Perinatal Cardiovascular Physiology - Neonatal Cardiology, 3rd Ed.

Neonatal Cardiology, 3rd Ed. Michael Artman

Chapter 3. Perinatal Cardiovascular Physiology

■ INTRODUCTION

■ FETAL CARDIOVASCULAR PHYSIOLOGY

Overview of Essential Facts of Fetal Cardiovascular Function

Tasks of the Fetal Ventricles

One Ventricle Can Maintain Fetal Cardiovascular Stability

Fetal Right Ventricular Dominance

Blood Flow Effects Cardiac and Vascular Structures

Vascular Ultrasonographic Evaluation of Hemodynamic Stability

■ TRANSITIONAL CIRCULATION

Essential Facts of the Transition to the Postnatal Circulation

Increase in Pulmonary Blood Flow Changes in Central Blood Flow Patterns Increase in Combined Ventricular Output

■ SUGGESTED READINGS

■ INTRODUCTION

A comprehensive understanding of fetal cardiovascular physiology and of the changes that occur at birth is essential for developing a systematic approach to the diagnosis and treatment of a newborn with congenital cardiovascular disease. Complex congenital cardiovascular disease rarely causes symptoms in the fetus but within hours or days after birth may cause the newborn infant to become critically ill. Specific defects lead to predictable cardiac and vascular alterations, and knowledge of such associations assists the clinician in the evaluation, diagnosis, and treatment of the critically ill newborn. This chapter reviews important physiologic aspects of the fetal circulation, how the fetal circulation can be monitored for hemodynamic stability, and the changes in circulatory physiology that occur at birth.

■ FETAL CARDIOVASCULAR PHYSIOLOGY

Overview of Essential Facts of Fetal Cardiovascular Function

There are four essential facts about the fetal circulation on which to base an understanding of fetal cardiovascular physiology and its impact on congenital cardiovascular defects: Fact 1. The right and left ventricles function in the fetus as they do postnatally, supplying blood for oxygen uptake and delivery, respectively.

Fact 2. Only one ventricle is required for cardiovascular stability in the fetus.

Fact 3. The right ventricle is the dominant ventricle in the fetus.

Fact 4. After embryogenesis, the size and orientation of a cardiovascular structure (cardiac chamber, valve, or blood vessel) is determined by the blood flow pattern and volume.

Tasks of the Fetal Ventricles

Central shunts, or vascular communications, between the major vascular beds (systemic, pulmonary, and placental circulations) and the two sides of the heart (Figure 3-1) are present in the normal fetus. The ductus venosus joins the placental venous return to the systemic venous return, the ductus arteriosus connects the pulmonary arterial circulation directly to the systemic arterial circulation, the umbilical arteries join the systemic arterial circulation with the placental arterial circulation, and the foramen ovale joins the left and right sides of the heart. Many investigators argue that these shunts create a parallel circuit such that the left and right ventricles perform the same tasks, receiving the same venous return and ejecting into the same vascular beds. This would be dramatically different than the postnatal state, in which the two ventricles perform very different tasks. However, careful analysis of fetal blood flow patterns indicates that the two fetal ventricles do not function in a completely parallel fashion, and, in fact, they function in a similar manner as in the postnatal circulation: oxygen uptake (right ventricle) and oxygen delivery (left ventricle). Fetal blood flow patterns promote the effective distribution of poorly oxygenated blood to the right ventricle, which then directs this blood primarily to the placenta for oxygen uptake. The well-oxygenated blood flows to the left ventricle, which then directs the majority of its output systemically to the highly metabolic organs (Figure 3-1). To understand this phenomenon, it is necessary to understand venous blood flow patterns to the heart and arterial flow patterns to the various vascular beds.

The fetal central venous system can be divided roughly into six components: (1) the superior vena cava, which receives upper body blood flow; (2) the coronary sinus, which receives myocardial flow; (3) the ductus venous, which receives most of the placental blood flow from the umbilical vein; (4) the inferior vena cava below the hepatic veins, which receives lower body flow; (5) the hepatic veins, which receive portal venous and hepatic arterial flow; and (6) the pulmonary veins, which receive pulmonary blood flow. The approximate percentage of total venous return from each of these components is presented in Figure 3-2.

Almost all of the blood flowing through the superior vena cava and coronary sinus returns to the right ventricle (Figure 3-3). The superior vena cava courses anteriorly and inferiorly as it enters the right atrium.

