Cardiac Physiology and Pharmacology

Fetal Circulation

In utero, the placental gas exchange provides the fetus with poorly oxygenated blood; the partial pressure of oxygen (P o ₂ ) in the umbilical vein is approximately 30 mm Hg, and in the umbilical arteries it is approximately 16 mm Hg. The fetal lungs are fluid filled and only minimally perfused (10%–15% of the cardiac output). The normal postnatal circulation can be described as a serial circuit: two pumps, the right ventricle (RV) and left ventricle (LV), support two different resistance systems, the pulmonary and systemic vasculatures, one after the other. In contrast, the fetal circulation is better explained by the concept of a parallel circuit: both ventricles provide systemic blood flow and a variety of fetal shortcuts or connections allow for mixing of oxygenated and deoxygenated blood ( Fig. 18.1 ). Oxygenated blood from the placenta returns via the umbilical vein to the portal venous system, where 30% to 50% of the blood flow is shunted across the ductus venosus to the inferior vena cava (IVC), bypassing the liver and thereby maintaining higher oxygenation and velocity. The rest of the umbilical venous blood passes through the hepatic microcirculation into the suprahepatic IVC.

The IVC blood entering the right atrium (RA) is a mixture of bloodstreams with different velocities and saturations: the low-velocity, deoxygenated venous return from the lower body and hepatic veins and the high-velocity, oxygenated umbilical venous blood from the ductus venosus. Valve-like tissue in the RA (eustachian valve) and the Chiari network preferentially direct the high-velocity bloodstream from the IVC across the foramen ovale into the left atrium (LA), bypassing the RV and pulmonary vessels. In the LA, the oxygenated blood mixes with the minimal amount of venous return from the pulmonary circulation and is then ejected by the LV into the ascending aorta and the major vessels of the aortic arch. This blood, with a saturation of 65% to 70%, provides the oxygenation for the growing heart and brain.

Most of the venous return from the superior vena cava (SVC) and about 20% of the IVC blood flow (mainly the low-velocity, deoxygenated part) reach the RV and are pumped into the pulmonary artery (PA), where the high pulmonary resistance in the nonexpanded lung redirects 90% of the blood flow into the descending aorta via the ductus arteriosus . The bulk of the blood flow in the descending aorta is generated by the RV, with minor contributions from the LV. The blood has a saturation of only 55% to 60%; two-thirds of it returns to the placenta for oxygenation, and the rest is distributed to the intestines, the kidneys, and the lower part of the body ( Fig. 18.2 ).

The fetal circulation has to support a growing fetus in a relatively cyanotic atmosphere (highest oxygen saturation, 65% to 70%). This difficult task is further complicated by the parallel circuit, which creates increased workload for the RV, and the limitations of the fetal shortcuts, which add additional volume load by incomplete shunting of oxygenated and deoxygenated blood. Initially, our understanding of the fetal circulation was based mainly on experimental animal data, but recent advances in ultrasound technology have facilitated assessment and monitoring of fetal cardiovascular parameters, especially stroke volume and cardiac output, under various conditions throughout the gestational period. RV stroke volume has been found to increase from about 0.7 mL at 20 weeks to 7.6 mL at 40 weeks, and LV stroke volume increases from 0.7 mL to 5.2 mL. The combined fetal cardiac output of both ventricles is estimated to be 400 to 425 mL/kg per minute, with an RV dominance because of the increased volume load. At 38 weeks, the RV provides approximately 60% of the combined cardiac output ( E-Table 18.1 ). Intrauterine growth restriction and placental compromise are associated with redistribution of cardiac output and relative changes in the size of the foramen ovale. A functional placenta, the fetal cardiovascular high-output state, greater hemoglobin concentrations, and additional alterations in oxygen binding and release (hemoglobin F, increased 2,3-diphosphoglycerate [2,3-DPG]) are all necessary to provide adequate tissue oxygenation for the developing fetus.

Until recently, CHD was thought to be relatively well tolerated in utero, but growing evidence suggests that fetal cardiovascular defects can induce intrinsic autoregulatory changes in cerebral perfusion and thereby compromise brain development. Ultrasound and magnetic resonance imaging demonstrate that 25% to 40% of neonates with CHD have neurologic abnormalities before any surgical intervention.

