Anatomy

The organ of prenatal respiration is the placenta. It is a large, low-resistance circuit that has an enormous influence on the pattern of fetal blood flow. The lungs are almost completely excluded from fetal circulation, and three special shunts (the ductus venosus, the foramen ovale, and the ductus arteriosus) allow the most oxygenated blood to perfuse the heart and brain (Fig. 4-1). Two umbilical arteries originate from the internal iliac arteries and deliver fetal blood to the placenta. One umbilical vein carries oxygenated blood from the placenta to the fetus. When umbilical venous blood approaches the liver, it can take two pathways. It is estimated that 50% to 60% of umbilical venous blood bypasses the liver via the ductus venosus, while the remainder perfuses the left lobe of the liver. Blood flow to the right lobe of the liver is predominantly from the portal circulation. The right and left hepatic veins, along with the ductus venosus, merge into the suprahepatic inferior vena cava (IVC) (Fig. 4-2). Bypassing the high-resistance hepatic microcirculation, umbilical venous blood in the ductus venosus remains not only more oxygenated, but it also flows at a higher velocity. Within the suprahepatic IVC there are now two streams of blood. The stream of blood with higher velocity is derived from the ductus venosus and drainage from the left hepatic vein. The stream of blood with slower velocity consists of drainage from the right hepatic vein mixed with venous return from the abdominal IVC. Upon entering the right atrium, these two streams of blood diverge. The blood with higher velocity is primarily directed across the foramen ovale to the left atrium. This right-to-left shunt is possible because left atrial pressure is low due to minimal pulmonary venous return. The Eustachian valve is a flap of tissue at the junction of the IVC and the right atrium. It functions to help direct the higher-velocity stream of blood across the foramen ovale and into the left atrium (Fig. 4-3). The lower-velocity stream of blood crosses the tricuspid valve and is ejected by the right ventricle. This anatomic arrangement allows the most oxygenated blood from the umbilical vein to bypass the liver and the right side of heart.

FIGURE 4-1 Fetal circulation. Ao, Aorta; DA, ductus arteriosus; DV, ductus venosus; LA, left atrium; LV, left ventricle; PA, pulmonary artery; RA, right atrium; RV, right ventricle.

(From Rudolph AM: The fetal circulation and postnatal adaptation. In Rudolph AM, editor: Congenital diseases of the heart, ed 2, Armonk, NY, 2001, Futura.)

FIGURE 4-2 The course of umbilical venous blood as it reaches the liver. The left lobe of the liver is supplied mainly by the umbilical vein, and the right lobe of the liver is supplied by the portal circulation. IVC, Inferior vena cava; SVC, superior vena cava; LHV, left hepatic vein; RHV, right hepatic vein.

(Modified from Rudolph AM: The fetal circulation and postnatal adaptation. In Rudolph AM, editor: Congenital diseases of the heart, ed 2, Armonk, NY, 2001, Futura.)

FIGURE 4-3 Transesophageal echocardiogram of an adult patient with a prominent Eustachian valve remnant (arrow). The Eustachian valve directs blood from the inferior vena cava across the foramen ovale into the left atrium. The thinnest part of the atrial septum is where the foramen ovale is during fetal life. IVC, Inferior vena cava; RA, right atrium; LA, left atrium; FO, foramen ovale.

(From Sawhney N, Palakodeti V, Raisinghani A et al.: Eustachian valve endocarditis: a case series and analysis of the literature, J Am Soc Echocardiogr 14:11, 2001.)

The majority of blood in the left atrium originates from the higher-velocity stream that crosses the foramen ovale. In the left atrium it mixes with a small amount of pulmonary venous return. The purpose of the ductus venosus and foramen ovale is to allow the most oxygenated blood from the umbilical vein to reach the left ventricle with the least drop in oxygen saturation possible. Oxygen saturation in the umbilical vein is approximately 80%. Inevitable mixing with more deoxygenated blood from the liver, IVC, and superior vena cava (SVC) results in the left ventricle ejecting blood with a saturation of 65% to 70% when the mother is breathing room air. The left ventricle pumps blood primarily to the heart and brain through the ascending aorta and great vessels of the aortic arch. SVC blood enters the right atrium and crosses the tricuspid valve into the right ventricle. Only a small amount of SVC blood and poorly oxygenated IVC blood enters the left atrium via the foramen ovale. High pulmonary vascular resistance (PVR) forces almost all of the right ventricular output to enter the systemic circulation via the ductus arteriosus. The ductus arteriosus is the continuation of the main pulmonary artery and inserts into the aorta at a point immediately distal to the origin of the left subclavian artery. The blood in the descending aorta is a mixture of left and right ventricular outputs with the right ventricle predominating. Consequently, the gut, kidneys, and lower extremities are perfused with blood that has an oxygen saturation of approximately 55%. Two umbilical arteries, branches from the internal iliac arteries, return blood to the placenta.

The key features of fetal circulation are shown in Figure 4-4 and listed below:

FIGURE 4-4 Fetal and neonatal circulation. Circled values are oxygen saturation, with values for pressure (systolic, diastolic, and mean) appearing beside their respective chamber or vessel. A, Fetal circulation near term. B, Transitional circulation at younger than 1 day old. C, Neonatal circulation at several days old. Ao, Aorta; DA, ductus arteriosus; IVC, inferior vena cava; LA, left atrium; LV, left ventricle; PA, pulmonary artery; PV, pulmonary veins; RA, right atrium; RV, right ventricle; SVC, superior vena cava.

(From Rudolph AM: The fetal circulation and Rudolph AM: Changes in the circulation after birth. In Rudolph AM, editor: Congenital diseases of the heart, Chicago, 1974, Mosby.)

Fetal Cardiac Output

The three important fetal shunts create a circulation that is parallel rather than the more efficient postnatal series circulation. Furthermore, the shunts do not function perfectly, which increases the work of the heart. Some of the oxygenated umbilical venous blood enters the right ventricle, crosses the ductus arteriosus, and flows into the descending aorta. Delivering this highly oxygenated blood back to the placenta is the equivalent of a left-to-right shunt, which increases the myocardial work. Additionally, some deoxygenated blood from the SVC and IVC flows across the foramen ovale and is ejected by the left ventricle. This is an effective right-to-left shunt, which decreases the oxygen saturation of the blood ejected by the left ventricle. The fetus and most critically, its very metabolically active heart and brain, grow and develop in a cyanotic environment.

In the fetus, right and left ventricular outputs are not equal. The ventricles, acting in parallel, pump different amounts of blood, and organs receive blood flow from both ventricles. Thus, it is customary to refer to the combined ventricular output (CVO) of fetal circulation. The fetal CVO is estimated at 400 mL/kg per minute, a value that is similar to that of the neonate but almost threefold higher than it is in adults. The ratio of right ventricular to left ventricular output is approximately 1.3:1 (Kenny et al., 1986). The volume load borne by the right ventricle combined with the high fetal PVR results in significant hypertrophy. After birth, the right ventricle remodels over time under the influence of a series circulation and lowered PVR (Fig. 4-5). The demands of a parallel circulation result in increased myocardial work superimposed on the demands of a fetus having to grow and develop in a cyanotic milieu. Nevertheless, the fetal circulation is an efficient arrangement with adequate physiologic reserve. This is demonstrated by the full spectrum of congenital heart lesions that are well tolerated in utero.

FIGURE 4-5 Transesophageal echocardiogram four-chamber view of a healthy newborn, A, and adult B. The ventricles are equal in the newborn heart. Growth of the left ventricle and remodeling of the right ventricle create the usual adult appearance.

Oxygen Delivery

The transfer of oxygen across the placental bed is inefficient when compared with the transfer of oxygen in the lungs. The normal alveolar-arterial gradient for oxygen is minimal for a patient with healthy lungs breathing room air. This is in contrast to the fetal state, in which maternal arterial oxygen tension (Pao₂) is close to 100 mm Hg, and the partial pressure of oxygen (Po₂) in the umbilical vein is no more than 30 to 35 mm Hg. It should be recalled that after umbilical venous blood is diluted with more poorly oxygenated blood, the Po₂ of the blood ejected by the left ventricle is about 25 to 30 mm Hg when the mother is breathing room air. With such a low fetal oxygen tension, any reductions in maternal oxygenation could severely impact the fetus. The large gradient for oxygen across the placenta means that when the mother is breathing 100% oxygen, maternal Pao₂ can be as high as 400 to 500 mm Hg, but the Po₂ in the umbilical vein rises to no higher than 40 mm Hg. In cases of suspected uteroplacental compromise, this small increase in umbilical vein Po₂ may be critical and justifies administering supplemental oxygen to the mother. The modest rise in umbilical vein Po₂ that occurs when the mother is breathing 100% oxygen can result in a large increase in fetal oxygen saturation. This occurs because fetal hemoglobin has a different oxygen-hemoglobin dissociation curve than adult hemoglobin.

Oxygen transport must be achieved in a relatively hypoxic environment (Lister et al., 1979). How does the fetus ensure adequate oxygen delivery? Fetal hemoglobin (HbF) has unique properties that allow the fetus to transport oxygen despite a low Po₂. Approximately 80% of fetal hemoglobin is HbF compared with an adult who has over 90% adult hemoglobin (HbA). The Pao₂ at which Hb is 50% saturated is called the P₅₀. Fetal hemoglobin (HbF P₅₀:19 mm Hg) is shifted to the left in comparison with adult hemoglobin (HbA P₅₀:26 mm Hg). A low level of 2,3-diphosphoglycerate (2,3-DPG) and the decreased affinity of HbF for 2,3-DPG cause the leftward shift of HbF. In vitro, HbF has a sigmoidal oxygen dissociation curve similar to that of HbA. The result is that for any given Po₂, the oxygen saturation is higher for HbF than for HbA.

Assuming a Pao₂ of 30 mm Hg in the blood ejected by the left ventricle, this value falls in the steepest part of the oxygen-hemoglobin dissociation curve. At a Pao₂ of 30 mm Hg, fetal hemoglobin would be approximately 70% saturated, and adult hemoglobin would only be 50% saturated (Fig. 4-6). Using the equation for oxygen content of the blood (Cao₂) demonstrates how the fetus can achieve levels of oxygen transport that are near those of an adult. Oxygen content of blood is defined by the following equation, Sao₂ is the arterial oxygen saturation of hemoglobin, and Hb is the hemoglobin concentration in g/dL:

FIGURE 4-6 Oxygen-hemoglobin dissociation curves for fetal (A) and adult (B) hemoglobin. The dashed lines represent the P₅₀ for fetal and adult hemoglobin, respectively. For any given Po₂, fetal hemoglobin has a higher oxygen saturation than adult hemoglobin.

(From Delivoria-Papadopoulos M, McGowan JE: Oxygen transport and delivery. In Polin RA, Fox WW, Abman SH, editors: Fetal and neonatal physiology, ed 3, Philadelphia, 2004, Saunders.)