The anatomy of the sinus venosus and of the eustachian valve promotes streaming so that almost all of the flow from the superior vena cava crosses the tricuspid valve into the right ventricle. Similarly, the coronary sinus enters the right atrium just above the medial aspect of the tricuspid valve annulus. The position of the coronary sinus ostium directs flow across the tricuspid valve into the right ventricle. Most of the superior vena caval blood is derived from the brain with lesser amounts from the upper extremities, and thus the blood is poorly oxygenated (Figure 3-4). Similarly, the coronary sinus blood is derived from the myocardium, and thus it is even more desaturated (Figure 3-4). Consequently, almost all of the poorly oxygenated blood from these two venous compartments enters the right ventricle.

The lower inferior vena cava joins with the right and left hepatic veins and the ductus venosus near the right atrium to form the upper portion of the inferior vena cava, which delivers all of the venous return from the lower body and placenta to the heart (Figure 3-3). Although these venous systems join to form a single connection with the right atrium, the upper inferior vena cava is relatively short and exhibits fascinating streaming patterns. These patterns allow for the effective distribution of the different venous systems to the two ventricles. The lower inferior vena cava carries blood from the lower body, which, although not as desaturated as that of the upper body or coronary sinus, is much more desaturated than umbilical venous blood (Figure 3-4). This blood courses along the lateral wall of the upper inferior vena cava. It remains separate from the other sources of blood except for that from the right hepatic veins, which also enters the lateral wall of the upper inferior vena cava. The right hepatic veins primarily receive poorly saturated portal sinus blood from the splanchnic circulation and from the right hepatic arteries (Figure 3-4). The lower body and right hepatic vein streams join and course into the right atrium along the inferior margin of the eustachian valve, which directs most of that flow, along with that of the superior vena cava, across the tricuspid valve into the right ventricle.

Conversely, although umbilical venous blood is also delivered to the upper inferior vena cava, its course into the heart is quite different. The umbilical vein enters the portal sinus. From there, umbilical venous blood splits into the ductus venosus (60% of umbilical venous blood) and the left portal venous streams (Figure 3-3). Ductus venosus blood is entirely derived from the umbilical vein and is thus well saturated (Figure 3-4). Left portal venous blood is mostly derived from the umbilical vein but joins with hepatic arterial flow in the left lobe of the liver to exit via the left hepatic vein. Because hepatic arterial blood represents only a small portion of hepatic blood flow, it does not appreciably decrease the saturation exiting the liver via the left hepatic veins. Blood from both the ductus venosus and the left hepatic vein enter the upper inferior vena cava along its medial margin. These two highly oxygenated streams flow together into the right atrium along the superior margin of the eustachian valve and are directed toward the foramen ovale. The foramen acts as a windsock, directing blood into the body of the left atrium and then across the mitral valve into the left ventricle (Figure 3-3).

FIGURE 3-1. Fetal circulation, showing blood flow patterns throughout the central blood vessels and cardiac chambers. Poorly oxygenated blood streams through the right ventricle to the placenta and lower body, and well-oxygenated blood streams through the left ventricle to the heart and brain.

FIGURE 3-2. Blood flow distribution in the fetus. The percent distribution of combined venous return is shown in circles, and the percent distribution of combined ventricular output is shown in squares. These numbers represent estimates for human fetal blood flow distribution and are derived from sheep and human data. Abbreviations: AAo, ascending aorta; DAo, descending aorta; DV, ductus venosus; IVC, inferior vena cava; LA, left atrium; LHV, left hepatic vein; LPV, left portal vein; LV, left ventricle; MPA, main pulmonary artery; MPV, main portal vein; PAs, branch pulmonary arteries; RA, right atrium; RHV, right hepatic vein; RPV, right portal vein; RV, right ventricle; SVC, superior vena cava; UV, umbilical vein.

FIGURE 3-3. Venous blood flow patterns within the central veins and cardiac chambers. Umbilical venous blood primarily flows to the ductus venosus and left portal vein, whereas splanchnic venous blood passes via the main portal vein primarily toward the right portal vein. Subsequently, the well- oxygenated blood from the ductus venosus and left portal vein flows preferentially via the foramen ovale to the left ventricle. Blood from the inferior and superior vena cavae, the coronary sinus, and the right portal vein flows preferentially across the tricuspid valve to the right ventricle. See legend to Figure 3-2 for definitions of the abbreviations.

Finally, pulmonary venous blood returns to the left atrium directly. Because the lungs are not very metabolically active in utero, this blood is not as desaturated as blood returning to the superior vena caval. Moreover, this relatively poorly saturated blood passing to the left ventricle represents only 8% of combined venous return (Figure 3-2) and thus does not appreciably decrease left ventricular oxygen saturation.