Transitional Circulation

At birth, a variety of humoral, biochemical, and physiologic changes occur abruptly. First, the placental circulation is eliminated shortly after the lungs expand. Second, expansion of the lungs to a normal functional residual capacity (FRC) results in an optimal geometric relationship of the pulmonary microvasculature. Third, air entering the lungs causes the alveolar P co ₂ to decrease and the alveolar P o ₂ to increase. These three factors act in concert to markedly reduce pulmonary vascular resistance (PVR). The net effect is a considerable increase in pulmonary blood flow, which augments pulmonary venous return to the left heart. Along with elimination of the placenta and the low-resistance umbilical circulation, the LV is suddenly subjected to increased volume and afterload ( Table 18.1 ). Typically, LV end-diastolic pressure, and thus LA pressure, increases enough to exert hydrostatic pressure on the septum primum, resulting in functional closure of the foramen ovale. In contrast to the increased stress for the LV, the RV is relatively unloaded by the transition to extrauterine life.

The three fetal connections (ductus arteriosus, ductus venosus, and foramen ovale) close over a variable period after birth. The ductus arteriosus functionally (but not anatomically) closes in 58% of normal full-term infants by day 2 after birth and in 98% by day 4. Although many substances (such as eicosanoids) have been implicated in initiating constriction of the ductus, initial constriction probably occurs primarily in response to the increased arterial oxygen tension and the reduction in circulating prostaglandins that follow separation of the placenta. The response to oxygen is age dependent: term neonates usually demonstrate effective constriction of the smooth muscles in the ductal tissue when exposed to oxygen, whereas preterm infants respond poorly and often require medical (prostaglandin inhibitor) or even surgical therapy. Additional catecholamine-induced changes in PVR and systemic vascular resistance (SVR) and other substances such as acetylcholine contribute to ductal closure. Within 2 to 3 weeks, functional constriction is followed by a process of ductal fibrosis, leaving a band-like structure, the ligamentum arteriosum. With ligation of the umbilical vein, the portal pressure falls, triggering functional closure of the ductus venosus. This process rarely requires more than 1 to 2 weeks; by 3 months only fibrous tissue, the ligamentum venosum, is left.

The foramen ovale is functionally closed when the LA pressure exceeds the RA pressure, but it remains anatomically patent in most infants, in 50% of children younger than 5 years of age, and in 25% to 30% of adults. Echocardiographic studies have confirmed right-to-left shunting via the foramen ovale in healthy infants emerging from general anesthesia, and this can be a significant cause of persistent arterial desaturation at that time despite ventilation with 100% oxygen.

Neonatal Cardiovascular System

Compared with the adult, the neonatal myocardium is immature and incompletely developed ( Table 18.2 ). Differences in cytoarchitecture and metabolism account for many of the functional limitations. The neonatal heart contains fewer muscle cells and more connective tissue than the adult myocardium. Contractile elements represent only 30% of the total cardiac mass, in contrast to 60% in the adult. The ratio of surface area to mass and water to collagen content are greater in neonates than older children. There are fewer myofibrils within the muscle cells, and they tend to be less organized (i.e., not parallel to the long axis of the cell). The sarcoplasmic reticulum and the T-tubule network, both important components of rapid and effective calcium regulation, are incompletely developed, and the immature myocardium relies substantially on the calcium flux through the sarcolemma to initiate and terminate contraction. One practical consequence of this disorganized and immature myocardium is a greater degree of contractile dysfunction in the infant exposed to substances that decrease extracellular ionized calcium, such as citrate (blood products) and albumin; there is also increased sensitivity to inhalational anesthetics and calcium channel blockers.

Reduced numbers of underdeveloped mitochondria and maturational differences in various signaling pathways and related messenger systems are also characteristic of the neonatal myocardium. Immature mitochondrial enzyme activity for fatty acid transport may explain the primary use of carbohydrates and lactates as energy sources and might be a reason for the greater anaerobic tolerance and faster recovery after periods of ischemia. A variety of developmental changes in contractile proteins occur from fetal through early postnatal life, including changes in pH, calcium sensitivity, and adenosine triphosphate (ATP) hydrolyzing activity. The key features of the immature cardiac function are summarized in Table 18.2 .