At normal levels of Pao₂, when an adult is breathing room air, the amount of oxygen dissolved in blood is negligible, because it is only 0.003 mL O₂/mm Hg. Therefore, the Cao₂ is typically calculated by determining the amount of oxygen that is carried bound to hemoglobin. For example, an adult with a Sao₂ of 100% and a Hb of 11 g/dL would have the following Cao₂:

The fetus maintains Cao₂ through two mechanisms. In addition to the leftward shift of HbF, the fetus is erythrocytotic compared with the adult. Using the equation for Cao₂ for a fetus with a Hb of 17 g/dL and an oxygen saturation of 65% yields the following:

Fetal hemoglobin’s greater affinity for oxygen improves oxygen uptake at the placenta. A greater affinity for oxygen is an advantage for uptake at the placenta but a drawback for the unloading of oxygen at the tissue level. Given that the purpose of hemoglobin is to deliver oxygen to the tissues, this poses a problem. The fetus copes with this problem with another modification to its internal milieu. Oxygen release, or rightward shifting of the oxygen-hemoglobin curve, is increased by acidosis. Fetal pH (normal values 7.25–7.35) is lower than it is in adults, facilitating oxygen release at the tissue level. It is important to realize that the preceding discussion has involved only oxygen content of the blood. Oxygen delivery, which is the goal, can only be achieved when an adequate capacity to carry oxygen is matched with a cardiac output that is sufficient to meet metabolic needs.

Pulmonary Blood Flow and Pulmonary Vascular Resistance

It is clear that the most fundamental and critical transition necessary for postnatal life is the establishment of breathing, accompanied by a fall in PVR. Therapeutic attempts to manipulate PVR occur in certain newborns with congenital heart disease. Deleterious changes in PVR also accompany critical neonatal disease states. Therefore, a brief discussion of pulmonary circulatory physiology is warranted.

At midgestation, PVR is estimated to be tenfold higher than it is 24 hours after an uncomplicated birth. During the last trimester, PVR decreases slightly to levels seven- to eightfold greater than it is 24 hours after delivery (Rudolph, 1979). This reduction results from the physical growth of the pulmonary vasculature that increases the cross-sectional area by more than the corresponding increase in blood flow. Yet, PVR still remains high immediately prior to birth and must fall dramatically in the first postnatal minutes to ensure survival. Pulmonary blood flow increases by an amount corresponding to the decrease in PVR, and pulmonary blood pressure falls by 50% (Fig. 4-7). Thus, the pulmonary vasculature presents a puzzle that flies in the face of the normal principles of cardiovascular embryology. The guiding principle of cardiac and vascular development is that once normal structures form, the correct pathway for blood flow is established. Once flow is established, normal growth ensues. The pulmonary vasculature must grow normally despite greatly reduced flow. The elevated PVR necessary for fetal existence cannot be solely the result of anatomic hypoplasia. If this were the case, the transition to postnatal life would be rocky indeed. Rather, the pulmonary vessels must be of normal size but retain the ability to markedly vasoconstrict. Even more remarkable is that the ductus arteriosus is an outgrowth of the pulmonary arterial system, yet it responds in a completely opposite fashion to the pulmonary vasculature. The very stimuli that raise PVR in utero cause dilation of the ductus arteriosus. The factors that govern pulmonary vasoreactivity have still not been fully elucidated, but our understanding has grown considerably in the last 20 years (Martin et al., 2006).

FIGURE 4-7 A, The changes in pulmonary arterial pressure, blood flow, and PVR from late gestation through the neonatal period in lambs and other species. B, The effect of oxygen tension and acid–base balance on PVR in newborn calves. A low Po₂ results in minimal increase in PVR if pH is maintained at 7.4. Conversely, dramatic rises in PVR occur when acidosis is combined with a low Po₂.

(From Rudolph AM: Prenatal and postnatal pulmonary circulation. In Rudolph AM, editor: Congenital diseases of the heart, ed 2, Armonk, 2001, Futura.)

The primary force driving high fetal PVR is hypoxemia. The estimated Po₂ in the pulmonary arteries is less than 20 mm Hg. This phenomenon of hypoxemia-induced pulmonary vasoconstriction (HPV) persists into adulthood, where it is vital in maintaining oxygen saturation during one-lung anesthesia. In utero, the mechanism of HPV is not fully understood. Oxygen is a potent stimulator of endothelial- derived vasodilating substances such as nitric oxide and prostacyclin. Nitric oxide activates soluble guanylate cyclase, which increases guanylate 3′-5′-cyclic monophosphate (cGMP). Prostacyclin stimulates adenylate cyclase to increase adenylate or adenosine 3′-5′-cyclic monophosphate (cAMP). Both cGMP and cAMP initiate vasodilation in pulmonary vessels. Under conditions of low oxygen tension, the release of nitric oxide and prostacyclin is presumably attenuated, tipping the balance in favor of vasoconstriction. The specific substances inducing pulmonary vasoconstriction are not well understood. Attention is focused on arachidonic acid and its metabolites and the potent vasoconstrictor endothelin (Tod and Cassin, 1984; Hickey et al., 1985a; Ivy et al., 1996).

At delivery, mechanical and biochemical factors lead to the abrupt fall in PVR (Teitel et al., 1990). Aeration of the previously fluid-filled lungs removes the external compressive force on the pulmonary vasculature. Responding to the sudden rise in oxygen tension, the endothelium secretes potent vasodilators, nitric oxide and prostacyclin. Luminal diameter increases as endothelial and smooth muscle cells become thinner. The increase in blood flow further recruits small lumen vessels, leading to an overall increase in the cross-sectional area of the pulmonary vascular bed. Smooth muscle relaxation occurs in the larger pulmonary vessels. This first, rapid phase of pulmonary vasodilation is followed by a period of remodeling that lasts for months. During this time there is maturation of vascular smooth muscles with continuing modest declines in PVR. PVR approximates adult values by about 2 months of age, and the remodeling process is usually complete by 6 months of age. During the first few years of life, new vessels develop to supply the growing lung parenchyma (Fig. 4-8). It is important to understand that in the early postnatal period, PVR is markedly affected by hypoxia and acidosis (Rudolph and Yuan, 1966). More recently, pain has also been associated with increasing PVR.

FIGURE 4-8 Pulmonary angiograms at birth (A) and from an 18-month-old infant (B). Growth of existing vessels and development of intra-acinar arteries create the prominent hazy background appearance.

(From Haworth SG: Pulmonary vascular development. In Long WA, editor: Fetal and neonatal cardiology, Philadelphia, 1990, Saunders.)

Preload

In 1895, the German physiologist Otto Frank published his observations on the relationship of diastolic filling of the heart and the pressure the heart was able to generate during systole (Frank, 1895). Ernest Starling, an English physiologist, conducted the classic experiment in the early 1900s that defined the length-tension relationship for cardiac muscle (Fig. 4-10). Understanding his experiment is important, because in the laboratory he was able to isolate that which is impossible to isolate in vivo. Using a fixed weight to keep afterload constant, he was able to prove that the tension developed was proportional to the length of the muscle strip prior to stimulation. The greater the length of the muscle strip, the greater the tension it was able to develop. The Frank-Starling mechanism, or Starling’s Law of the Heart, is taken from a famous lecture by Dr. Starling himself, in which he stated, “the energy of contraction, however measured, is a function of the length of the muscle fiber” (Starling, 1918).

FIGURE 4-10 A schematic diagram of the classic Starling experiment. The suspended weight (afterload) is held constant, allowing the tension developed to be measured at different lengths (preload) of the muscle strip.

(From Epstein D, Wetzel RC: Cardiovascular physiology and shock. In Nichols DG, Ungerleider RM, Spevak PS, et al., editors: Critical heart disease in infants and children, ed 2, Philadelphia, 2006, Mosby.)

The clinical correlates of length and tension are left ventricular end-diastolic volume (LVEDV) and stroke volume, respectively. In the laboratory, the length of a muscle strip is easily determined because both ends can be fixed. This is very different from the intact heart, where the ventricle is a three-dimensional structure with complex geometry that defies the simple concept of length. Nevertheless, it is clinically appropriate to regard length as LVEDV. The LVEDV represents the loading of the ventricle. It is present before contraction, and therefore has come to be called preload. The force of ventricular contraction increases with increasing preload until a point is reached where the ventricle is over stretched and the force of contraction decreases. This point is the apex of the well-known Starling curve. Force of contraction is not synonymous with contractility, and for all points along a Starling curve, contractility is equal. Changes in the force of contraction, however, occur when preload changes (Fig. 4-11). Laboratory evidence has shown that resting sarcomere distance is 1.6 microns, with optimal conditions occurring at 2.2 microns. Excessive stretch, causing decreased force of contraction, does not occur until sarcomere length reaches 3.5 microns (Sonnenblick, 1974). In the laboratory the force of contraction increases until the sarcomere is stretched to over twice its resting length. If this translated fully to the intact heart, any increase in preload would result in increased force of contraction, because physiologically achieving a doubling of resting sarcomere length is almost impossible. However, well before a doubling of resting sarcomere length is reached, the patient falls on to the descending limb of the Starling curve. The reason is the relationship between volume and pressure, which is known as compliance.

FIGURE 4-11 Starling’s Law of the Heart. Contractility is the same for each curve. Moving from point A to point B requires an increase in LVEDV. Moving to point C or point D can only occur if there is a change in contractility. For the same LVEDV, the stroke volume falls progressively with impaired contractility. The figure demonstrates that the failing ventricle is dependent on preload.

(Modified from Opie LH, Perlroth MG: Ventricular function. In Opie LH, editor: The heart: physiology from cell to circulation. Philadelphia, 1998, Lipppincott-Raven.)

The Starling curve describes the relationship between LVEDV and stroke volume. The problem is that measuring LVEDV in a way that is simple, accurate, and available in real time is not possible. Echocardiography is the best method to quantify LVEDV. However, the two-dimensional images seen echocardiographically may not faithfully represent the volume contained in a three-dimensional ventricle with its elliptical shape. The equations used to objectively measure volume are not practical in most clinical situations and certainly not in the dynamic environment of the operating room. Subjective assessments of LVEDV using echocardiography depend on the skill of the operator and will detect only the extremes of preload conditions. Given the problems in measuring volume, the clinician is forced to use a surrogate measure of LVEDV. A catheter placed in a central vein and connected to a transducer measures pressures simply, accurately and continuously. Using pressure as a guide to volume requires understanding the relationship between the two variables, defined as compliance and described by the following equation:

The change in pressure resulting from a change in volume is compliance. Volume is in the numerator of the equation meaning that if a large increase in volume is met by a relatively small rise in pressure, compliance is high. As a completely empty ventricle is filled, the initial rise in LVEDP is small. In this situation the ventricle is said to be compliant. When the ventricle is full, a small increase in volume results in a large increase in pressure. The ventricle is now poorly compliant or “stiff.” As with the Starling curve, it is important to note that moving to different points on the compliance curve does not mean that the intrinsic compliance of the ventricle has changed. A true intrinsic change in compliance will be reflected in a new compliance curve (Fig. 4-12). In adult cardiac medicine it is readily appreciated that ischemia, infarction, or hypertrophy result in a stiffer, or less compliant, ventricle. However, no ventricle, regardless of its intrinsic compliance, has an infinite ability to accept volume. Eventually the inflection point on the curve will be reached and pressure will climb rapidly for any given increase in volume. It is this sharp increase in pressure beyond the inflection point that is responsible for the descending limb of the Staring curve.