The result of these circulatory patterns is that the right ventricle receives almost all of the blood with the lowest oxygen saturation (venous return from the superior vena cava, coronary sinus, lower body, and right hepatic veins). Conversely, the left ventricle receives most of its blood from the ductus venosus and the left hepatic vein, the two sources of the most highly saturated umbilical venous blood. The oxygen saturation of blood in the left ventricle is estimated to be about 28% higher than that in the right ventricle. This difference is similar to that seen between the ventricles in the postnatal state.

In order for the ventricles to accomplish their tasks effectively, the left ventricle must not only receive more highly oxygenated blood but also deliver the majority of its blood to the organs with high metabolic rates (heart, brain, and adrenal glands), while the right ventricle must deliver the majority of its blood to the placenta for oxygen uptake (Figure 3-2). Although the adrenal glands use a great deal of oxygen per gram of tissue, they are small and thus receive only a very small portion (<1%) of combined ventricular output. The heart and the brain receive all of their blood from the left ventricle. Approximately 7% of left ventricular output is delivered to the heart via the coronary arteries, and 55% is delivered to the brain via the carotid and vertebral arteries. Of the remaining left ventricular output, 15% is delivered to the upper extremities, and only 23% is delivered across the aortic isthmus to the descending aorta. Note that the aortic isthmus is very narrow in the fetus. The relative narrow isthmus functions as a resistor, providing further evidence that the ventricles do not eject blood in parallel.

FIGURE 3-4. Hemoglobin oxygen saturations in various central blood vessels and cardiac chambers. These numbers are approximations derived from fetal sheep data. See legend to Figure 3-2 for definitions of the abbreviations.

Thus, the descending aorta receives most of the output of the right ventricle; only a small portion of left ventricular output joins that from the right ventricle in the descending aorta. The right ventricle delivers its output according to the relative resistances of the pulmonary, systemic, and placental vascular beds. In the fetal circulation, the resistance to blood flow in the pulmonary vascular bed is extremely high, much more so than that of the systemic and placental vascular beds. Thus, only a very small percentage of fetal right ventricular output (15%, or 8% of combined ventricular output) is delivered to the lungs. The remainder crosses the ductus arteriosus into the descending aorta. Of that flow, approximately one- third is delivered to the lower body and two-thirds to the placenta for oxygen uptake. Thus, the majority of the relatively desaturated right ventricular output goes to the placenta for oxygen uptake, and most of the remainder goes to organs of low metabolic activity. As discussed above, the majority of highly saturated left ventricular output is delivered to the highly metabolic heart and brain. Thus, the ventricles perform their tasks in an effective manner, albeit somewhat less so than in the postnatal state.

The efficiency of the circulatory system is apparent from analysis of the proportion of available oxygen that is actually used by the fetus. Fractional extraction of oxygen is defined as the fraction of oxygen removed by the tissues from the blood that is delivered by the arterial system. In the postnatal state, only 25% to 30% of available oxygen is extracted from blood. Thus, there is a large oxygen reserve for extraction during stress, even without an increase in cardiac output. In the fetus, despite the lower oxygen saturation of blood delivered to the fetal body, only about 30% of oxygen is extracted, leaving the fetus with almost the same oxygen extraction reserve. This reserve is achieved in part by the remarkable fetal blood flow pathways described in this section.

One Ventricle Can Maintain Fetal Cardiovascular Stability

The mixing of left and right ventricular output through central shunts decreases the efficiency of oxygen delivery somewhat, but this inefficiency is advantageous to the fetus with congenital cardiovascular disease when one ventricle is underdeveloped. Because these shunts allow both ventricles to eject into all three vascular beds, only one ventricle is necessary for cardiovascular stability.