The increased amount of noncontractile tissue in the neonate decreases ventricular compliance and limits the response to an increased preload. Compliance of both ventricles progressively increases during fetal life and the postnatal period, so that maximal stroke volume occurs at a significantly reduced atrial pressure in the neonate compared with the fetus ( Figs. 18.3 and 18.4 ). The high metabolic rate of the neonate (oxygen consumption, 6-8 mL/kg per minute, compared with 2-3 mL/kg per minute in the adult) requires a proportional increase in cardiac output. The neonatal heart meets this demand, in part, by a greater heart rate (HR). The cardiac output is commonly described as depending primarily on HR owing to a fixed stroke volume, but echocardiographic studies in human fetuses and neonates have demonstrated the capacity to increase stroke volume ( Fig. 18.5 ) In fact, the neonate uses both tachycardia and stroke volume adjustments to meet metabolic demand. On the other hand, neonates exhibit exquisite sensitivity to pharmacologic agents that produce negative inotropic or chronotropic effects. At birth, both ventricles are equal in mass and connected via a common septum. Increased pressures in one ventricle shifts the septum, decreasing compliance of the other ventricle. The net effect is a reduction in cardiac output. Neonates and infants often present with biventricular failure as a result of this interventricular dependence.

Immature autonomic regulation of cardiac function persists throughout the neonatal period. Both sympathetic and parasympathetic innervation of the heart can be demonstrated at birth. However, evidence suggests that development of the sympathetic nervous system is incomplete at both the postganglionic nerve-receptor level and the receptor-effector level. The sympathetic system reaches maturity by early infancy, whereas the parasympathetic system reaches maturity within a few days after birth. The relative imbalance of these two components of the autonomic nervous system at birth may account for the clinical observation that neonates are predisposed to marked vagal responses to a variety of stimuli.

Pulmonary Vascular Physiology

At birth, pulmonary vascular development is incomplete. Lung sections demonstrate a diminished number of arterioles, and the arterioles exhibit thick medial muscularization ( Fig. 18.6 ). The pulmonary vasculature matures during the first few years of life. During this period, arterioles proliferate faster than alveoli, and the medial smooth muscle thins and extends more distally in the vascular tree. PVR continues to decrease as long as pulmonary mechanics and alveolar gas composition remain favorable, with a significant decrease occurring immediately after birth as the result of lung expansion and oxygenation. Progressive remodeling of the pulmonary vasculature facilitates further decreases in PVR (assuming normal physiology) during the first 2 to 3 months of life; by 6 months of age, the PVR has almost reached adult levels.

The fetal pulmonary vasculature is extremely reactive to a number of stimuli. Hypoxia, acidosis, increased levels of leukotrienes, and mechanical stimulation (e.g., coughing on an endotracheal tube) can cause significant and prolonged increases in PVR (e.g., reactive pulmonary hypertension). On the other hand, acetylcholine, histamine, bradykinin, prostaglandins, β-adrenergic catecholamines, and nitric oxide (NO) are strong vasodilators. In the first days after birth, many pathophysiologic conditions can trigger severe and sustained increases in PVR and prevent the normal adjustment to extrauterine life ( E-Table 18.2 ). The acute load imposed on the RV can induce diastolic dysfunction and promote right-to-left shunting via the foramen ovale. Once PVR exceeds the SVR, a right-to-left shunt develops through both the ductus arteriosus and the foramen ovale. This situation is called persistent fetal circulation , and it can result in a life-threatening hypoxemia that may require inhaled NO, sildenafil, or extracorporeal support (i.e., extracorporeal membrane oxygenation) (see Chapter 21 ) to provide oxygenation and sustain life.

Pulmonary vascular occlusive disease (PVOD) describes the structural changes in the pulmonary vasculature after long-standing exposure to abnormal pressures and flow patterns in utero and after birth. Lung biopsies demonstrate thickened muscle layers in the small pulmonary arteries, intimal hyperplasia, scarring, and thrombosis as well as a decreased number of distal (intraacinar) arteries. Over time, these changes lead to a progressive and ultimately irreversible obstruction to pulmonary blood flow with increases in PVR and PA pressures. The very muscularized pulmonary arteries are also extremely sensitive to pulmonary vasoconstrictors, which can easily trigger a pulmonary hypertensive crisis.

Many cardiac defects are associated with abnormal pulmonary flow patterns and can be categorized into three basic groups:

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  Exposure of the pulmonary vasculature to systemic arterial pressures and high flow: The classic example is a large, nonrestrictive ventricular septal defect (VSD) with rapid progression of PVOD.

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  Exposure of the pulmonary vasculature to high flow without increased pressure: Large atrial septal defects (ASDs) and small, restrictive patent ductus arteriosus (PDA) defects fall into this category. PVOD develops much more slowly in this setting.