FIGURE 4-12 Diastolic-compliance curves. Each curve represents a different intrinsic compliance. Movement between points A, B, and C reflects a change in preload with no change in compliance. Movement from point A to point D can only occur when the ventricle becomes less compliant.

(From Mark JB: Atlas of cardiovascular monitoring, New York, 1998, Churchill Livingstone.)

Decreases in the force of contraction represented by the descending limb of the Starling curve are due to the result of pressure and not volume or “overstretch.” The reason is that the rise in pressure causes an imbalance in the myocardial oxygen supply/demand ratio that results in decreased force of contraction. The left ventricle is perfused according to the following equation:

When the maximum increase in blood pressure achieved by volume loading has been reached, further volume only serves to increase LVEDP at the expense of coronary perfusion pressure. Thus, myocardial oxygen supply decreases. A key determinant of myocardial oxygen demand is wall stress defined by the modified Law of Laplace:

Wall stress is usually, but erroneously, thought of as similar to afterload, because the value for pressure in the numerator is assumed to be systolic blood pressure. In fact, blood pressure is a key component of wall stress, but they are clearly not the same. Oxygen consumption increases with increasing wall stress, and wall stress has both systolic and diastolic components. During systole the value for pressure in the wall stress equation is the systolic blood pressure. In the diastole the value for pressure is LVEDP. A patient with a value on the steep part of the compliance curve has sharp increases in LVEDP disproportionate to the increase in volume. Concomitantly, the ventricular cavity is fully distended from the volume load. Thus, excessively high LVEDP combined with an enlarged ventricular radius simultaneously causes an increase in myocardial oxygen demand and a decrease in myocardial oxygen supply. This situation, if unchecked, leads to ischemia and a decrease in the force of contraction.

The response of the newborn heart to volume loading (relative insensitivity) has been the source of great confusion (Rudolph, 1974). This confusion stems from experimental work done in the 1970s and is the logical extension of the known structural differences in the newborn heart (Romero and Friedman, 1979; Gilbert, 1980). The response to preload was investigated in fetal sheep for the left and right ventricles. For either ventricle, isolated output rose only slightly with increases in filling pressures. Using a microsphere technique in fetal sheep, alterations in combined cardiac output were measured as blood volume was modulated (Gilbert, 1980). With a decrease of 10% in circulating volume, there was a significant drop in right atrial pressure, as well as in cardiac output. In contrast, cardiac output did not significantly change despite a significant change in right atrial pressure with a 10% increase in circulating blood volume from baseline. These data lead the author to conclude that the fetus operates at the upper end of the Starling curve and possesses limited cardiac reserve.

With only half the amount of sarcomere volume that is in an adult, connective tissue comprises a much greater percentage of the newborn heart. The myofibrils are fewer in number with a disorderly arrangement in the myocyte. There is much more stiff connective tissue. The sum total of these changes makes it plausible that the relatively noncompliant newborn heart does function at the upper end of its Starling curve, where the response to volume loading is blunted. In fact, the original experiments failed to account for an inevitable consequence of increases in preload. An increase in the preload leads to greater stroke volume, and if heart rate is unchanged, cardiac output must increase as well. Blood pressure must now rise unless there is a corresponding drop in SVR. Therefore, an increase in preload leads to an increase in afterload, which then acts to reduce stroke volume. This created the impression that the newborn heart could not increase stroke volume in response to volume loading. Other work, controlling for arterial pressure, shows that the newborn heart is indeed responsive to volume within the limitations of its decreased compliance (Fig. 4-13) (Kirkpatrick et al.; 1976, Hawkins et al., 1989). This has been shown in the laboratory with a sheep model and though echocardiography in the human fetus. The newborn can be likened to the hypertensive adult with diastolic dysfunction. This is not to suggest that the otherwise healthy newborn has diastolic dysfunction, because the newborn heart is not dysfunctional but normal for its stage of development. Rather, the lesson of diastolic dysfunction is that the ventricle is preload dependent. At the low end of the Starling curve, reduced preload is poorly tolerated. The upper end of the Starling curve is flattened, reflecting its reduced compliance. Between these two points is the steepest part of the curve, where increases in LVEDV result in significantly greater stroke volume. Clinical experience observing the response to volume infusion confirms this property of the newborn heart.

FIGURE 4-13 The response of the immature heart to changes in preload and afterload. When afterload is held constant, left ventricular stroke volume (LVSV) increases linearly with increased left atrial (LA) pressure. Increasing afterload creates an inverse linear relationship with LVSV when LA pressure is constant.

(From Hawkins J, Van Hare GF, Schmid KG, et al.: Effects of increasing afterload on left ventricular output in fetal lambs, Circ Res 65:127, 1989.)

Afterload

In addition to preload, there is another loading force that influences myocardial performance. The force that resists the ejection of blood is known as afterload. In isolated muscle strip experiments, the afterload is represented by the weight against which the muscle contracts or shortens. The stretch applied to the isolated muscle strip before contraction is fixed, allowing the experiment to be conducted at a constant length, or preload. Plotting the velocity of myocardial shortening against progressively increasing afterload reveals an inverse relationship. The shape of the curve is exponential with the points of maximal and zero shortening both occurring at physiologically impossible limits. The greatest shortening velocity occurs at zero load. When the load is so great that no muscle fiber shortening can occur, isometric contraction occurs. Between these two extremes, it is intuitive that increasing afterload results in reduced velocity of muscle fiber shortening. Transferring this straightforward laboratory concept to the intact circulation is difficult (Martin et al., 2006). The force generated by the shortening of an isolated muscle strip is directed in only one plane. This is very different from the three-dimensional contraction of the left ventricle with its asymmetric geometry. Additionally, in the laboratory the force that resists the shortening of the muscle is the weight applied to the muscle strip. Physiologically, the force that resists the ejection of blood is a complex interplay between blood pressure, vascular impedance, walls stress, and inertia. Finally, blood pressure and SVR are commonly used measures of afterload, but neither is fully accurate.

In most situations, the systemic blood pressure does provide an appropriate surrogate for afterload. One common exception is in conditions in which there is obstruction to left ventricular outflow. In adults, the most common cause is aortic stenosis, but pediatric patients may also have congenital lesions that cause obstruction at the subvalvular level in the left ventricular outflow tract (LVOT) in addition to aortic valve disease. The left ventricle must generate enough pressure to overcome both the systolic blood pressure and the gradient across the valve or the LVOT obstruction. Assuming that the ventricle must only overcome the systolic blood pressure leads to a significant under estimation of afterload. The use of SVR to approximate afterload is also problematic. The concept of SVR describes resistance, which is defined as the pressure drop across a system divided by the flow across that same system. This is reflected in the equation for SVR:

Multiplication by 80 converts SVR from mm Hg/L/min/m into SI units (dynes•s•cm^–5). The calculated SVR may be similar for patients with very different cardiovascular performance. Consider these two patients:

These two hypothetical patients are very different, yet the SVR is similar. The first patient has normal cardiovascular function and the second patient’s cardiovascular function is compromised. A reduction in contractility has caused a fall in cardiac output despite the attempts of the ventricle to compensate with a higher diastolic filling pressure. This example demonstrates how SVR in isolation does not necessarily reflect large changes in loading conditions and cardiac output. The modified Law of Laplace describes a better approximation of afterload (see Preload section p. 91). As discussed in the section on preload, wall stress was demonstrated to be a key component of myocardial oxygen demand. During left ventricular ejection, the value for pressure is the systolic blood pressure. By including the radius and accounting for the compensatory mechanism of left ventricular hypertrophy the modified Law of Laplace provides a more comprehensive view of the forces that resist ventricular ejection. Importantly, it demonstrates the concept that the dilated ventricle with an increased radius must eject blood under increased afterload conditions. Given the inability to easily measure ventricular radius and thickness, the modified Law of Laplace is not a clinical parameter to guide management. It is presented here to help the reader conceptualize afterload. It still cannot describe all the variables that account for afterload in the intact cardiovascular system.

Studies of the intact heart that assess the effect of changes in afterload on cardiac output are difficult to interpret without controlling for the other variables. The most important additional variable is preload. Preload and afterload are linked. For instance, pharmacologically increasing afterload decreases stroke volume. As the heart ejects less blood with each contraction, the end-diastolic volume must increase if venous retum is held constant. With an increase in LVEDV the Starling curve dictates an enhanced ventricular force of contraction, which acts to return stroke volume to its previous level. The general inverse relationship between afterload and stroke volume holds across the spectrum from fetal life to adulthood (Friedman, 1972). The question is whether the immature myocardium is excessively sensitive to increases in afterload. In the laboratory, afterload can be assessed while strictly controlling for preload. These studies have revealed that the fetal myocardium is indeed more sensitive to increases in afterload than the adult myocardium (Friedman, 1972). Animal experiments with an intact circulation also show a decrease in ventricular output under conditions of increasing afterload (Fig. 4-13) (Gilbert, 1982; Thornburg and Morton, 1986). Van Hare and colleagues (1990) used a balloon occluder in the aortas of fetal sheep to modulate afterload while keeping preload constant. Combined ventricular output was measured by transducing aortic flow. They noted that at physiologic mean atrial pressures, there was an inverse linear relationship between mean arterial pressure and stroke volume. This exists for both right and left ventricles. Despite this, a fetus normally makes a smooth transition to postnatal life when the low-resistance placenta is removed. At birth, pulmonary blood flow dramatically increases, raising left-ventricular preload. Stroke volume increases, which leads to an increase in systemic blood pressure. Despite the rise in blood pressure and the loss of the low-resistance placenta, cardiac performance in the newborn is not compromised. The explanation is that much of the rise in afterload is secondary to increased preload. In clinical practice with newborns and young children, it is rare to encounter conditions of purely increased afterload. A more likely situation is significant hypovolemia that results in hypotension. Despite the low afterload state, overall cardiac performance is impaired, because the decrease in afterload is caused by decreased preload. The correct therapy is to restore intravascular volume. Blood pressure improves, and the increased afterload is well tolerated. This example illustrates the interrelationship between these two variables of cardiac output.