This fact can be most readily demonstrated in the fetus with only one functional ventricle. Hypoplasia of one atrioventricular valve, usually in association with atresia of the corresponding semilunar valve, is a relatively common form of complex cardiovascular disease. Describing physiology of the fetus with one of the more common defects, hypoplastic left heart syndrome, is instructive in understanding the impact of congenital cardiovascular disease on fetal cardiovascular physiology (Figure 3-5). In a fetus with this condition, all of the venous return (except the very small amount of blood that passes through the pulmonary circulation) enters the right atrium normally. Rather than crossing the foramen ovale to the left atrium, blood in the ductus venosus and left hepatic veins crosses the tricuspid valve with the rest of the systemic venous return. Pulmonary venous return, instead of crossing the mitral valve, crosses the foramen ovale in a left-to-right direction and then enters the right ventricle. Thus, the right ventricle receives all of the venous return. As is normally the case, the right ventricle ejects its blood into the main pulmonary artery, and about 8% enters the pulmonary circulation. The remaining 92% crosses the ductus arteriosus to the descending aorta. Because the aortic valve is atretic, blood flow from the ductus arteriosus not only passes down the descending aorta to the lower body and placenta but also passes retrograde, up the aortic isthmus and around the arch, to supply the upper body and heart. Although cardiovascular stability is maintained in the vast majority of fetuses with hypoplastic left heart syndrome, brain development may be impaired, possibly to a decrease in either flow or its perfusion pressure due to the isthmic resistor. Furthermore, pulmonary problems can occur after birth if the foramen ovale is restrictive in utero, leading to pulmonary venous hypertension.

Fetal Right Ventricular Dominance

Although the left and right ventricles eject the same output in the mature postnatal circulation, the left ventricle generates a much higher pressure. Consequently, its mass greatly exceeds that of the right ventricle. Because of the greater mass and wall stress, the left ventricle is less compliant than the right ventricle. The decreased compliance and greater ejection pressure causes the left ventricle to exert a direct effect on the filling and ejection of the right ventricle (much more so than the right exerts on the left). Thus, the left ventricle is considered the dominant ventricle in the mature circulation.

In the fetus, however, the relationship between the left and right ventricles is quite different. The peak systolic pressure in the two ventricles is the same because they eject into the same vascular beds. However, the fetal ventricles do not eject the same volume of blood. The right ventricle ejects 55% of the combined output of the ventricles. The mass of the right ventricle is therefore somewhat greater than that of the left, and the diastolic and systolic interactions are reversed, though not as pronounced as in the mature circulation. The fetal right ventricle is thought to significantly constrain left ventricular filling and is considered the dominant ventricle. This constraint of left ventricular filling may contribute to the underdevelopment of the fetal left ventricle in conditions in which the right ventricle receives even more of the combined venous return, such as total anomalous pulmonary venous connection. In this lesion, pulmonary venous blood returns to the right atrium, not the left, and that blood is directed across the tricuspid valve. Despite the fact that this represents only a small amount of combined venous return, the left ventricle is small at birth. Similarly, the right ventricle is even more dominant than normal in the fetus with coarctation of the aorta. Contrary to the postnatal circulation in which this obstruction is imposed on the left ventricle, in the fetus the right ventricle is exposed to the effects of the coarctation because far more blood crosses the ductus arteriosus from the right ventricle than crosses the aortic isthmus from the left ventricle. Consequently, that load increases the constraint of the right ventricle on the left ventricle. Echocardiography of a fetus with coarctation of the aorta demonstrates a marked discrepancy in ventricular size. The fetal echocardiographer must carefully evaluate the aortic arch whenever the right ventricle appears more dominant than normal.

FIGURE 3-5. Hypoplastic left heart syndrome. Blood flow patterns show that all of the venous return is directed across the tricuspid valve to the right ventricle because of reversal of blood flow across the foramen ovale. The right ventricle is able to supply blood to all vascular beds, ejecting blood to the upper body and heart by reverse flow across the aortic isthmus. Note that the ascending aorta is markedly hypoplastic because it only receives coronary blood flow. LB represents blood flow from the lower body, consisting of splanchnic and lower limb venous return. See legend to Figure 3-2 for the definitions of the other abbreviations.

Blood Flow Effects Cardiac and Vascular Structures

The primary defect in cardiac structure occurs during embryogenesis in most forms of congenital cardiovascular disease. These abnormalities of embryogenesis are discussed in detail in Chapter 1. Once the primary defect is established, however, secondary alterations in the structure and size of various cardiac chambers, blood vessels, or shunts can occur. These secondary changes result from abnormalities in the amount and direction of blood flow through the fetal cardiac and vascular structures and are important determinants of the clinical presentation of neonates with congenital cardiovascular disease. For example, the primary event in the fetus with hypoplastic left heart syndrome likely is inadequate development of the aortic valve. Once this occurs, several secondary abnormalities develop. Normally, somewhat over one- third of venous return passes through the foramen ovale from the right atrium to the left atrium and left ventricle. In hypoplastic left heart syndrome, the diminutive or atretic aortic valve limits the amount of forward flow across the mitral valve, and both that valve and the left ventricle do not develop normally. This obstruction to forward flow inhibits the normal flow of blood from right to left across the foramen ovale. If the aortic valve is completely atretic, foramen ovale flow reverses and becomes left to right as the small amount of pulmonary venous blood decompresses into the right atrium (Figure 3-5). Thus, the foramen ovale may be quite small and abnormally configured, which is of great consequence after birth, when pulmonary blood flow increases markedly. The large postnatal increase in left atrial venous return must cross the small foramen ovale, which may result in obstruction to pulmonary venous drainage. This is often associated with markedly increased left atrial pressures and secondary pulmonary edema.

