovenous malformations are very common and are usually very small and rarely shunt enough blood to affect pulmonary blood flow. However, in those cases where an extremely large amount of blood bypasses the systemic bed to return to the systemic venous system and the lungs. Lesions present very early, with severe respiratory distress in the newborn. However, it is also important to note that obligatory shunts, unlike dependent shunts, also may present with hypoperfusion rather than respiratory distress alone, as a large portion of cardiac output is directed to the malformation and away from the systemic vascular beds. If hypoperfusion occurs in the fetus, hydrops develops. If it occurs soon after birth, when the pulmonary vascular bed also steals blood from the aorta via the ductus arteriosus, the neonate presents much like one with hypoplastic left heart syndrome. It is important to be aware that presentations of the various pathophysiologies may overlap at certain times of postnatal life.

Dependent shunts present with the typical findings of “high-output heart failure” if the infant is symptomatic. The increase in pulmonary blood flow and shear forces, caused by elevated pulmonary arterial pressures, increase the production of interstitial fluid in the lung. When this exceeds the capacity of the lymphatic system, the interstitium of the lung becomes less compliant, and the work of breathing increases. The work of breathing added to the work of feeding and absorption may cause a large increase in work for the infant, leading to sweating with feeding and shortened feeding. The decrease in intake in combination with an increase in demand commonly leads to failure to thrive. Thus, infants with “high-output heart failure” present with tachypnea, diaphoresis, and failure to thrive.

FIGURE 483-7. A: Blood flow patterns in a patient with a ventricular septal defect and only a left-to-right shunt—all systemic venous (SV) blood passes via the right heart to the pulmonary artery (PA), whereas some pulmonary venous (PA) blood passes on its normal course via the left heart to the systemic arteries (SA) and a large portion joins the SV blood via the defect to the PA. Thus, there is no desaturated SV blood in the SA. B: Blood flow patterns in a patient with truncus arteriosus and bidirectional shunting—SV blood crosses the truncal valve into the truncus arteriosus and joins with the PV blood. There the two streams pass both into the PA and the SA, although much more goes into the PA because of the lower resistance of the lungs. Thus, there is both a left-to-right shunt of PV blood into the PA and of SV blood into the SA, but the primary pathophysiology is excessive pulmonary blood flow. The decreased arterial saturation in the SA is only mild and has no significant effect on oxygen delivery.

An infant will develop excessive interstitial fluid due to greater pulmonary blood flow under greater pressure. It is important to appreciate that most of the flow through the peripheral vessels occurs in diastole, so that infants with lesions associated with diastolic hypertension in the pulmonary vascular bed are more likely to develop symptoms than those with only systolic hypertension, which are more likely to develop symptoms earlier than infants with normal pulmonary arterial pressures with the same flow. Timing of the increased flow and fluid production is crucial to the development of symptoms as well. As the infant becomes older, the airways become less compliant and the respiratory muscles strengthen, and it is much less likely that the increased flow and fluid production will be associated with symptoms. There is likely a critical period, in the first half year of life, when symptoms usually manifest. Thereafter, symptoms of the high flow become less likely, and concern for pulmonary vascular changes becomes the greater concern in patients with large shunts. The peak time to develop symptoms is around 1 to 3 months of age, when pulmonary vascular resistance is at its lowest and baseline flows are at their highest, because of the nadir in hemoglobin seen at this age.

Left-to-Right Shunt

As with the other hemodynamic categories, left-to-right shunts are best considered along lines of blood flow (Table 483-4). At the first level of venous return to the heart, pulmonary venous blood can be redirected to the lungs if there is connection of some of the pulmonary veins anomalously to the systemic veins or right atrium. This is called partial anomalous pulmonary venous connection. There is no right-to-left shunt because there is adequate flow via the other veins to the left atrium and ventricle to maintain normal systemic blood flow. In fact, if there is an associated atrial septal defect, as often occurs, the shunt across the ASD is left-to-right, further augmenting pulmonary blood flow. These infants are not symptomatic because the increase in pulmonary blood flow is not great, usually about 70% to 100%, and pressures are normal in the pulmonary arteries.