It has been shown that when preload is held relatively constant, cardiac output moves inversely within the physiologic range of afterload. The relevance of afterload in the newborn stage might be questioned, because systemic hypertension is so rare. The right ventricle develops in an environment of raised PVR, yet after birth it is more sensitive to increases in afterload. Although there is limited ability of the systemic circulation to become hypertensive, the pulmonary circulation, under appropriately provocative conditions, can revert to its fetal state. Postnatally, the right ventricle begins to remodel in response to decreasing pulmonary artery pressures. Sustained elevations in pulmonary artery pressures decrease right ventricular output and reduce left-ventricular preload (Thornburg and Morton, 1983). Because both ventricles share the septum, the strain on the right ventricle impairs left-ventricular filling and contraction (Rein et al., 1987). Reductions in left-sided preload and contractile force demonstrate how the inability of the right ventricle to cope with increased afterload can lead to decreases in systemic cardiac output. In the newborn stage, the potential for pulmonary hypertension far exceeds that of systemic hypertension. This is the most common scenario for a significant rise in afterload while preload remains relatively unchanged. The strain on the right side of the heart and ventricular interdependence may lead to biventricular failure.

Contractility

The third parameter of myocardial performance is contractility. Seemingly intuitive, contractility is often confused with changes in stroke volume brought about by alterations in loading conditions. Contractility, synonymous with inotropy, is the intrinsic ability of the myocardium to contract when loading conditions are held constant. The Starling curve is the first source of confusion. As discussed in the section on preload, every point on an individual patient’s Starling curve represents the same inotropic state. Movement along the curve is solely because of changing conditions of preload. In the same way, the demonstration in the laboratory of decreased myocardial shortening velocity in response to increased weight (afterload) is not evidence of a fall in contractility. Contractility has remained constant, but the force of contraction is reduced. Contractility and force of contraction are clearly not the same. The force of contraction, related to loading conditions, can vary widely. Contractility is relatively fixed. It can be increased pharmacologically but is usually either normal or reduced. Further demonstrating misconceptions about contractility, a hypertrophied ventricle is often assumed to have increased contractility. Hypertrophy is a response to increased afterload, but contractility, once corrected for the greater cross-sectional area of the ventricular muscle mass, is normal. Any disease process that injures the myocardium decreases global contractility. In adults, this most commonly occurs secondary to ischemia or infarction. In addition to these causes, pediatric patients may suffer decreased contractility on the basis of genetic disorders, infiltrative diseases, infections, or nutritional deficiencies.

The immature myocardium has a reduced sarcomere concentration combined with a transport system for calcium that is not fully developed. The myofibrillar arrangement is also more disorganized in the infant heart when compared with the adult heart. Mitochondria, the energy powerhouse of the myocyte, are reduced in number in the immature heart (Barth et al., 1992). Based on the above differences, a reduction in contractility is expected. Contractility is measured by the tension developed in the isolated muscle strip. This expected reduction in contractility of the immature myocardium is confirmed in laboratory experiments where preload and afterload are controlled. Across the entire range of loading conditions, fetal cardiac muscle generates less tension than adult myocardium (Fig. 4-14) (Friedman, 1972; Romero et al., 1972). In an intact heart it is not possible to fully separate the influences of different loading conditions. Nevertheless, fractional area shortening of the ventricle measured echocardiographically is used as a measure of contractility. Decreased fractional area shortening has been observed in the fetal heart (St. John Sutton et al., 1984). Effecting a true increase in contractility requires either a greater number of contractile elements or more vigorous action by the contractile elements already present. Increasing the number of contractile elements (hyperplasia and hypertrophy) occurs as a normal part of development. Improving the action of the contractile elements already present requires an understanding of the singular role of calcium. Therapy to improve inotropy exerts its action at the myocyte level by affecting the levels of intracellular calcium.

FIGURE 4-14 Length-tension relationships in adult sheep compared with fetal lambs. The fetal myocardium has greater resting tension but is able to generate less active tension. This represents a state of decreased compliance or a “stiffer” ventricle combined with decreased contractility.

(From Friedman WF: The intrinsic properties of the developing heart, Prog Cardiovasc Dis 15:87, 1972.)

Heart Rate

As mentioned in the section on preload, it has long been considered that the newborn’s heart rate is dependent on and relatively insensitive to changes in end-diastolic volume. Assuming the maintenance of sinus rhythm, heart rate is believed to determine cardiac performance through its influence on preload and myocardial oxygen supply and demand. At very high heart rates, hypotension ensues, because diastolic filling time is severely restricted and preload markedly falls. Coronary perfusion to the left ventricle occurs during diastole, and systolic ejection time is fixed. Thus, tachycardia shortens the time for perfusion of the left ventricle and results in an increased oxygen demand combined with a decreased oxygen supply. The absence of coronary artery disease in newborns offers them some protection in accepting imbalances in myocardial oxygen supply and demand. However, extremes of heart rate are poorly tolerated by adults and newborns alike.

The question is whether the newborn who has a heart rate within normal range is fundamentally different than the adult. When corrected for weight, stroke volume is similar across all ages. The high cardiac output of newborns and infants can only be achieved with a heart rate that is significantly higher than in adults. This has created the idea that the newborn is dependent on heart rate. Here it becomes difficult to sort out the isolated effect of heart rate from its effects on loading conditions and contractility. It is not intuitive as to why changes in heart rate alter contractility. The mechanism is known as the force-frequency relationship. Experiments using atrial pacing, while controlling loading conditions, demonstrate an increase in stroke volume with an increase in heart rate (Anderson et al., 1982).With constant loading conditions, the only explanation for increased stroke volume is that contractility has increased. Thus, an increased heart rate improves contractility. The basis for the force-frequency relationship is that an increase in heart rate is accompanied by enhanced release of intracellular calcium (Parilak et al., 2009). There is a suggestion that the force-frequency relationship has minimal effect in newborns but is present during infancy (Wiegerinck et al., 2008). Spontaneous increases in heart rate also improve cardiac output. In this scenario, the increase in heart rate is the result of a neurohumoral stimulus with an effect that cannot be isolated to producing tachycardia. Both preload and contractility can be expected to increase, as long as the increase in heart rate does not lead to deleterious changes in preload or myocardial oxygen supply and demand. The combination of these factors allows the newborn and infant to use heart rate to significantly augment cardiac output.

Integrating Preload, Afterload, and Contractility

The determinants of myocardial performance, while discussed in isolation, are actually intricately linked. Diagrammatically, the determinants of myocardial performance can be represented by ventricular pressure-volume loops (Suga et al., 1973). The loop shows the pressure and ventricular volume changes that occur during one cardiac cycle. Increases in preload while afterload is held constant result in greater stroke volume (Fig. 4-15). This simple curve does not provide any information about contractility. The end systolic pressure-volume relationship (ESPVR) is a family of curves that is generated by rapidly altering preload or afterload. The curves create a series of points that are connected to become the ESPVR line. The slope of this line represents contractility (Fig. 4-16). The pressure-volume loop illustrates the concept that movement along the ESPVR line reflects changes in loading conditions while contractility remains constant. In Figure 4-16, the increases in afterload result in a series of points that are connected to become the ESPVR line. The slope of the ESPVR line represents contractility. The two figures of ventricular pressure-volume loops represent an idealized situation where preload and afterload can be manipulated independent of each other. In the intact organism, preload and afterload are linked. The interdependence of preload and afterload is shown in a new ventricular pressure-volume loop (Fig. 4-17).

FIGURE 4-15 Ventricular pressure-volume loop. As preload increases from point A to points E and F, the end-diastolic pressure-volume curve represents compliance. The increased preload results in greater stroke volume (SV) when afterload is held constant.

(Modified from Braunwald E, Ross J, Sonnenblick EH: Mechanisms of contraction of the normal and failing heart, Boston, 1976, Little, Brown.)

FIGURE 4-16 Ventricular pressure-volume loop. As afterload is increased, stroke volume falls when preload is held constant. The slope of the line connecting points D, E, and F is the end-systolic pressure-volume relationship and represents contractility. Only alterations in the slope of the line represent changes in contractility. The contractility at points D, E, and F is identical.

(Modified from Braunwald E, Ross J, Sonnenblick EH: Mechanisms of contraction of the normal and failing heart, Boston, 1976, Little, Brown.)

FIGURE 4-17 Ventricular pressure-volume loop. The interdependence of preload and afterload is demonstrated. The increase in preload from point 1 to point 2 results in a rise in stroke volume (SV₁ to SV₂) that is less than anticipated because the increase in preload causes a corresponding increase in afterload.

(Modified from Strobeck JE, Sonnenblick EH: Myocardial contractile properties and ventricular performance. In Fozzard HA, Haber E, Jennings RB, et al., editors: The heart and cardiovascular system, New York, 1986, Raven.)

In states of decreased contractility, the ventricular pressure-volume loop displays the limitations of the failing heart. Analysis of the ventricular pressure-volume loop shows that the failing ventricle is sensitive to changes in loading conditions (Fig. 4-18). The ESPVR line has shifted down and to the right. With preload held constant, stroke volume is reduced. The body’s response to this situation is to increase LVEDV in an attempt to preserve stroke volume. Stroke volume has improved at the expense of a higher end-diastolic pressure. The ventricular pressure-volume loop demonstrates why afterload reduction is the cornerstone of medical therapy for the failing heart. Any increases in afterload come at the expense of stroke volume, with a limited ability for compensatory changes in preload.

FIGURE 4-18 Ventricular-pressure volume loop with decreased contractility. The line representing contractility is shifted down and to the right. Curve 1 is the stroke volume with normal contractility. Curve 2 shows that when contractility is reduced, stroke volume can be maintained through increased preload. Curve 3 demonstrates a significant reduction in stroke volume when afterload is increased in the presence of decreased contractility.

(Modified from Braunwald E, Ross J, Sonnenblick EH: Mechanisms of contraction of the normal and failing heart, Boston, 1976, Little, Brown.)

The reflex of the trainee when confronted with a patient with significantly decreased contractility is to withhold or restrict fluids in a well-meaning attempt to avoid pulmonary edema. The ventricular pressure-volume loop for the patient with heart failure shows the fallacy and danger of this approach. Positive pressure ventilation is associated with decreases in preload. Venous tone is decreased by most anesthetic agents. The combination of these two events means that while the patient’s global volume status is unchanged, he or she has become relatively hypovolemic. He or she is below the optimum LVEDV for his or her failing heart. Far from being on the verge of pulmonary edema, this patient now requires intravascular volume to compensate for the effects of anesthesia and positive pressure ventilation. Although maintaining LVEDV is critical for patients, there are currently limited means to accurately assess preload. Central venous pressure must be interpreted in light of the altered ventricular compliance of the failing heart. Lastly, while the failing heart requires adequate preload, its ability to accept volume rapidly is limited. Cautious infusion of volume with frequent reassessment is necessary lest a rapid bolus of fluid results in pulmonary edema, which is exactly the outcome the trainee sought to avoid by restricting volume in the first place.

Subcellular Structures

Myocardial Energy

Newborn sheep have a higher myocardial oxygen consumption than adult sheep. These metabolic demands of the developing heart are met by a capillary network of higher density than that found in adults (Fisher et al., 1982).

The immature myocardium uses lactate as a primary energy source. This is in contrast to the mature myocardium, where fatty acids are the primary energy source. To be metabolized, fatty acids must first be transported into the mitochondria. This is accomplished by carnitine palmitoyl-CoA transferase. Activity of this enzyme is reduced in the immature myocardium, suggesting the necessity of carbohydrate as the primary energy source (Fisher et al., 1980, 1981).