Abnormal flow patterns also affect the development of the ascending aorta and aortic arch. Normally, the ascending aorta receives 45% of fetal combined ventricular output (Figure 3-2). Because the aortic arch and ascending aorta are perfused in a retrograde manner via the ductus arteriosus (Figure 3-5), blood flow from the ductus arteriosus separates into a stream that courses inferiorly to the lower body and placenta and a stream that passes superiorly into the aortic arch. This divergence of blood flow within the aorta may cause a shelf to develop between the aortic isthmus and descending aorta, leading to coarctation of the aorta that is manifest after birth. In addition, most of the blood coursing superiorly in the aorta is delivered to the upper body. Only the very small volume of blood that eventually perfuses the coronary arteries flows in a retrograde manner down the ascending aorta, causing the ascending aorta to be hypoplastic in this syndrome.

The secondary alterations in cardiac and vascular structures are extremely important in congenital cardiovascular disease. Some are serious problems and may require urgent therapy in the newborn to ensure survival. Others may be of no hemodynamic significance but may lead to a specific diagnosis because they cannot occur in the presence of the other potential defects under consideration (this is discussed in greater detail with examples of specific associations in Chapters 6 to 8). For these reasons, it is always important to consider normal and abnormal physiology and blood flow patterns when evaluating the newborn with suspected congenital cardiovascular disease to help narrow the differential diagnosis.

Vascular Ultrasonographic Evaluation of Hemodynamic Stability

The use of fetal echocardiography in the diagnosis of congenital cardiovascular disease and fetal cardiac dysfunction is discussed in Chapter 4. This section will briefly review how fetal vascular ultrasonography can be used to evaluate metabolic stability. Over the years, many of the findings regarding blood flow distribution and flow mechanics described in fetal sheep have been corroborated in human fetuses by echocardiography, and normal blood flow patterns in all major vessels and vascular beds have been described. Fetal ultrasound can be used clinically to determine when there is a disturbance in cardiovascular dynamics, which can lead to the diagnosis, prognosis, and treatment of specific pathophysiologic processes.

Inadequate placental oxygen uptake leads to fetal hypoxemia, inadequate substrate delivery, and fetal growth retardation. Anemia, primary ventricular dysfunction, and arrhythmias also cause metabolic decompensation in the fetus. In all of these situations, blood flow patterns are abnormal in both arterial and venous circulations. On the arterial side, compensatory mechanisms are initiated by arterial chemoreceptors and other signals that lead to redistribution of blood flow to the cerebral and myocardial vascular beds. This is associated with specific changes in arterial waveforms. As metabolic decompensation progresses, significant alterations in fetal venous waveforms appear. It is hypothesized that when arterial blood flow is maximally redistributed and is no longer able to maintain sufficient oxygen delivery, fetal heart failure ensues, at which time characteristic changes in venous flow waveforms occur. The predictable progressive appearance of specific Doppler waveforms and other signs corresponding with worsening fetal status has led to development of scoring systems that can be used to assess fetal cardiovascular stability.

On the arterial side, hypoxemia, growth retardation, or decreased ventricular output lead to increased resistance in the lower body and fetal placenta vascular beds. This is demonstrated by a reduction in peak systolic velocity in the descending aorta and umbilical artery and an even greater reduction in end-diastolic velocity, leading to increased pulsatility (Figure 3-6). The pulsatility index is calculated to quantify this change:

where S is the peak systolic velocity, D is end-diastolic velocity, and M is the mean velocity across the cardiac cycle. Conversely, end-diastolic velocities increase in the cerebral and myocardial circulations, leading to a reduction in the measured pulsatility index. These findings demonstrate the “brain and heart sparing” effects of metabolic stress on the fetus because of local metabolic regulation and/or autoregulation.

On the venous side, blood flow patterns reproducibly change as afterload increases and the heart begins to fail. The veins typically interrogated by ultrasound are the inferior vena cava, the ductus venosus, and the umbilical vein within the umbilical cord. The blood flow patterns are very different from each other, and sequential changes reflect the progression of hemodynamic instability.