The next level of shunting occurs at the atrial septum. Shunting across atrial septal defects depends on the relative compliance of the 2 ventricles. At birth, the right ventricle is hypertrophied because it ejects at systemic pressure throughout fetal life. When the tricuspid and mitral valves open as venous blood returns to both atria, there is little difference in the compliance of the 2 ventricles, so that the atrial left-to-right shunt is small. Over the next few months, the right ventricle thins in the presence of low pulmonary vascular resistance, and the shunt increases. However, the pressure in the pulmonary arteries remains low, even with high pulmonary flows. Thus, normal infants with atrial septal defects rarely have symptoms and thus rarely need either early medical therapy or transcatheter or surgical closure.

Table 483-4. Congenital Cardiovascular Defects Presenting with an Exclusive Left-to-Right Shunt

The next level of shunt is at the atrioventricular level. Atrioventricular septal defects, commonly called atrioventricular canal defects, are very variable in their extent, from primum atrial septal defects, cleft mitral valves, or small inlet ventricular septal defects, to lesions in which there is almost no atrial or ventricular septum, with a common atrioventricular valve.  The majority of infants with complete atrioventricular septal defects have Down syndrome, although a fair number of patients are normal, and a smaller percentage have left atrial isomerism. Occasionally the defects are “unbalanced,” such that one or the other ventricle is hypoplastic, which then may be associated with secondary lesions such as coarctation of the aorta with a dominant right ventricle. As with ventricular septal defects, described below, the shunt occurs during ventricular systole, so that there is a lesser elevation in pulmonary arterial pressures in diastole. When symptomatic, the infants usually present within a few weeks to months of age, as the shunt is dependent on the decrease in pulmonary vascular resistance and the increase in cardiac output secondary to the physiologic anemia.

The next level of shunt is at the ventricular level.  Neonates with ventricular septal defect and no other problems are rarely symptomatic in the first days or weeks of life but usually present around 6 weeks to 3 months of age with respiratory distress and failure to thrive. There may, in fact, be no murmurs in the first days, if pulmonary vascular resistance falls slowly, but most infants, by the time of discharge after birth, have audible murmurs. Those infants with large defects and symptoms usually undergo repair within 2 to 6 months of life to prevent the development of pulmonary vascular changes. If the defect is large and the infant does not shows clinical findings associated with excessive pulmonary blood flow, the clinician should be more concerned, because this may indicate that pulmonary vascular resistance did not fall normally at birth, limiting the shunt, but increasing the likelihood of pulmonary vascular disease. Generally, a ventricular septal defect is closed early in infancy because of symptoms, and later in the absence of symptoms, if there is a concern of pulmonary vascular disease. The approach to children with ventricular septal defects beyond infancy is discussed later in this chapter.

Most infants with symptomatic patent ductus arteriosus are born prematurely, with immature lungs and low pulmonary vascular resistance, leading to symptomatic shunts at a very early age. This lesion is discussed in Chapter 55. Rarely, a term infant will present with a symptomatic ductus arteriosus. The ductus arteriosus in the term infant usually closes, at least partially and is thus pressure restrictive. Thus, the infant is asymptomatic and undergoes elective transcatheter closure later in infancy. Occasionally, the ductus is widely patent, and the infant presents with symptoms. This happens most commonly in infants with lung disease, as discussed in infants with atrial septal defects. In patent ductus arteriosus, the shunt occurs primarily during diastole, so that it may be very large, and the high pulmonary arterial systolic and diastolic pressures lead to the production of symptoms at an early age. It also can lead to early development of pulmonary vascular disease, as in patients with aortopulmonary window or an isolated pulmonary artery from the ascending aorta, so in all of these conditions, early intervention is necessary.

The most distal left-to-right shunt is the arteriovenous malformation. Though it is not obvious, infants with arteriovenous malformation present with the same symptomatology as those with a ventricular septal defect, secondary to high pulmonary blood flow. The only caveat occurs when the malformation is so large that the obligatory shunt impairs systemic perfusion, as discussed above.

Bidirectional Shunting with Excessive Pulmonary Blood Flow

Infants in whom there is a right-to-left shunt of systemic venous blood out the aorta will have decreased systemic arterial saturation, but if pulmonary blood flow is not obstructed but increased significantly, and if the great vessels are not transposed, the resultant systemic arterial oxygen saturation will only be mildly decreased, neither clinically appreciable nor metabolically significantly. Considering such lesions along lines of blood flow, the first lesion to consider is total anomalous pulmonary venous connection.