Electrophysiology

The sinus node can initially be identified as a horseshoe-shaped structure at the lateral junction of the superior vena cava and the right atrium. As the heart develops, it assumes the elongated spindle shape that is seen in the mature heart. Using voltage-sensitive dyes, spontaneous cellular depolarization has been observed prior to the development of contractile function. Although spontaneous depolarization is also seen in the developing atrium and bulboventricular portion, cells that are destined to form the sinus node have a higher intrinsic rate of depolarization (Pickoff, 2007).

Discrete connections between the sinus node and the atrioventricular (AV) node are a matter for debate. The lack of an identified cell type insulated from the surrounding atrial myocardium has been considered evidence of a lack of specialized internodal conducting pathways (Anderson et al., 1981). Preferential conduction along bands of atrial myocytes in the anterior septum may be to the result of a more organized cellular alignment (Racker, 1989). More recent evidence from studies of developing human hearts has demonstrated three internodal pathways identified by antibody staining (Blom et al., 1999).

Functional changes in the electrophysiologic properties of the atrium have been described. Action potential duration in human neonates is shorter than in adults. This is relevant in that it may explain the highest incidence in childhood of atrial arrhythmias in the fetus and neonate (Pickoff, 2007). Once these dysrhythmias are terminated in the newborn, there is a low incidence of recurrence.

Delay in contraction between the atrium and ventricle is seen before the development of the AV node. Action-potential recordings from the AV canal area of the developing chicken heart demonstrate characteristics that are to be expected of slowing areas of conduction—namely, a slow rate of rise and a prolonged duration. These characteristics are further linked to differential expression of acetylcholinesterase. Expression is higher in the AV canal region compared with expression in the free wall of the atrium or ventricle (Mikawa and Hurtado, 2007; Pickoff, 2007).

AV nodal cells are distinct from the other embryonic myocardial cells. They have differential expression of calcium-regulatory proteins and membrane channels (Mikawa and Hurtado, 2007). Formation of the AV node is an incompletely understood complex series of events that likely involve modulation by the gene NK×2-5 (Mikawa and Hurtado, 2007; Briggs et al., 2008).

Formation of the Purkinje system is an area of active investigation. Purkinje-like function is seen after cardiac looping (Pickoff, 2007). However, the network is still developing in the fetal heart. Studies suggest a paracrine interaction between the fetal myocardium and the cardiac endothelial cells. Purkinje fiber development is seen primarily in two sites, periarterially and subendocardially. Phenotypical recruitment of a beating myocyte to a conduction fiber is thought to be modulated by endothelin-1 (ET-1). The ET-1–induced expression of conduction-tissue markers in myocytes is dependent on dosage and inhibited by ET-1 antagonists (Mikawa and Hurtado, 2007). Exposure of myocytes to ET-1 is also associated with downward regulation of markers found primarily on muscle cells.

In chicken embryos, conduction velocities increase with age and are related to the emergence of fast-conducting sodium channels (Shigenobu and Sperelakis, 1971; Pickoff, 2007). Findings have been similar in mammalian systems (Rosen et al., 1981; Pickoff, 2007). Of note is the maintenance of conduction slowing from atrium to ventricle seen in the primitive heart. In a canine model, measurement of AV-nodal conduction demonstrated that conduction was faster in immature hearts, but the AV node, not the ventricular myocardium, remained the site of conduction slowing with differential atrial pacing (McCormack et al., 1988).

Through fetal magnetocardiography, conduction times have been noted to increase with gestational age (Kahler et al., 2002; Stinstra et al., 2002; van Leeuwen et al., 2004). This is thought to be related to myocardial growth (van Leeuwen et al., 2004). Intracardiac conduction times have been measured in children and compared with those in adults. There were no age-related differences in atrial, AV-nodal, or His Purkinje-conduction times (Gillette et al., 1975).

Central Nervous System Regulation of Cardiovascular Function

The regulation of cardiac output and blood flow is controlled by neural and circulation mechanisms. Neural regulation is accomplished by modulating the output through the sympathetic and parasympathetic nervous systems in response to input from receptors in the heart and vasculature. Hormonal regulation occurs by receptor stimulation by circulating molecules.

The autonomic nervous system is developed in the human by about 27 weeks’ gestation. Parasympathetic innervation precedes sympathetic innervation (Fig. 4-19). In sheep, at least, the postnatal increase in contractile function with adrenergic stimulation is a consequence of higher resting adrenergic tone rather than a maturation of the myocardium (Teitel et al., 1985). The β-adrenergic/adenylate cyclase system develops during fetal life. The density of the β-adrenergic receptor density peaks at term and declines postnatally, mirroring the maturation of cardiac sympathetic innervation. Calcium channels in neonatal myocardium do, however, respond less to β-adrenergic stimulation than they do in the adult, and isoproterenol stimulation of adenyl cyclase is blunted in the late fetus and neonate (Osaka and Joyner, 1992). In the late term fetus and the neonate, coupling of the β-receptor and adenylate cyclase may be decreased, because differential β-adrenergic response to isoproterenol and forskolin, a direct activator of adenylate cyclase, has been observed (Schumacher et al., 1982; Tanaka and Shigenobu, 1990). This finding may help explain the decreased response of calcium channels to β-adrenergic stimulation in the neonatal myocardium (Baum and Palmisano, 1997).

FIGURE 4-19 A timeline of human fetal autonomic development.

(From Papp JG: Autonomic responses and neurohumeral control in the early antenatal heart, Basic Res Cardiol 83:2, 1988.)

The sinoatrial node is sensitive to β-adrenergic stimulation in the fetus before the development of ventricular sensitivity, and this sensitivity tends to parallel the development of autonomic innervation to these regions of the heart.

Vagal myelination in humans continues through the fetal period and reaches adult levels by about 50 weeks postconceptual age (Sachis et al., 1982). In humans, parasympathetic input to the heart is from the superior, inferior, and thoracic branches of the vagus nerve (Hildreth et al., 2009). The relative balance of sympathetic and parasympathetic stimulation is reflected in the decreasing mean heart rate as a child reaches adolescence.

The aortic arch and carotid bodies have baroreceptors that provide the afferent limb of the feedback circuit. Stimulation of these receptors sends impulses to the cardioinhibitory and vasomotor centers of the medulla. In turn, the efferent signals result in decreased blood pressure, vasodilation, and slowing of the heart rate. Arterial baroreflexes are present and operational in healthy and critically ill human neonates; human neonates, even preterm neonates, have well-developed vagally mediated cardiac responses to hypoxemia and other stimuli, although the course of maturation is unclear (Thoresen et al., 1991; Buckner et al., 1993). Decreasing sensitivity in studies of awake animals suggests a decreasing role for heart rate in the control of blood pressure in aging animals (Palmisano et al., 1990).

Stretch receptors in the myocardium also provide afferent signals to the central nervous system. Within the atrium there are two types of stretch receptors. Type A receptors are sensitive to pressure and are activated by atrial systole. Type B receptors are sensitive to volume and fire during ventricular systole. They have opposing effects on the sympathetic nervous system, with Type A receptors stimulating sympathetic activity. Secretion of vasopressin is inhibited by stimulation of stretch receptors. Stretch receptors are also found in the ventricular myocardium and when activated cause hypotension and bradycardia (Teitel et al., 2007).

Pulmonary Vascular Development

The pulmonary vasculature is a unique low-flow, high-pressure system in utero that must convert to a high-flow, low-pressure system after birth. In the absence of shunts, the right and left sides of the heart are connected through the pulmonary vasculature, which becomes the major determinant of right-ventricular afterload and left-ventricular preload. Effective cardiopulmonary interactions are crucial for a smooth transition to postnatal life. Primary lung problems, such as severe meconium aspiration or respiratory distress syndrome, through their effects on the pulmonary vasculature, can severely stress the heart. Congenital heart disease causes abnormalities of pulmonary blood flow, which can profoundly influence the pulmonary vasculature in its transition to postnatal life. This section begins with a review of normal pulmonary vascular development and concludes with a discussion of the changes present in pulmonary arterial hypertension.

Pulmonary vessels are described by their relation to the bronchioles. Terminal bronchioles are the smallest purely conductive airways. Beyond them lie respiratory bronchioles, with dual conductive and gas-exchange functions, and then more distally, the alveolar units. Resistance in the pulmonary vasculature is at the level of the small pulmonary arteries (approximately fifth to sixth generation), which are defined as preacinar if they are proximal to the terminal bronchioles and intraacinar if they course parallel to the respiratory bronchioles and alveolar units. Conductive airways and preacinar arteries are fully present by 16 weeks’ gestation (Hislop and Reid, 1973). There is a thickened muscular layer in the medial wall of preacinar vessels, most prominent at the fifth and sixth generation arteries (Hlastala et al., 1998). Beyond the preacinar arteries there is a transition zone of vessels at the level of the respiratory bronchioles with incomplete muscularization in the medial layer. The medial layer of these incompletely muscularized vessels contains pericytes (mesenchymal cells capable of differentiation) and precursor smooth muscle cells. Compared with a complete muscular layer, partial muscularization is believed necessary to aid the gas exchange function of respiratory bronchioles because alveolar development at birth is very immature. Arteries associated with immature alveoli are completely free of a muscular medial layer at birth.

The developing pulmonary vasculature must be of a caliber that can accommodate the enormous increase in postnatal blood flow without a damaging rise in pressure. In a setting of low blood flow, the pulmonary vasculature grows normally but retains a high resistance because of increased vascular tone. The increased vascular tone is primarily modulated by hypoxemia. Expansion of the lungs and a rise in alveolar oxygen tension after birth leads to the marked vasodilation of small arteries required to accept the increase in blood flow. Normal volume, low pressure pulmonary blood flow in the newborn period begins a process of regression of the muscular medial layer of the small arteries. Morphologically recognizable alveoli develop over the first 2 months of postnatal life with continued development until 18 months of age. After this, growth of existing alveoli continues until late childhood. The sparse numbers of alveoli at birth are associated with nonmuscularized intraacinar arteries. The rapid period of alveolar development is matched by growth of new intraacinar arteries. Both existing and new intraacinar arteries develop a thin, muscular medial layer. Thus, the process of normal pulmonary vascular development involves both the regression of muscularity in preacinar existing vessels and the growth of new intraacinar vessels that acquire a thin muscular layer. Disturbances of flow or pressure during this time can have profound consequences.

Diseases that affect normal pulmonary blood flow patterns have far-reaching consequences. In fetuses with abnormal restriction of pulmonary blood flow, there is often hypoplasia of the pulmonary arterial system. The degree of hypoplasia can be mild to fulminant, with atresia of all or parts of the pulmonary arterial system. For example, with tetralogy of Fallot, the level of pulmonary outflow obstruction is typically in the infundibulum of the right ventricular outflow tract. The resulting decrease in pulmonary blood flow affects the main and branch pulmonary arteries, which can be variably hypoplastic. Despite being hypoplastic, the vasculature has the ability to remodel and grow with improved blood flow. In patients who receive an early modified Blalock-Taussig shunt that provides augmentation of pulmonary blood flow, growth of the pulmonary arteries is seen. Also, in patients with hypoplastic pulmonary arteries, patch augmentation can result in reversal of pulmonary artery hypoplasia (Agnoletti et al., 2004).