The normal flow signal in the inferior vena cava shows the largest forward wave in ventricular systole (S), a somewhat lower forward wave during peak forward flow across the tricuspid valve during diastole (D), and a relatively small backward wave during atrial systole (a). A pulsatility index for veins has been calculated as

but is not used routinely. Another index used in describing the flow patterns is |a|/S. More distal from the heart, the negative “a” wave no longer exists—within the ductus venosus, end-diastolic flow (just after atrial contraction), the “a” wave, is usually positive. This is also probably in part because the ductus venosus, which carries a large amount of forward flow, functions as a resistor in the retrograde direction. Finally, the effect of the differential pressures in the venous system caused by the fetal heart becomes less prominent as compared to the continuous signal coming from the highly capacitant placental bed as one interrogates closer to the placental circulation. In the umbilical vein in the cord, the flow pattern varies only minimally, showing a continuous forward flow pattern that undulates only slightly (Figure 3-7).

FIGURE 3-6. Umbilical arterial blood flow patterns by Doppler ultrasonography in normal and stressed fetuses. A. Normal pattern with forward flow throughout systole and diastole. B. Stressed pattern showing decreased systolic velocity and a significantly more decreased diastolic velocity so that the pulsatility index is increased. Note that the velocity scale is reduced compared to A.

FIGURE 3-7. Venous blood flow patterns by Doppler ultrasonography in normal and stressed fetuses. A. Normal venous waveform in the inferior vena cava, with positive systolic and early diastolic waves followed by a very small negative “a” wave during atrial systole. B. Stressed fetus, with a much larger negative “a” wave. C. Normal venous waveform in the ductus venosus, showing pulsatility but no negative waves. D. Stressed fetus, showing “a” wave reversal. E. Normal waveform in the umbilical vein, consisting of a low-velocity wave with little pulsatility. F. Stressed fetus, with the umbilical venous waveform demonstrating significant pulsatility.

If a fetus develops increased afterload and eventually heart failure, pulsatility increases in the proximal veins and extends more distally. The first sign of decompensation is an exaggeration of the negative “a” wave in the inferior vena cava, which is less than 7% of the forward flow area normally. Subsequently, there is increased pulsatility in the ductus venosus, with the development of “a” wave reversal as a late event. Increases in |a|/S correlate with the severity of growth retardation and of hydrops fetalis. The finding of atrial pulsations in the umbilical vein in the cord represents the end-stage heart failure. This finding has been called “diastolic block,” and it is a strong predictor of perinatal mortality. When the umbilical vein demonstrates a pattern similar to the inferior vena cava (the “double venous pulsation”), fetal death is usually imminent (Figure 3-7).

■ TRANSITIONAL CIRCULATION

Essential Facts of the Transition to the Postnatal Circulation

At birth, rapid and profound changes in cardiovascular function and blood flow patterns occur as the newborn adapts to a new circulation; oxygen exchange occurs in the lungs, the placenta is removed from the circulation, and thermoregulation becomes a challenging necessity. For the newborn to remain hemodynamically and meta- bolically stable during the first few minutes of postnatal life, three critical adaptations must occur:

1. Pulmonary blood flow increases dramatically to about 20 times that of pulmonary blood flow in the midgestation fetus.

2. Central blood flow patterns are significantly altered. The central shunts (the ductus venosus, the foramen ovale, the umbilical artery, and the ductus arteriosus) are abolished, and the pulmonary and systemic arterial circulations are separated.

3. Combined ventricular output increases greatly to meet the newly increased energy requirements imposed by the work of breathing and thermoregulation.

As with fetal cardiovascular physiology, much of the information on these changes is derived from studies in fetal sheep in which the animals were instrumented chronically in utero. The independent effects of ventilation, oxygenation, umbilical cord occlusion, and thermoregulation on cardiovascular function have been ascertained. Knowledge of these effects increases understanding not only of how a fetus normally adapts to the postnatal environment but also of what stresses are imposed on the fetus with congenital cardiovascular disease during adjustment to the extrauterine environment.

Increase in Pulmonary Blood Flow

Much of the change in the circulation occurs in the first few minutes after birth (Figure 3-8). Subsequently, more subtle and gradual changes occur during the next several weeks after birth.

The initial circulatory changes occur as the fetus is delivered and starts to breathe. There is an immediate and dramatic increase in pulmonary blood flow to levels approximating 10 to 20 times resting levels during fetal life (pulmonary vascular resistance decreases gradually in late gestation so that the extent of the decrease at birth depends greatly on gestational age).