Total anomalous pulmonary venous frequently presents immediately after birth, with pulmonary edema due to obstruction of the large amount of pulmonary blood flow which suddenly enters the lungs as pulmonary vascular resistance falls precipitously with the first breaths of the newborn. These patients present with severe respiratory distress and hypoxemia, often being misdiagnosed as having pulmonary hypertension of the newborn. If the obstruction is less severe, they may present over the first few days of life, with respiratory distress and desaturation. However, some infants have no obstruction to pulmonary venous return at all. This occurs in some patients where the connection is above the diaphragm, particularly when it is to the coronary sinus. In such patients, pulmonary blood flow is very high so that systemic arterial saturation does not reach levels to cause visible cyanosis. Occasionally, these patients may reach adulthood without diagnosis, but more commonly, they present in infancy with failure to thrive or recurrent pulmonary symptoms.

Intracardiac causes of bidirectional shunting with excessive pulmonary blood flow are myriad (examples are presented in Table 483-5), but all have a common physiology of mixing of pulmonary and systemic venous blood in association with unrestricted pulmonary blood flow. There may be a common atrioventricular valve, atresia of the mitral or tricuspid valve, or commitment of both valves to the left ventricle (double-inlet left ventricle). If there is no obstruction to either the pulmonary or aortic outflow, pulmonary and systemic blood flows will depend on their relative resistances. Soon after birth, the neonate may appear mildly cyanotic, as pulmonary vascular resistance falls. If not appreciated at that time, however, cyanosis no longer is evident.

Table 483-5. Examples of Congenital Cardiovascular Defects with Bidirectional Shunts and Excessive Pulmonary Blood Flow

The last level at which mixing can occur is at the outlet of the ventricles. Truncus arteriosus is a relatively common lesion that is highly associated with chromosome 22q11 microdeletion, particularly when there is a right aortic arch or an interruption of the arch. Incomplete migration of cardiac neural crest derived cells is thought to lead to abnormalities in arch development,18 aortopulmonary septation, and septation of the truncus arteriosus into the aortic and pulmonary valves, which almost invariably also leads to absence of septation of the outlet ventricular septum . As discussed previously, the initial presentation of an infant with truncus arteriosus may be cyanosis, but this is only apparent in the first hours of life. Because of the large left-to-right shunt that develops rapidly, and the large runoff of blood into the pulmonary arteries in diastole, these infants present very early, within days or weeks of life, with respiratory distress and failure to thrive.

MEDICAL THERAPY FOR SHUNT LESIONS

If the common pathophysiologic process causing symptoms in patients with shunt lesions is excessive pulmonary blood flow and interstitial fluid production, and the symptoms are primarily respiratory distress and failure to thrive, then medical therapy should be directed toward ameliorating these symptoms in all patients. Surgical therapy, on the other hand, is very different among the lesions, and depends on the severity of symptoms, the likelihood of spontaneous closure of the defect, the likelihood and speed of progression of pulmonary vascular changes, and the type of surgery, palliative or corrective.

Medical therapy should be directed to minimizing respiratory symptoms and maximizing growth. To minimize respiratory symptoms, therapy can be directed at decreasing pulmonary blood flow and the production of interstitial fluid. Pulmonary blood flow depends on the relative resistances of the pulmonary and systemic beds as well as on the absolute amount of systemic blood flow. To minimize absolute systemic blood flow, the clinician should ensure that blood hemoglobin content is maximized, so that oxygen delivery is not impaired. In most infants, blood transfusion is not warranted, but iron deficiency should be treated, and occasionally, in the symptomatic infant in whom surgery is not an option at the moment (for example, the very premature infant with complex cardiac anatomy), erythropoietin could be considered.

In addition to minimizing systemic blood flow, the ratio of systemic to pulmonary vascular resistance can be manipulated. Systemic vascular resistance can be decreased by a variety of agents, but most commonly, an ACE inhibitor is used. The decrease in systemic vascular resistance theoretically should decrease the pulmonary-to-systemic blood flow ratio. If systemic blood flow remains relatively constant, this should decrease pulmonary blood flow. Unfortunately, in most infants, systemic resistance is already quite low, and in those in high-output heart failure, it may even be lower than lower. Thus, there is often little room to substantially decrease systemic vascular resistance.19

Increasing pulmonary vascular resistance should also decrease the pulmonary-to-systemic blood flow ratio, and thus absolute pulmonary blood flow. There are usually few mechanisms available to do so in the infant at home. However, the seriously ill infant on a ventilator can be improved by either increasing hematocrit, which increases blood viscosity when hematocrit is above about 55% to 60%, increasing pCO2, or decreasing FiO2. This is a purely temporizing maneuver, when surgery is contraindicated, such as in an infant with a systemic infection awaiting surgery.