Disruption of normal pulmonary vasculature has also been observed when the perturbation to pulmonary flow is on the venous side. In hypoplastic left heart syndrome, blood returning to the left atrium must cross over to the right atrium via the foramen ovale. If the foramen ovale is widely patent, blood returning via the pulmonary veins to the left atrium is shunted across to the right atrium. Right-sided structures are often enlarged to accommodate the flow. However, if the patent foramen ovale is restrictive, pulmonary venous pressure rises and development of the pulmonary arterial vasculature is compromised. There is pressure rather than volume stress on the pulmonary vasculature. At birth, the increase in pulmonary blood flow with lung expansion leads quickly to left-atrial hypertension, compromising pulmonary blood flow and resulting in severe hypoxemia. Even if the emergent situation is optimally treated, surgical mortality remains high. At autopsy, the pulmonary veins of these infants are thickened and “arterialized” (Rychik et al., 1999). In juxtaposition to the pulmonary hypoplasia seen in patients with reduced pulmonary blood flow, patients with increased pulmonary blood flow may develop enlarged pulmonary arteries. In an uncommon variant of tetralogy of Fallot, the pulmonary valve is absent, resulting in free pulmonary insufficiency. This increased volume of blood flowing back and forth through the main and branch pulmonary arteries leads to massive dilation.

PVR decreases to near adult levels over the first 2 months of life. During these early months of life the concepts of pulmonary resistance and pulmonary reactivity are well demonstrated. Compared with the in utero state, resistance in young infants is low, though not quite yet at adult levels. However, the pulmonary reactivity is high, because the muscular pulmonary vasculature retains an impressive ability to increase vascular tone. By age 4 to 6 months, if the pulmonary vasculature has developed normally, both resistance and reactivity are low. The appropriate regression of the muscular layer of small pulmonary arteries leaves a healthy older infant unable to mount significant pulmonary hypertension. The contrast with the neonate is striking. Stressed by surgery that involves cardiopulmonary bypass or by pulmonary insults (such as respiratory distress syndrome or meconium aspiration) the neonate’s reactive pulmonary vasculature is primed for a dangerous pulmonary hypertensive crisis.

The most common scenario of altered postnatal pulmonary blood flow occurs in patients with left-to-right shunts. Despite the increased pulmonary blood flow in the first few months of life, PVR continues to fall, leading to even greater pulmonary blood flow. The consequence of increased flow through the same cross-sectional vascular area is pulmonary hypertension. Because resistance is defined as pressure divided by flow, the diagnosis of pulmonary hypertension is not synonymous with increased PVR. The pulmonary vasculature accepts the increased blood flow at the expense of a rise in pressure. Resistance only increases when pressure remains high and pulmonary blood flow falls. Untreated, the natural result of this situation is a condition of pulmonary hypertension, elevated PVR, and fixed, irreversible pulmonary vascular disease. This is known as Eisenmenger’s syndrome. In 1897, Dr. Eisenmenger described a 32-year-old male with cyanosis and exercise intolerance who died from massive hemoptysis (Eisenmenger, 1897). The autopsy revealed a large ventricular septal defect (VSD) and overriding aorta. It was the first demonstration of congenital heart disease causing pulmonary vascular changes.

The normal process of pulmonary vascular remodeling consists of a reduction in the thickness of the muscular layer in preacinar small pulmonary arteries. Simultaneously, there is development of new intraacinar arteries and growth of existing intraacinar arteries that acquire a thin, muscular layer. The overall cross-sectional area of the pulmonary vasculature increases in concert with alveolar growth and development. Persistent high pulmonary blood flow from left-to-right shunting profoundly alters this process. The thickened muscular medial layer of small pulmonary arteries persists instead of involuting. In the transition zone of the respiratory bronchioles, precursor cells transform into vascular smooth muscle. Increased blood flow induces a shear stress in the pulmonary bed. Although felt to be a protective mechanism, this induces a reactive process that stimulates the muscularization of the pulmonary arteries and reduces the capacity for vasodilation. Development of new acinar arteries is impaired. Pulmonary artery pressure remains elevated. With persistent pulmonary hypertension, there are progressive changes in the pulmonary arteries that have been histologically characterized.

Heath and Edwards (1958) first described the following histologic changes in the pulmonary vasculature that are created by excessive blood flow and pressure:

Abnormal pulmonary vascular remodeling begins at birth if there is excessive pulmonary blood flow (Hall and Haworth, 1992). The Heath and Edwards scale is prognostic but limited, because pathologic stages are not correlated with clinical parameters. Rabinovitch overcame this problem by correlating pathologic severity with the hemodynamic state and assigning a simple three-stage grading system (Rabinovitch, 1999):

Grade A or mild grade B changes are histologically equivalent to Heath-Edwards Stage I. Grade C changes are associated with Heath-Edwards stage II or III and the possibility of irreversible changes in the pulmonary vasculature. Severe grade B or grade C disease is predictive of postoperative pulmonary hypertensive problems after surgery to repair the defect (Rabinovitch et al., 1984).

Any discussion of the pulmonary vasculature would be incomplete without exploring the role of the endothelium. Far from being a passive structure, modern understanding of the endothelium has evolved to recognize its singular place in the regulation of vascular tone (Rabinovitch, 1999). Exposure to high flow has multiple negative effects. Endothelial barrier function is compromised, which leads to the release of growth factors that increase vascular smooth muscle and deposition of subendothelial matrix proteins. Luminal diameter eventually decreases with superimposed increased vascular reactivity. Normally antithrombogenic, damaged endothelium reacts abnormally with marginating platelets, resulting in activation of the coagulation system. The endothelium is a key source of the endogenous vasodilators prostacyclin and nitric oxide. When subjected to high flow and shear stress, the release of the endogenous vasodilators is increased, but it may not be enough of an increase to counteract the increased vascular reactivity when pulmonary blood flow is high.

History

One of the most basic indicators of adequate cardiac function is age-appropriate exercise tolerance. In infants, heart failure is marked by a history of tachypnea and diaphoresis, particularly with feeding. A history of cyanosis may be abnormal or may be a normal finding. Many healthy infants develop acrocyanosis or perioral cyanosis with crying or cold.

Physical Examination

“Failure to thrive” is determined by plotting patient data on weight, height, and head circumference growth charts. Specific growth charts are available, for example, for children with Down’s syndrome, where normal growth may not mirror that of the population at large (Cronk et al., 1988). More important than the current position on growth charts is the child’s trajectory. The tenth percentile may be adequate for an individual patient. However, it becomes worrisome if the child’s growth had previously been recorded at the fiftieth percentile. In general, most conditions causing failure to thrive will result first in loss of weight, followed by loss of height, preserving head circumference if at all possible. Certain metabolic disorders, however, show a preferential loss in height first.

Vital signs need to be corrected for age, as indicated above. Normal values for heart rate, respiratory rate, and blood pressure are shown in Tables 4-1 and 4-2 and Figures 4-20 and 4-21. Blood pressure cuffs need to be appropriately sized to avoid artifact. Although it was originally taught that the cuff width should be approximately two-thirds the length of the humerus, the current recommendation is now similar to that for adults. The width of the cuff should be approximately 40% to 50% of the circumference (approximately 125% to 155% of the diameter) of the limb where the pressure is being measured and long enough to approximately encircle it. The cardiovascular physical examination begins with inspection, and proceeds to palpation and then auscultation.

TABLE 4-1 Normal Respiratory Rates in Children

FIGURE 4-20 Normal resting blood pressures in boys (A) and girls (B) aged 1 to 17 years. Pressures reflect those in children at the fiftieth percentile for height. Blood pressure varies slightly in children who are significantly taller (several mm Hg higher) or shorter (several mm Hg lower). Blood pressures also do not reflect normal values obtained when children are under anesthesia.

(Data from National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents: The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Available at www.nhlbi.nih.gov/guidelines/hypertension/child_tbl.htm.)

FIGURE 4-21 Systolic (A) and diastolic (B) blood pressures on the first day of life. Data are shown as the regression line and 95% confidence limits.

(Data from Versmold HT, et al.: Aortic blood pressure during the first 12 hours of life in infants with birth weight 610 to 4,220 grams. Pediatrics, 67:607, 1981.)

Auscultation

Are the lungs clear without wheezing or rales, both of which could result from cardiac dysfunction? Are there any murmurs? Murmurs are almost universally heard in all children at some point, as heart sounds readily transmit through the thinner pediatric thorax. The differentiation between functional (innocent) murmurs and pathologic murmurs is often easy, but it can at times be challenging. A further discussion of murmurs is included in Chapter 36, Systemic Disorders. Figure 4-22 summarizes the changes in heart rate, cardiac output (CO), and stroke volume (SV) that occur in childhood.

FIGURE 4-22 Changes in cardiac output (CO), stroke volume (SV), and heart rate (HR) with age.

(From Rudolph AM, editor: Congenital diseases of the heart, Chicago, 1974, Mosby.)

Chest Radiograph

Evidence of heart disease on the routine chest radiograph includes cardiomegaly (heart failure or large left-to-right shunts), decreased pulmonary blood flow (right-to-left shunts), abnormal cardiac silhouette (small pulmonary artery segment with tetralogy of Fallot), widened angle at the carina (large left atrium), pruning (decreased peripheral pulmonary arteries, as in pulmonary arterial hypertension), and rib notching (in children over about age 5 years with coarctation). Artifacts are more commonly seen in children. Given the inability of young children to cooperate, films taken during exhalation are more common in children, and the cardiac silhouette may appear artifactually large (Fig. 4-23). Although the lungs may appear abnormally small in an expiratory film, a more sensitive finding on a film taken in exhalation is buckling of the trachea. The shadow of a normal large thymus in infants can overlay the heart shadow, tempting a diagnosis of cardiomegaly. Sometimes a “sail sign” can be seen at the inferolateral border of the thymus, where it separates from the cardiac shadow, clearly identifying it as the thymus and not the heart (Fig. 4-24).

FIGURE 4-23 A, Apparent cardiomegaly that is really an artifact of an expiratory film (and a large thymus). B, A repeat film taken shortly thereafter shows a normal cardiac size.

FIGURE 4-24 A thymic sail sign (arrows). When seen, this can aid in differentiation of true cardiomegaly from a large thymic shadow.

(From Keats TE, Anderson MW: Atlas of Roentgen variants that may simulate disease, Philadelphia, 2007, Mosby.)