Although oxygen is a potent pulmonary vasodilator, ventilation with low concentrations of oxygen is capable of inducing a large proportion of the decrease in pulmonary vascular resistance and increase in pulmonary blood flow that are observed at birth. In fact, rhythmic ventilation is not required, as similar changes can be induced by inflating the lungs with a syringe containing nitrogen gas. The decrease in pulmonary vascular resistance induced by ventilation alone is mediated by direct mechanical effects and triggering of prostaglandin release.

The decrease in pulmonary vascular resistance induced by oxygen is multifactorial and is likely mediated by potassium channel activation as well as by stimulation of various local and circulating vasodilators. The production of local endothelium-derived nitric oxide, an important mediator of normal fetal pulmonary vascular tone, is likely dramatically augmented by oxygenation. Endothelium-derived nitric oxide causes vasodilation via cGMP generated by soluble guanylate cyclase localized to the smooth muscle cells. Endothelium-derived prostacyclin may also be stimulated by oxygenation and cause a decrease in pulmonary vascular tone mediated by cAMP. Inhibition of both nitric oxide and prostacyclin (the latter by indomethacin) attenuate the normal decrease in pulmonary vascular resistance at birth.

Alterations in circulating vasoactive substances also have a role in the normal balance of fetal and postnatal pulmonary vascular tone. Adenosine, bradykinin, prostaglandins, histamine, and endothelin-1 acting on endothelial cells produce vasodilation. Leukotrienes and endothelin-1 acting on smooth muscle cells produce vasoconstriction. Alterations in their relative concentrations at birth alter pulmonary vascular resistance and may contribute to normal postnatal pulmonary vasodilation.

Further remodeling of the pulmonary vascular bed occurs over the next several weeks as the muscularity of the proximal arteriolar bed decreases and the muscularity of the most distal bed increases. These changes decrease pulmonary vascular resistance to mature levels within 1 to 2 months after birth and transfer control of pulmonary vascular tone to local metabolites present in the distal pulmonary bed.

Changes in Central Blood Flow Patterns

Concomitant with the dramatic increase in pulmonary blood flow, changes in central blood flow patterns occur postnatally (Figure 3-8).

Umbilical arterial flow ceases as soon as the infant is separated from the placenta by the clamping of the umbilical cord. With the associated loss of umbilical venous flow, ductus venosus flow markedly decreases. Anatomic closure of the ductus venosus is probably delayed for several hours or days, as demonstrated by the ability to pass a catheter through the umbilical vein and ductus venosus in newborn infants. Thereafter, the ductus venosus is no longer patent because of the absence of flow and, possibly, the effects of prostaglandin metabolites and sympathetic stimulation.

Flow through the foramen ovale is abolished primarily by the large increase in pulmonary blood flow. The foramen ovale is the central shunt within the fetal heart that allows for right-to-left flow of over one-third of combined venous return to enter the left atrium and left ventricle. This shunt is maintained in the fetus by the 10-fold greater venous return directly to the right atrium as compared to the left. The floor of the foramen ovale consists of a flap, or windsock, of tissue that protrudes into the left atrium. At birth, the amount of pulmonary venous return directly to the left atrium increases dramatically. This causes the flap to be displaced toward the right atrium, effectively abolishing the right-to-left shunt immediately after birth. Left atrial pressure usually exceeds that of the right, and it is frequently possible to demonstrate a very small left-to-right shunt through the foramen ovale in newborn infants. This physiologically normal flow through the foramen ovale precludes the ability to diagnose a small atrial septal defect in the newborn. Because the foramen ovale is only functionally closed from a right-to-left direction because of the pressure differential between the left and right atria, a right- to-left shunt can occur when a newborn infant cries and increases thoracic impedance to right ventricular output, which in turn may cause a transient increase in right atrial pressure. Infants with this transient desaturation must be distinguished from those with cyanotic heart disease, who may present with duskiness only with crying or feeding. Although not apparently cyanotic at rest, infants with cyanotic congenital heart disease show some desaturation by pulse oximetry at all times, whereas the normal newborn has normal saturations at rest by about 12 hours after birth, when routine screening pulse oximetry is usually performed.

FIGURE 3-8. Transitional circulation. At birth, pulmonary vascular resistance decreases immediately. This increases pulmonary blood flow above systemic levels by abolishing the right-to-left ductal shunt and creating a small left-to-right ductal shunt. The increased left atrial return in turn abolishes the right-to-left shunt across the foramen ovale. Blood flow through the umbilical vein ceases with loss of the placental circulation, which then stops flow through the ductus venosus (although both remain patent for several days). DA indicates ductus arteriosus. See legend to Figure 3-2 for the definitions of the other abbreviations.