Decreasing interstitial fluid in the lungs is a mainstay in the treatment of these infants. Diuretics are commonly used and can significantly improve the work of breathing, allow the infant to both feed better and to direct those calories toward growth. Care needs to be given toward maintaining normal hydration status, particularly when the infant has decreased intake or vomiting and diarrhea, and preventing electrolyte disturbances.

The second mainstay of treatment of these infants is ensuring adequate caloric intake. With the increased oxygen consumption associated with the respiratory distress and catecholamine stimulation of this state, this is not an easy goal. Caloric intake of 140 kcal/kg/day is often required, but, in addition to poor feeding due to respiratory distress, the infants often vomit regularly. Increasing caloric density, as tolerated, is routinely used, and antireflux therapy is common. Occasionally, nasogastric or g-tube feeding is required, particularly when the infant is premature, or is in uncontrollable failure and needs to grow before repair or palliative surgery is considered.

PHYSICAL EXAMINATION TO EXCLUDE SYMPTOMATIC HEART DISEASE

It is essential that the clinician be able to quickly and accurately detect symptomatic heart disease in the neonate and young infant. Many forms of critical heart disease are rapidly lethal without therapy, yet acute therapy with drugs such as PGE1, followed by transcatheter or surgical intervention, can often lead to a normal hemodynamic status and healthy survival. Vigilance to detect symptomatic heart disease is particularly important during the first few weeks of life, when the neonate is transitioning from a fetal to a mature circulatory system.

A neonate or young infant may have symptomatic heart disease if there is central cyanosis, hypoperfusion, respiratory distress, or failure to thrive. A systematic approach, evaluating the infant for 1 of these modes of presentation at each step in the examination, and, if present, placing the infant in 1 of the 2 hemodynamic categories, will immediately lead to recognition of the problem. The pediatrician does not need to diagnose the specific defect to understand the pathophysiologic problem and institute remedial therapy.

There are many ways to approach the physical examination of the young infant to exclude heart disease, but a straightforward and rapid approach is to evaluate the patient from general to specific, then distal to proximal. The general examination includes measuring vital signs and observing the infant, unclothed, in a radiant warmer. In addition to the standard vital signs, pulse oximetry should be measured at least once in every neonate. In this way, a decrease in saturation that is not clinically detectable can be appreciated. The infant should be plotted on a growth chart at each visit, to identify failure to thrive. Any postnatal decrease in weight percentiles compared to length and head circumference should raise the possibility of heart disease. The periphery, head, and neck should be examined for dysmorphic features of syndromes associated with heart disease, such as 22q11 deletion (DiGeorge) syndrome and trisomy 21.

The first sign to assess on general observation is cyanosis. An approach to the clinical diagnosis of a newborn infant with cyanosis is provided in Table 483-6. Peripheral cyanosis, or acrocyanosis, is common in newborn infants and reflects their normally variable peripheral vasomotor tone. Central cyanosis is indicative of arterial oxygen desaturation, so that the clinician must evaluate vascular beds with little vasoconstrictor tone, such as the tongue, gums, and buccal mucosa. If pulse oximetry is not available, it is worthwhile to observe the infant during conditions such as feeding or crying, which are most likely to produce central cyanosis. If cyanosis is present, the clinician must be aware of the possibility that the upper and lower systemic circulations may be perfused via different great vessels, and perform pulse oximetry in the upper and lower bodies. If the right hand is used to measure upper body circulation oximetry and there is no difference with the lower measurements, it is of value to measure ear pulse oximetry, in the rare situation that the patient has a right aortic arch or an aberrant origin of the right subclavian artery from the descending aorta. If the patient demonstrates cyanosis or mildly decreased pulse oximetry without clinical cyanosis, an oxygen challenge test is occasionally of value, particularly if the infant is showing signs of respiratory distress or has an x-ray suggestive of parenchymal lung disease. The patient should be placed under a hood with 100% oxygen delivered under high flow, to ensure that the inspired oxygen concentration is close to 100%. An arterial blood gas sample should be obtained from the right radial artery or a temporal artery, to ensure that any decrease in pO2 is not caused by a right-to-left ductal shunt. If there is any question of saturation differential between the upper and lower body, blood gases can be measured both from the upper body and the umbilical artery, to determine the validity. With modestly low pulse oximetry values (mid 80s to low 90s), most patients with a respiratory problem should be able to increase pO2 to 200 mmHg or higher, whereas the infant with congenital heart disease causing an obligatory right-to-left shunt rarely reaches a level of 200 mmHg.