Electrocardiogram

Normal values of the electrocardiogram are dependent on age and heart rate. With development and growth, neonatal right-ventricular predominance is replaced with left ventricular predominance, the heart rate slows, and all durations and intervals lengthen. Between the ages of 3 and 8 years, the electrocardiogram of a child looks similar to that of the adult, with the exception of right precordial T waves, which are normally inverted until about age 10 years. Upright T waves over the right precordium in children younger than 10 years are an indication of right ventricular hypertrophy. Normal values for heart rate, QRS width, frontal-plane QRS axis, and PR interval are shown in Tables 4-3 and 4-4. It can be seen that the ranges of normal are fairly wide. In addition, these values are for children who are awake or resting. Heart rates in anesthetized children are likely to be somewhat lower. The QT interval (QTc), corrected by Bazett’s formula (QTc = QT/), has an upper limit of normal of 0.44 seconds in infants and children 6 months of age and older. The upper limit of normal is 0.47 seconds in the first week of life and 0.45 in the first 6 months.

Cardiac Catheterization

A cardiac catheterization includes one or more of the following:

Although major advances have been made in deriving physiologic measures of cardiac function by means of echocardiography and magnetic resonance imaging (MRI), cardiac catheterization remains the gold standard for many of these, in addition to providing images of radiologic anatomy and function (Odegard et al., 2004). In addition, the number of interventional procedures performed or proposed is expanding, while the patient population is increasingly complex. New procedures, including stenting of a variety of vessels, closure of atrial and ventricular septal defects, percutaneous placement of prosthetic valves, and hybrid repairs of defects jointly in the catheterization laboratory by both cardiac surgeon and an interventional cardiologist have expanded therapeutic options for patients (Kapoor et al., 2006; Galantowicz et al., 2008; Lurz et al., 2008). Transvascular replacement of pulmonary and aortic valves is also on the near horizon. These increasingly complex procedures require the attendance of an anesthesiologist, and the care rendered transcends beyond keeping the child from moving. The physiologic state of children undergoing such procedures can be tenuous, and the anesthetic care is provided in an environment that is foreign to many anesthesiologists (Cua et al., 2007) (See Chapter 21, Anesthesia for Children with Congenital Heart Disease Undergoing Non-Cardiac Surgery, Closed Cardiac Procedures, and Cardiac Catheterization). The environment may become increasingly foreign, because there are proposals to develop MRI suites for cardiac catheterization procedures in order to lower the radiation exposure to patients. More and more complex electrophysiologic procedures are also being done, some of which can take many hours to complete. All of these factors have contributed to a general shift from sedation toward general anesthesia in the pediatric cardiac catheterization laboratory. Additionally, transesophageal echocardiography guidance is required for many of the procedures, which requires endotracheal intubation.

Over the years, cardiac catheterization has become safer despite the increasing complexity of the procedures. Beyond routine potential anesthetic complications, complications include cardiac perforation and arrhythmias from catheter manipulation, embolization of closure devices, hypothermia (readily addressed with forced-air warming mattresses) and brachial-plexus injury from positioning (cardiologists try to extend the arms over the head to remove the upper arms from the field of the lateral x-ray tube), and vascular complications. Femoral venous injury is marked by a bluish color to the leg, whereas femoral arterial insufficiency is marked by a cold, white leg. However, these are almost always transient.

Vitiello and colleagues (1998) studied pediatric cardiac catheterization laboratory complications in a consecutive series of almost 5000 patients. One or more complications occurred in 8.8% of children. Vascular complications were most common (in 3.8%) and death occurred in 0.14%, most commonly in infants. With the large introducer sheaths needed for many newer interventional procedures, one might expect the incidence of vascular complications to increase.

Echocardiography

For many infants and children, echocardiography has supplanted the need for cardiac catheterization, and many children now have cardiac surgery based on the results of echocardiography rather than catheterization. For some problems, such as AV valve anatomy, echocardiography is distinctly superior to catheterization (see www.expertconsult.com for further discussion). The thin chests and lack of hyperinflated lungs in children mean that echocardiographic views in children are often superior to those in adults. In common parlance, echocardiography also includes the use of Doppler to assess blood flow and to infer intracardiac pressures, shunts, and pressure gradients (see Doppler Echocardiography Basics, p. 110).

Modern echocardiography is derived from sonar used on ships. A brief electrical impulse is sent to a transducer, which converts (transduces) it and emits it as high frequency sound. As the sound wave encounters a change in density, such as a cardiac structure, some of the sound energy continues on and some is reflected. The echo transducer acts as a receiver and converts the transmitted sound to electrical energy, which is sent to an image processor and displayed on a screen. Because the speed of sound through the body is both known and constant, the distance of the structure from the transducer is easily calculated. This process occurs many times each second. The original format was A-mode echocardiography, where A stood for amplitude. The intensity of the reflected wave was shown as the height or amplitude, like a series of mountain peaks. The first clinical use was echoencephalography, where a beam was directed across the skull looking for shifts of midline structures. The next modification was B-mode echocardiography, where the intensity of the reflected wave was shown as the brightness of a dot. If the reflected waves were recorded on a rolling piece of paper, the series of dots would meld into a series of moving lines, with each line representing a separate cardiac structure with its own distinctive movement pattern. This was the M-mode echocardiograph. M-mode echocardiography was particularly useful for measuring vessel and chamber size and thickness. Although it showed only a one-dimensional representation of the heart (an “ice pick view”), ventricular function could be estimated by ventricular end-systolic and end-diastolic dimensions or by measuring systolic time intervals. The next major advance was two-dimensional echocardiography. Several (32, then 64) separate B-mode ultrasound emitting transducers were mounted together such that a fan-shaped series of lines of light and dark was created. These were repeated rapidly and formed a real-time image of the moving heart. This was exactly analogous to a black-and-white television set, where there is not really a picture but rather a series of rapidly refreshed lines of bright dots that the eyes and brain integrate into a picture. Quality improved with the development of phased array transducers, which generated multiple B-mode lines electronically. These transducers were miniaturized so that they could be mounted onto a gastroscope, resulting in transesophageal echocardiography. Current pediatric transesophageal probes are useful down to infants who weigh approximately 3 kg. Finally, electronic manipulation has allowed the representation of three-dimensional views of the heart. This is currently available on transesophageal probes, although as of this writing, it is not available on pediatric transesophageal probes. Intraoperative transesophageal echocardiography has been shown in several studies to improve intraoperative surgical repairs in a cost-effective manner and is routine in centers with the capability (Sutherland et al., 1989; Muhiudeen et al., 1992; Bettex et al., 2005). This technique is not totally without risk, however. In addition to the risks of local pharyngeal and esophageal injury, which attend its use in both children and adults, introduction or manipulation of the probe can cause acute and massive obstruction of the easily compressible aorta or large bronchi in infants.

Cardiac shunts, particularly right-to-left shunts, can be qualitatively visualized through contrast echocardiography with extraordinary sensitivity in terms of both the presence of the shunt and the site of the shunt. A milliliter or two of air is drawn up into a syringe of saline or other fluid and vigorously agitated. The gross air is expelled and the aerated fluid rapidly injected into a systemic vein. The numerous tiny bubbles (microcavitations) appear somewhat like the snow in an agitated snow globe. Normally these transverse the right side of the heart to be eliminated via the pulmonary capillaries into the alveoli, leaving the left atrium, left ventricle, and aorta without any contrast. If there is a right-to-left shunt, these bubbles pass to the left atrium (atrial level shunt), ventricle (ventricular level shunt), or descending aorta (ductal level shunt). This technique is not helpful in determining whether there are multiple levels of shunts (unlike catheterization), and it is not particularly qualitative, also unlike catheterization.

A variety of advanced measurement techniques, such as automated (endocardial) border detection and tissue velocity measurement are available, but they are not generally used in routine intraoperative clinical management. They are useful to more fully quantitate myocardial mechanics.

Doppler Echocardiography Basics

This technique utilizes the Doppler phenomenon, the frequency shift well-known to anyone who has heard a train whistle approach with increasing frequency and then depart with decreasing frequency. In general, this technique involves insonating the heart with a high-frequency sound wave. Using fast Fourier transformation and filtering to prevent measuring the velocity of other structures, such as heart and vascular components, the velocity (and direction) of moving blood can be determined. There are three modes of Doppler in routine use. Continuous mode shows the fastest velocity along the Doppler beam, but cannot resolve distance. Pulse wave mode can resolve distance from the transducer. Thus, it can be “aimed” from the real-time two-dimensional echocardiograph image so that specific areas of the heart can be interrogated. Finally, color-flow mapping allows the color coding of specific pixels on the two-dimensional echocardiograph in essentially real time to allow superposition of blood flow and cardiac anatomy.

Data obtained from Doppler interrogation can be used to derive a wide variety of physiologic information. For example, cardiac output (or output across a specific valve or area) can be determined as follows:

CSA = cross-sectional area, and Vm = mean flow velocity. Vm is the integral of the flow under the spectral Doppler velocity display, also known as time-velocity integral (TVI). Thus, with each beat:

and

If flow is measured across both the aortic and pulmonary valves, the presence and degree of an intracardiac shunt can be determined.

Valve area can also be determined by Doppler examination by using the principle of continuity. This states that in the absence of shunts that either add or subtract volume, the stroke volume at any two points in the heart must be equal. The continuity principle leads to the continuity equation, where CSA₁ × TVI₁ = CSA₂ × TVI₂. Knowing three of the values in the equation allows one to rearrange the equation and solve for the fourth.

Consider the example of aortic stenosis. CSA₂ is aortic valve area, CSA₁ and TVI₁ are measured in the left ventricular outflow tract, and TVI₂ is a high-velocity jet across the stenotic valve.

The continuous-wave function of Doppler echocardiography allows the calculation of pressure gradients. If the flow between the two points occurs across a narrow orifice, for example in aortic stenosis, blood-flow velocity increases. Measuring the peak velocity allows the calculation of a pressure gradient. This technique is widely used in echocardiography but has certain limitations. The angle of interrogation of the Doppler beam must be accurately aligned with the direction of blood flow. The more poorly aligned the direction of blood flow is with the Doppler beam, the greater the underestimation of the true velocity of blood flow. Mathematically, the degree of underestimation is described by the cosine of the angle theta (θ) between the direction of blood flow and the Doppler beam, the angle of incidence. The cosine function is nonlinear between 0 degrees (cosine 0 = 1) and 90 degrees (cosine 90 = 0). For example, if θ is 30 degrees, cosine 30 = 0.87. Therefore, at an angle of 30 degrees, the measured velocity is only 87% of the true blood velocity. The software of the echocardiography works on the assumption that the direction of blood flow and the Doppler beam are in perfect alignment.

The equation that relates peak velocity to pressure is known as the modified Bernoulli equation, where V is velocity in meters/sec:

Readers are referred to textbooks of echocardiography for a complete derivation of the modified Bernoulli equation. Assuming good alignment of the Doppler beam and the direction of blood flow, peak velocity is now easily converted into the pressure gradient across the lesion (Fig 4-25).