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  Obstruction of pulmonary venous drainage resulting in increased PA pressures: Pulmonary vein stenosis (e.g., total anomalous pulmonary venous return [TAPVR], cor triatrium) or increased LA pressures (e.g., mitral atresia, congenital aortic stenosis, severe coarctation) can cause backpressure in the pulmonary vasculature and induce PVOD.

The muscle tone in the pulmonary arteries is regulated by numerous factors, and various therapeutic interventions can be used to manipulate the PVR ( Table 18.3 ) :

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  Arterial oxygen tension (Pa o ₂ ): Alveolar as well as arterial hypoxia increases PVR. A Pa o ₂ value less than 50 mm Hg, especially when associated with an acidic pH (<7.4), leads to significant pulmonary vasoconstriction. On the other hand, increased inspired oxygen can lead to pulmonary vasodilation and overcirculation.

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  Arterial carbon dioxide tension (Pa co ₂ ): Hypercapnia increases PVR, independent of the blood pH. In contrast, hypocapnia induces alkalosis and thereby decreases PVR. Reliable pulmonary vasodilation can be achieved with a Pa co ₂ of 20 to 33 mm Hg and a pH of 7.5 to 7.6.

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  pH: Respiratory and metabolic acidosis increase PVR; alkalosis reduces PVR.

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  Lung volumes: PVR is optimized at a lung volume close to the FRC; larger volumes compress small intraalveolar vessels, and smaller volumes can cause atelectasis and vascular collapse.

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  Stimulation of the sympathetic nervous system: Catecholamine surges from stress, pain, or light anesthesia can trigger significant increases in PVR.

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  Vasodilators: Most intravenous (IV) agents used for pulmonary vasodilation also affect the systemic circulation and induce hypotension. Alternatively, inhaled substances such as NO or prostacyclin can provide a more selective pulmonary vasodilation (see “ Cardiovascular Pharmacology ”).

In summary, the pulmonary vasculature undergoes a complex maturation process that can be influenced by a multitude of external factors and congenital heart defects. Persistent fetal circulation and PVOD are examples of inadequate adaptation and development. In cases of increased PVR, ventilator strategies using greater inspired oxygen concentrations, lung volumes close to the FRC, and interventions aiming for a Pa o ₂ greater than 60 mm Hg, a Pa co ₂ of 30 to 35 mm Hg, and a pH of 7.5 to 7.6 can improve pulmonary blood flow.

Shunting

Shunting occurs when blood return from one circulatory system (systemic or pulmonary) is recirculated to the same system, completely bypassing the other circulation. For example, if deoxygenated blood from the systemic veins flows directly to the aorta, the result is a right-to- left shunt with recirculation of deoxygenated blood in the systemic circulation. In contrast, redirection of oxygenated blood from the pulmonary veins to the PA causes a left-to-right shunt with recirculation of oxygenated blood within the pulmonary circulation. The terms physiologic and anatomic are often used to describe shunting. Basically, any kind of recirculation of blood within one circulatory system is called physiologic shunting . In most cases, physiologic shunting is caused by an anatomic shunt (i.e., a communication between the cardiac chambers or the great vessels), but physiologic shunting can also exist by itself, as in the classic transposition physiology.

To really understand the pathophysiology of shunting and its implications, it is important to introduce the concepts of effective and total systemic/pulmonary blood flows. Effective blood flow is the quantity of venous blood from one circulatory system that reaches the arterial system of the other circulatory system. Effective pulmonary blood flow is the volume of systemic venous blood reaching the pulmonary circulation, whereas effective systemic blood flow is the volume of pulmonary venous blood reaching the systemic circulation. Effective pulmonary blood flow and effective systemic blood flow are always equal, no matter how complex the lesions. Total blood flow , on the other hand, is the sum of recirculated and effective blood flow and a measure of the workload of the circulatory system. Total systemic and pulmonary blood flows are not equal. Even in healthy patients there is a small amount of normal physiologic shunting (e.g., thebesian cardiac veins, bronchial vessels), but with CHD the difference can be quite substantial. Physiologic shunting or recirculation should be viewed as a noneffective, superfluous load added to the essential nutritive blood flow (effective blood flow).