Table 483-6. Approach to the Clinical Diagnosis of a Newborn Infant with Cyanosis

Step 1. Decide if the blue discoloration is due to deoxygenated blood, or to methemoglobinemia.

1A. Although most infants who appear dusky or blue have cyanosis, occasionally one can be misled by methemoglobinemia. This is a rare finding, due either to congenital deficiency of NADPH-methemoglobin reductase or to exposure to toxins such as nitric oxide, nitrates in water, or benzocaine or similar analgesics. The affected patient usually has a slaty-gray color of skin, nail beds and mucous membranes, but most are initially thought to be cyanotic. The patients are often symptomatic. Oximetry shows decreased oxygen saturation (due to an increased amount of reduced hemoglobin), but the arterial oxygen tension is normal. By oximetry the saturation is almost always about 85%, no matter how deep the discoloration. An easy diagnostic test is to oxygenate some blood. If the hemoglobin is normal, the blood becomes bright red, whereas blood with methemoglobin has a chocolate-brown color.

1B. True cyanosis is caused by an increased amount of deoxygenated hemoglobin. It is essential to distinguish between peripheral and central cyanosis.

Step 2. Decide if cyanosis is peripheral or central.

2A. If there is reduced peripheral perfusion from congestive heart failure or shock, hyperviscosity, vasoconstriction, or very cold weather, the slow flow of blood through peripheral tissues results in greater oxygen extraction from hemoglobin and therefore more deoxygenated hemoglobin in the capillaries and venules. Once the amount of deoxygenated hemoglobin exceeds 5 g/dL of blood, the extremities appear blue. There are two corollaries to this fact. One is that in severe anemia there will never be cyanosis, no matter how slow the blood flow or how low the arterial oxygen saturation. The other is that polycythemia with slowed peripheral blood flow readily shows cyanosis, even if the arterial oxygen saturation is normal.

2B. The crucial distinctions between central and peripheral cyanosis are that in peripheral cyanosis the slowed peripheral blood flow leads to cold extremities, whereas these are usually warm with central cyanosis. Even more important is evaluating the color of the tongue and mucous membranes inside the mouth. Because these structures are warm and because the tongue has a huge blood flow that is not compromised in shock or congestive heart failure, the tongue will be pink in peripheral cyanosis and blue in central cyanosis. Perioral cyanosis is often normal in neonates and does not indicate either peripheral or central cyanosis.

Step 3. Decide if respiration is normal.

Once a diagnosis of central cyanosis has been made, the crucial distinction between lung and heart disease must be made. The first procedure is to assess the respiration.

3A. If there is quiet respiration, no retractions and no rales (and a chest roentgenogram to match), then the lungs are not stiff and there is no pulmonary edema. These findings exclude lung disease or a high pulmonary venous pressure.

3B. If the patient has tachypnea, retractions, and rales (and a chest roentgenogram to match), then there is either intrinsic lung disease or some cardiac lesion causing pulmonary venous hypertension and pulmonary edema.

Steps 4A, 4B. Normal lungs: Differentiate cyanotic heart disease from polycythemia.

The two major causes of cyanosis and normal respiration are the neonatal hyperviscosity syndrome and cyanotic heart disease.

4A. The hyperviscosity syndrome is caused by polycythemia due to excessive placental transfusion, placental insufficiency, or fetal hypoxemia; it is rarely due to congenital heart disease. With excessive placental transfusion, the increased blood volume is mitigated by diuresis, but the red cells are left behind to increase the hematocrit. As mentioned above, polycythemia can cause cyanosis. The diagnosis is made by a combination of a high hematocrit (which is seldom a feature of congenital heart disease) and normal arterial oxygen saturation and tension. If the infant is seen early before the increased blood volume has been reduced, the infant often has abnormal lung function, and will be considered in that section.