FIGURE 4-25 Transesophageal echocardiogram in aortic stenosis. A, Deep transgastric view with very good alignment of the Doppler beam (dashed arrow) with the left-ventricular outflow tract and aortic valve. AV, aortic valve, LA, left atrium, LV, left ventricle, LVOT, left-ventricular outflow tract. B, Spectral Doppler tracing of the velocity of blood as it accelerates across the stenotic aortic valve. Velocity (y axis) is plotted versus time (x axis). The peak velocity is 3.16 m/sec, which translates into a peak gradient of 40 mm Hg using the modified Bernoulli equation.

Anesthetic Effects on Ion Currents

Both volatile anesthetics and several intravenous anesthetics can affect many of the voltage-dependent myocardial ion currents, although studies in immature myocardium are limited. Halothane, for example, can inhibit I_Ca,L the L-type calcium current in fetal as well as adult myocardium (Fig. 4-30). Baum and Klitzner (1991) have shown that both halothane and isoflurane can decrease the height of the action potential in neonatal right-ventricular papillary muscle, consistent with an effect on trans-sarcolemmal calcium entry. A variety of anesthetics are known to shift the activation and inactivation kinetics of I_Ca,L. These include halothane and ketamine (Baum et al., 1994). These might decrease calcium entry via I_Ca,L in cells with more negative resting potential, such as immature myocardial cells.

FIGURE 4-30 Calcium current (I_Ca,L) measured from a single ventricular myocyte isolated from a 28-day-old rabbit fetus (term = 31 days). Control to the left, 0.125% halothane to the right. The axes are picoamps (pA) and milliseconds (ms).

(From Baum VC, Palmisano BW: The immature heart and anesthesia, Anesthesiology 87:1529, 1997.)

BAY K8644, a calcium-channel agonist, can only partially prevent or reverse halothane- or isoflurane-induced depression in right-ventricular papillary muscles of neonatal rabbits (Baum and Klitzner, 1993). This is consistent with the view that mechanisms other than decreased trans-sarcolemmal calcium entry contribute to anesthetic-induced myocardial depression. Halothane, even in clinically appropriate doses, reversibly inhibits Na⁺ -Ca²⁺ exchange in neonatal ventricular myocytes. This provides for an additional mechanism for the more pronounced volatile anesthetic-induced depression of immature myocardium, with its increased reliance on Na⁺-Ca²⁺ exchange relative to adult myocardium (Baum et al., 1994).

A variety of volatile and intravenous anesthetics can affect the various K⁺ channels, with implications for arrhythmia generation and anesthetic-induced myocardial preconditioning (Baum, 1993; Buljubasic et al., 1996; Stadnicka et al., 1997; Stadnicka et al., 2000; Fujimoto et al., 2002; Suzuki et al., 2003). However, there is no information on the effects in the young or immature heart, and the phenomenon of anesthesia-induced preconditioning, mediated at least in part by potassium current, has not been fully evaluated in immature myocardium.

Anesthetic Effects on the Conduction System

In vitro, infant rabbit hearts are more resistant than adult rabbit hearts to the direct sinus-node pacemaker depression of halothane and isoflurane (Palmisano et al., 1994). Maximal depression of the sinus node is about 10%, suggesting that indirect effects rather than direct effects are primarily responsible for the bradycardia seen during clinical anesthesia. It is likely that cholinergic effects play a major role, as baseline cholinergic tone is present in neonates and infants, and under halothane and nitrous-oxide anesthesia there is a dose-related increase in heart rate with atropine (Palmisano et al., 1991b).

For both infant and adult hearts, the sinus rate is more resistant to the effects of halothane and isoflurane than are other measurements of cardiac function (Palmisano et al., 1994). These anesthetics decrease spontaneous pacemaker discharge by decreasing the rate of diastolic depolarization and increasing the action potential duration (Bosnjak and Kampine, 1983). In the adult heart, where it has been studied, halothane decreases the rate of diastolic depolarization and moves the maximal diastolic depolarization (V_m) closer to threshold potential. These two effects counterbalance with little effect on sinus rate (Hauswirth and Schaer, 1967).

Halothane prolongs AV conduction time more than isoflurane, and the effect in infants is greater than it is in adults (Palmisano et al., 1994). The age difference for isoflurane is much less marked than for halothane. There has been little information evaluating the effects of the newer inhalational agents on sinus-node function in healthy children. Sevoflurane and isoflurane have little effects on sinus node function or AV conduction in children with pre-excitation conditions such as Wolff-Parkinson-White syndrome, suggesting they have little if any effects on normal tissue (Chang et al., 1996; Sharpe et al., 1999). In a study of in vitro rabbit hearts, propofol had no effects on atrial or AV conduction, although it did prolong AV conduction in adult hearts of rabbits (Wu et al., 1997).

Anesthetic Effects on Myocardial Metabolism

Reactivity of the coronary vasculature to a variety of physiologic and pharmacologic stimuli has been shown to be present in newborn animals of a variety of species (Toma et al., 1985; Downing and Chen, 1986; Buss et al., 1987; Hickey et al., 1988; Ascuitto et al., 1992). In infant rabbit and in vitro fetal lamb hearts, both halothane and isoflurane vasodilate coronary arteries and result in increased coronary flow, and these effects are similar to those in adult hearts of those animals (Palmisano et al., 1994; Davis et al., 1995). Isoflurane decreases oxygen consumption, which coupled with increased coronary flow, results in relative overperfusion (Hickey et al., 1988; Stowe et al., 1991; Palmisano et al., 1994). Because isoflurane causes a greater decrease in heart rate in adults, the decrement in oxygen consumption is more pronounced in adult hearts than in neonatal hearts (Palmisano et al., 1994). However, when heart rates are kept similar, there are no age differences. In the hypoxic, stressed, neonatal lamb, neither halothane nor isoflurane alter redistribution of blood flow to vital organs, including the heart (Cameron et al., 1985; Brett et al., 1989).

Myocardial flow in the neonatal lamb decreases at 1 MAC isoflurane (from 250 to 88 mL/100g per minute), but this fall is in exact proportion to the decrease in myocardial oxygen consumption, resulting in unchanged myocardial oxygen extraction and endocardial-to-epicardial flow ratios (Brett et al., 1987). Consistent with this, 1.5% halothane was not found to affect steady state levels of myocardial high energy phosphates or intracellular pH in neonatal myocardium, despite a decrement in myocardial performance (McAuliffe and Hickey, 1987). This indicates that uncoupling of oxidative phosphorylation does not account for volatile anesthetics’ depressant effect on myocardial function.

Anesthetic Effects on Systolic Function

Young hearts show an increased susceptibility to myocardial depression from the volatile anesthetics (Cook et al., 1981). Although it has been suggested that the apparent increased hemodynamic depression in the young human heart may be the result of differences in anesthetic uptake and distribution, several studies have indicated that the increased hemodynamic effects of the volatile anesthetics are a result of increased direct action on the myocardium in the immature heart (Barash et al., 1978; Boudreaux et al., 1984; Schieber et al., 1986; Murray et al., 1992).

A major effect on myocardial contractility is via limitation of calcium availability to the contractile apparatus. Trans-sarcolemmal and sarcoplasmic reticular calcium flux are altered with the net effect of depleting intracellular stores (Nakao et al., 1989; Wilde et al., 1991; Frazer and Lynch, 1992; Schmidt et al., 1993; Wilde et al., 1993). Halothane depresses contractility more than isoflurane does (Lynch, 1986; Krane and Su, 1987; Baum and Klitzner, 1991; Palmisano et al., 1994). Halothane decreases peak intracellular calcium concentration more than isoflurane does and is a more potent depressant of contractile function in vitro in both neonatal and adult hearts (Komai and Rusy, 1987; Krane and Su, 1989; Lynch, 1990; Bosnjak et al., 1992; Pan and Potter, 1992; Palmisano et al., 1994). Although there were no age effects of isoflurane, halothane was more depressant to neonatal hearts than adult hearts. However, there may be some dependence on species, because a study in isolated rat atrium did not find that the depression was dependent on age (Rao et al., 1986).

Studies in neonatal lambs have shown that both halothane and isoflurane decrease cardiac output to the same degree that they decrease myocardial oxygen consumption (Cameron et al., 1985; Brett et al., 1987; Brett et al., 1989). Isoflurane at 1 MAC decreased blood pressure primarily by decreasing cardiac output rather than by affecting vascular resistance (Brett et al., 1987). Results in human neonates, infants, and children are more variable, probably because of differing techniques and the confounders of changes in heart rate and afterload. Nicodemus, in an early study, showed increased hypotension in neonates and less hypotension in older children (Nicodemus et al., 1969).

Murray et al. (1992), using echocardiographic indexes of cardiac function, could show no difference between halothane and isoflurane at equipotent concentrations. Sevoflurane has been shown to cause less myocardial depression in young children than halothane, although very young infants were not studied (Holzman et al., 1996).

Anesthetic Effects on Diastolic Function

Anesthetic effects of calcium flux that might impair systolic function could also affect diastolic function, which requires temporary reuptake of released calcium into stores. Indexes of diastolic relaxation show a more depressant effect of halothane than isoflurane, and the effects are greater in infant rabbit hearts than in adult rabbit hearts (Palmisano et al., 1994). There was no age effect seen with isoflurane. This prominent effect of halothane may be a reflection of immature myocardium’s limited capacity to remove calcium from the contractile proteins. The principle mechanism for relaxation in adult myocardium is sequestration of calcium in the sarcoplasmic reticulum, and this is relatively undeveloped in immature myocardium; thus, these hearts may depend more on removal via Na⁺-Ca²⁺ exchange (Hoerter et al., 1981; Bers and Bridge, 1989; Fisher and Tate, 1992). It is possible that developmental changes in the actin-regulatory proteins could also affect anesthetic mediation of relaxation.

Anesthetic Effects on Autonomic Control

Halothane, isoflurane, fentanyl, sevoflurane, and nitrous oxide all depress baroreceptor control of heart rate through the central nervous system, autonomic ganglia, and the heart (Biscoe and Millar, 1966; Duke et al., 1977; Duncan et al., 1981; Seagard et al., 1982; Seagard et al., 1983; Kotrly et al., 1984; Murat et al., 1988; Murat et al., 1989). The effect of halothane is more pronounced in younger animals when animals are made pharmacologically hypertensive, but there does not seem to be an age effect when animals are made pharmacologically hypotensive (Wear et al., 1982; Dise et al., 1991; Palmisano et al., 1991a). In (anesthetized) infants undergoing ligation of a patent ductus arteriosus, a heart rate change is typically not seen with acute alterations in blood pressure (Gregory, 1982). Constant showed that while halothane preserves cardiac vagal activity in children, it does not preserve baroreceptor activity any better than sevoflurane (Constant et al., 1999; Constant et al., 2004). Murat showed that isoflurane-mediated tachycardia may be less pronounced in neonates (Murat et al., 1989). Although acute increases in the inspiratory concentration of desflurane or isoflurane can cause an abrupt increase in heart rate and systemic blood pressure from stimulation of the tracheobronchial tree, this effect is not seen with acute increases in sevoflurane concentration (Ebert et al., 1995).

Hemodynamic Effects of Specific Agents