Anatomic shunts are communications between the two circulatory systems, either within the heart or at the level of the great vessels. They can be divided into simple and complex shunts, depending on the presence of additional outflow obstructions. In simple shunts without any additional outflow obstruction, the size of the communication (the so-called shunt orifice) determines the flow characteristics. For small orifices (restrictive shunts) with large pressure gradients across the communication, the size of the opening essentially regulates the amount of shunting. Changes in SVR or PVR have little influence. In contrast, for large orifices or nonrestrictive shunts (also classified as dependent shunts ), the quantity and direction of blood flow are controlled by the respective outflow resistances (i.e., the ratio of SVR to PVR) ( Table 18.4 and Fig. 18.7 ).

Complex shunts are defined by an additional outflow obstruction, which can be at various levels within the ventricle, valves, or great vessels and is often described as subvalvular, valvular, or supravalvular. These obstructions can be fixed (e.g., valvular stenosis) or variable (e.g., dynamic infundibular obstruction by muscle bundles) . Shunt flow and direction are determined by the combined resistance across the outflow obstruction and the pulmonary/systemic vascular beds. For severe obstructions downstream, SVR or PVR will have little influence on the shunt. Tetralogy of Fallot (TOF) is a good example of a complex shunt lesion. The amount of right-to-left shunt and therefore the amount of cyanosis are influenced by the degree and type of right ventricular outflow tract obstruction (RVOTO). This is especially evident in the setting of a dynamic infundibular obstruction, where changes in preload, contractility, and HR can lead to significant decreases in pulmonary blood flow and increased shunting ( Table 18.5 ).

Intercirculatory Mixing

The concept of intercirculatory mixing is often used to explain the unique physiology in children with transposition of the great arteries (TGA). In this cardiac defect, the aorta arises from the RV, transporting deoxygenated blood back to the right heart, and the PA originates from the LV, returning oxygenated blood to the pulmonary circulation (see Fig. 17.6 ). Unless there is some mixing of blood via an ASD, VSD, or PDA, this defect will result in a complete separation of the two systems, a parallel circulation with 100% physiologic shunting, or recirculation of oxygenated and deoxygenated blood that is incompatible with life once the fetal ductus arteriosus has closed. Effective pulmonary blood flow (i.e., deoxygenated blood reaching the pulmonary vascular bed for oxygenation) has to be provided by some form of right-to-left shunt; effective systemic blood flow (i.e., oxygenated blood returning to the systemic circulation) must be achieved by a left-to-right shunt. Intercirculatory mixing is the combined systemic and pulmonary effective blood flow and is only a small portion of the total blood flow. The bulk of the respective systemic and pulmonary total blood flows consists of recirculated blood ( Fig. 18.8 ). Usually the total blood flow and the volume in the pulmonary system are two to three times greater than in the systemic circulation.

The arterial saturation (Sa o ₂ ) is influenced by the volumes and saturations of recirculating and effective systemic blood flows and can be calculated with the use of the following equation:

Increasing the intercirculatory mixing will improve the arterial saturations, and in severely cyanotic neonates with TGA, intact ventricular septum, and inadequate atrial communication, a balloon atrial septostomy (balloon dilation of an existing patent foramen ovale or small ASD, either echo-guided at the bedside or under fluoroscopy in the catheterization laboratory) can be lifesaving. Additional measures to improve systemic and pulmonary venous saturations (e.g., blood transfusion, inotropic support, ventilatory strategies) can help to stabilize the arterial saturation.

Single Ventricle Physiology

Single ventricle physiology defines the circulation present in a wide variety of complex cardiac defects. It is characterized by complete mixing of systemic and pulmonary venous blood return at either the atrial or the ventricular level; the mixed blood is then distributed to both systemic and pulmonary circulations in parallel. The defects can consist of one anatomic single ventricle with severe hypoplasia and inflow or outflow obstruction of the other one (hypoplastic left heart syndrome [HLHS] or pulmonary atresia with intact ventricular septum) or even two well-developed ventricles with atresia of the outflow tract or severe obstruction (TOF with pulmonary atresia, interrupted aortic arch). In some lesions, a PDA is the only source of systemic or pulmonary blood flow; these are called duct-dependent circulations. In others, intracardiac communications provide adequate blood flow to both circulations ( Table 18.6 ).