The last central shunt to close after birth is the ductus arteriosus. Unlike the other three shunts, flow through the ductus arteriosus does not cease immediately but does so over the first 12 to 48 hours of life. During fetal life, a large volume of blood flows through the ductus arteriosus in a right-to-left direction. Although the right-to-left shunt is abolished immediately at birth because of the large decrease in pulmonary vascular resistance, a small left-to-right shunt occurs, thereby increasing pulmonary blood flow to levels exceeding systemic blood flow. Closure of the ductus arteriosus is induced by oxygen, to which the mature newborn ductus is very responsive. Other factors that play a role in the decrease in pulmonary vascular resistance, such as bradykinin, catecholamines, and arachidonic acid metabolites, may contribute to ductus arteriosus closure. Arachidonic acid metabolites are particularly important agents in controlling ductus tone. This explains the efficacy of prostaglandin E1 to maintain patency of the ductus arteriosus in newborn infants and of the prostaglandin inhibitors in stimulating closure of the ductus arteriosus.

The last major change in central blood flow patterns is the change from right ventricular dominance to left ventricular dominance. The left ventricle is dominant (ie, has more ventricular mass) in the mature circulation because it pumps the same amount of blood as the right ventricle but at higher pressure. During transition from fetal to postnatal life, the left ventricle not only pumps at a higher pressure than the right ventricle but also ejects more blood. Right ventricular systolic pressure decreases in the newborn infant because pulmonary vascular resistance falls and the ductus arteriosus begins to constrict, decreasing the exposure of the right ventricle to the higher resistance of the systemic circulation. The left ventricle ejects blood not only to the systemic circulation but also via the ductus arteriosus to the pulmonary circulation until the ductus fully closes. Systemic vascular resistance increases because the very compliant placental vascular bed is removed from the systemic circulation and because local systemic vascular beds, such as those in the myocardium and the brain, constrict in response to the increase in oxygen tension. The combination of the large decrease in pulmonary vascular resistance and increase in systemic vascular resistance causes all of the output of the right ventricle to flow to the pulmonary vascular bed and some of the output of the left ventricle to flow through the ductus arteriosus into the pulmonary artery.

Increase in Combined Ventricular Output

The third important change in cardiovascular status at birth is the near tripling of left ventricular output, required because of the large increase in oxygen demand. In the fetus, systemic arterial oxygen levels are very low, averaging about 20 to 25 torr. However, oxygen demand is similarly low, and the oxygen dissociation curve is shifted to the left, allowing for a considerable amount of oxygen to be taken up by hemoglobin in the placenta despite the low oxygen tension. Thus, the fractional extraction of oxygen, which is perhaps the best indication of the reserve that exists to respond to periods of stress, is approximately 30% (similar to the postnatal state).

Birth is associated with two new major metabolic requirements that mandate a large increase in oxygen delivery. Respiratory work uses about 30% of the oxygen consumed by the newborn. Thermoregulation can require almost as much oxygen, and feeding and digestion further increase oxygen requirement. Thus, oxygen consumption nearly triples at birth. Moreover, the left ventricle, which primarily supplies oxygen to the heart, brain, and upper body before birth, must supply oxygen to the entire body immediately after birth. Consequently, left ventricular output must increase nearly threefold if fractional oxygen extraction remains unchanged. The increase in left ventricular output occurs because of increases in heart rate and stroke volume.

It has been of great interest to investigators that the left ventricle can greatly increase its output after birth, yet its ability to increase output in the fetus is very limited. The fetal left ventricle can eject, at most, only 50% more blood in response to alterations in load, heart rate, or contractility. In contrast, the left ventricle at birth is capable of increasing its output nearly threefold even though contractility does not increase. Results from a variety of studies indicate that the primary reason that the left ventricle is able to increase output is because its function is no longer constrained by the right ventricle. As the systemic vascular bed constricts while the pulmonary vascular bed dilates, the lungs, which received less than 10% of the combined ventricular output during much of fetal life, receive significantly more than half immediately after birth and under a lower pressure. The pulmonary veins return about 55% to 60% of total venous blood to the heart, which flows almost exclusively to the left ventricle. Thus, both the filling and the ejecting pressures are greater in the left than in the right ventricle. The left ventricle is dominant in the postnatal circulation and is able to increase its output greatly. Other contributing factors to the large increase in left ventricular output at birth include increased β-adrenergic receptor activity in association with thyroid hormone and cortisol surges in the perinatal period and a change in the relationship between preload and afterload.