4B. If there is no polycythemia, then cyanosis with apparently normal lungs is due to heart disease. (This excludes episodic cyanosis from periodic apnea that may be central or obstructive and is fairly common in neonates, especially if premature.) Arterial oxygen tension and saturation are below normal, usually considerably so. Most of these children have lesions that are potentially ductus dependent and require rapid treatment and referral. Those at least risk from ductus closure are those where increased pulmonary blood flow makes cyanosis mild but may also cause abnormal breathing. These latter patients may also have abnormal lung function. Some of these infants may be only moderately cyanosed at birth but become deeply cyanosed within a few days as the ductus arteriosus begins to close.

Steps 4C, 4D. Abnormal lungs: Differentiate lung disease from cyanotic congenital heart disease.

4C. Most newborn infants with intrinsic lung disease have a presumptive cause: prematurity and RDS, meconium aspiration, or pneumonitis/sepsis. Transient tachypnea of the newborn, due to retained fetal lung fluid, may occur and cause tachypnea usually without rales or ronchi. In them, cyanosis is usually mild, and the chest roentgenogram shows signs of pulmonary edema with fluid in the fissures and sometimes pleural spaces. The child gets better over 3 to 4 days.

Although some patients with lung disease have no apparent underlying cause, these should always be considered carefully for the possibility of congenital heart disease (see below), especially if the lung disease does not improve.

4D. Congenital heart diseases causing cyanosis and abnormal lungs have in common a raised pulmonary venous pressure. This may be due to anatomic or functional obstruction to pulmonary venous drainage. Anatomical obstruction is due most often to total anomalous pulmonary venous connection or occasionally stenosed pulmonary veins. These patients have intense cyanosis and severe pulmonary dysfunction, and because they have no specific murmurs, they are at high risk of being misdiagnosed as having only lung disease. These anomalies should be suspected if there is no apparent cause for lung disease. Patients who have tetralogy of Fallot and an absent pulmonary valve have severe lung dysfunction due to airway compression by the dilated pulmonary arteries. They may be severely cyanosed at birth and then improve as pulmonary vascular resistance decreases and reduces the right-to-left shunt. They have prominent cardiac murmurs. These anomalies cause pulmonary venous hypertension, but cyanosis is present only if there is enough lung disease to impair oxygenation or in the unusual instance of a cor triatriatum with a right-to-left shunt through an atrial septal defect distal to the obstructing membrane.

Next, the infant’s respiratory status should be carefully evaluated. Infants who have cyanosis without increased pulmonary flow usually breathe more rapidly but without distress. If the respiratory distress is severe, particularly with grunting, likely there are increased pulmonary venous pressures with edema, so that evidence of hypoperfusion should be sought. If there is moderate distress without cyanosis, significant grunting, or severe retractions, particularly after the early neonatal period, concern for a cardiac lesion with excessive pulmonary blood flow should be raised. If oximetry had not been performed before this time, it should be now. Levels at about 95% or above would put the patient in the “left-to-right shunt” category, if the infant is found to have increased pulmonary blood flow as the cause of the distress.

Signs of hypoperfusion, including the temperature and color of the skin, blood pressure, peripheral pulses, and capillary refill in each extremity should be assessed next. Upper extremity pulses are best to feel in the axilla in an infant—the right axillary pulse should always be examined, and if decreased, the carotid should then be palpated, to exclude a coarctation of the aorta with an aberrant right subclavian artery or right aortic arch. Lower extremity pulses are more easily palpated in the feet rather than in the inguinal area. If the infant has a normal dorsalis pedis or posterior tibial pulse, then pulsatile blood flow to the lower extremity is not impaired. If the pulses are not normal, blood pressure should be measured in the lower extremity as well as the upper extremity. The left subclavian artery arises from the aortic isthmus and may be involved in a coarctation, so the left arm is not an appropriate location to measure upper body pressures. Blood pressures should be measured in the right arm and either leg, and simultaneously, if possible. Systolic, not mean pressures, should be compared, because blood flows through the aortic arch in systole.

At this point in the examination, the clinician knows whether the infant has cyanosis, hypoperfusion, respiratory distress, or failure to thrive. Examination of the abdomen, lungs, and heart is then directed to defining the hemodynamic category. The abdomen should be palpated because hepatomegaly is often a sign of right atrial hypertension or increased circulating volume from excessive pulmonary blood flow. The location of the liver and stomach is reversed in situs inversus. The liver may be midline in the heterotaxy syndromes, consisting of 2 anatomic right lobes in right atrial isomerism, or asplenia syndrome, or 2 left lobes, in left atrial isomerism, or polysplenia syndrome.

The cardiac examination begins with palpation of the precordium. The normal newborn infant has a mild parasternal and subxiphoid impulse, because the sternum is thin and the right ventricle is thick walled. The parasternal and subxiphoid impulses are increased in most infants with cyanotic heart disease because the right ventricle is ejecting at systemic pressure or greater into a transposed aorta or against right ventricular outflow obstruction. A decreased right ventricular impulse suggests inflow obstruction to the right ventricle, either tricuspid atresia or hypoplastic right heart syndrome. A parasternal thrill suggests the presence of a ventricular septal defect, but this occurs in only a minority of infants with ventricular septal defects. However, the presence of a parasternal thrill in a cyanotic infant is diagnostic of tricuspid atresia with ventricular septal defect, because only in this form of cyanotic heart disease is the ventricular shunt directed anteriorly, from the left to the right ventricle.

The left ventricular apical impulse is not usually palpable in a normal neonate because the dominant right ventricle displaces the left ventricle posteriorly. A palpable left ventricular impulse usually indicates increased volume load as the ventricular cavity dilates and extends anteriorly and laterally. A suprasternal notch thrill is usually suggestive of obstruction of the left ventricular outflow, although occasionally, valvar pulmonary stenosis, because of enlargement of the main pulmonary artery impinging on the undersurface of the aortic arch, can cause a suprasternal notch thrill as well.

Auscultation should be performed in a systematic manner. The first heart sound is rarely helpful but may be louder than normal in the infant with a complete atrioventricular septal defect. The quality of the second heart sound provides important information. Although it is often difficult to appreciate splitting of the second heart sound because of the rapid heart rates in early infancy, the presence of a well split second heart sound suggests markedly increased pulmonary blood flow. Most cyanotic infants have a single heart sound because the pulmonary valve is either diminutive or atretic, or because it is malposed, posterior to the aorta.

The presence of clicks and gallops should be evaluated next. Clicks may be difficult to hear, but when present usually indicate a bicuspid aortic valve or persistent truncus arteriosus. A click is not present in patients with severe aortic stenosis because valve mobility is greatly decreased. In contrast, truncus arteriosus can frequently be diagnosed in the patient with tachypnea and modest desaturation based on the presence of an ejection click caused by a dysplastic truncal valve. Mid-systolic clicks are rarely heard but may be present in Ebstein anomaly. Gallop rhythms may be present in newborn infants with severe left ventricular dysfunction.

Last, heart murmurs should be evaluated. Murmurs occur in normal infants and may be absent in many infants with symptomatic cardiovascular disease.20 Thus, the presence of a murmur is of little predictive value for symptomatic heart disease. However, specific murmurs are much more likely to be appreciated if the clinician has a differential diagnosis in mind at the time that auscultation is performed. Conversely, the presence of a nonspecific murmur is of much less concern in an infant who has an otherwise normal examination. Specific diagnoses are based upon unique features of the murmurs, such as pitch, location, and transmission. A murmur is best localized by determining the location of its highest frequency components, because high-frequency sounds transmit very short distances as compared to lower-frequency sounds. Conversely, loudness may be a poor indicator of the site of origin. Thus, a murmur with high-frequency components heard in the left axilla is extracardiac in origin and likely reflects physiological peripheral pulmonary artery stenosis in a normal newborn infant. This helps distinguish the presence of more than one systolic murmur. If a murmur of high pitch is heard, decreases in pitch as the stethoscope is moved in one direction, and the pitch then increases again, that increase in pitch indicates a different murmur.

The pitch of a murmur correlates directly with the pressure gradient where the murmur originates. A high-frequency murmur indicates a high-pressure gradient, and a low-frequency murmur indicates a low gradient. Mid-diastolic murmurs are difficult to appreciate and are often noticed as the absence of silence in diastole. Early diastolic murmurs caused by semilunar valve insufficiency are usually easy to hear, but occur rarely. Their presence indicates specific lesions, such as absent pulmonary valve syndrome or aortic-left ventricular tunnel.