Irrespective of the anatomic features, in single ventricle physiology the ventricular output (delivered by one or two ventricles) is the sum of the pulmonary and systemic blood flows. The distribution of the respective flows depends on the relative outflow resistances into the two parallel circulations. Oxygen saturations in the aorta and PA are equal. The severity and location of anatomic obstructions and the ratio of PVR to SVR determine the balance of flows to the two circulations

The following equation illustrates the various factors that influence the arterial saturation (Sa o ₂ ) in a single ventricle physiology:

Accordingly, three major variables determine arterial saturation and the initial management options for patients with single ventricle physiology:

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  The ratio of pulmonary to systemic blood flow ( Q̇ _pulm /Q̇ _sys ). With high Q̇ _pulm /Q̇ _sys , a greater percentage of the blood in the ventricle (or ventricles) is oxygenated because more fully saturated pulmonary venous blood is entering the heart to mix with desaturated systemic venous return. Saturations greater than 85% can be achieved only by significant pulmonary overcirculation. Q̇ _pulm /Q̇ _sys can be influenced by careful manipulations of the PVR/SVR ratio.

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  Systemic venous saturation (S _sys v o ₂ ): For a given Q̇ _pulm /Q̇ _sys and pulmonary venous saturation (S _pulm v o ₂ ), any decrease in S _sys v o ₂ causes a decrease in arterial saturation. Oxygen delivery and consumption are the basic determinants for Sv o ₂ . Adequate oxygen delivery depends on cardiac output and arterial oxygen content and thus on hemoglobin levels and arterial saturation. All measures that increase oxygen delivery (e.g., transfusion to increase the hematocrit to 0.45-0.50 or decrease oxygen consumption (e.g., adequate analgesia and sedation during painful procedures) improve arterial saturations.

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  Pulmonary venous saturation (S _pulm v o ₂ ): Normally the blood in the pulmonary veins should be fully saturated (S _pulm v o ₂ = 100%) on room air, but lung disease, V̇/Q̇ mismatch, or large intrapulmonary shunts can cause pulmonary venous desaturation. V̇/Q̇ mismatch usually responds to therapy with increased inspired oxygen, whereas intrapulmonary shunts are refractory to oxygen therapy. Pulmonary venous desaturation will decrease arterial saturations.

Exercise Physiology in the Child With Repaired Congenital Heart Disease

Children with CHD, including those with lesions considered repaired, exhibit an array of abnormalities elicited during exercise testing consistent with reduced exercise capacity ( E-Table 18.4 ). It is worthwhile to review the various exercise testing abnormalities to gain insight into the limitations imposed by the presence of congenital heart lesions.

Oxygen consumption (V̇ o ₂ ) is equal to the product of cardiac output and O ₂ extraction. O ₂ extraction is equal to the arterial-venous oxygen content difference. Peak V̇ o ₂ is the greatest measure of V̇ o ₂ obtained during a progressively more difficult exercise test. V̇ o ₂ at rest is defined as 1 metabolic equivalent energy expenditure unit or 1 MET (approximately 3.5 mL O ₂ /kg per minute). A typical elite endurance athlete can reach 20 to 22 METs, or 70 to 77 mL O ₂ /kg per minute, at peak exercise. Activities of daily living require at least 4 METs or 14 mL O ₂ /kg per minute. Peak V̇ o ₂ is the best overall assessment of the capabilities of the cardiovascular system, but determination of normal values is difficult owing to the effects of age, gender, effort, and body composition (e.g., adipose tissue) on peak V̇ o ₂ . Nonetheless, peak V̇ o ₂ has been demonstrated to be a reliable predictor of hospitalization and mortality in patients with a wide variety of congenital heart lesions.

During exercise, the HR normally increases linearly with increases in V̇ o ₂ . Normal peak HR is generally defined (in beats per minute [beats/minute]) as 220 minus age in years. In children with chronotropic incompetence, which is defined as the inability to increase HR to greater than 80% of the predicted value at peak exercise, the relationship between HR and V̇ o ₂ is depressed. Chronotropic incompetence is an indicator of poor prognosis and is most commonly the result of sinus node dysfunction. By comparison, well-trained endurance athletes have a normal peak HR and a depressed HR/V̇ o ₂ relationship, because they can generate a larger-than-normal stroke volume increase as exercise progresses. The inability to increase stroke volume (discussed later) during exercise results in an increased HR/V̇ o ₂ relationship as a compensatory mechanism.

The oxygen pulse is the quantity of oxygen delivered per heartbeat. The peak O ₂ pulse is calculated by dividing the peak V̇ o ₂ by the peak HR. Because peak V̇ o ₂ = cardiac output × O ₂ extraction and because O ₂ extraction remains remarkably constant over a wide range of exercise, O ₂ pulse is proportional to stroke volume. Determination of normal peak O ₂ pulse is hampered by the same factors that confound determination of normal peakV̇ o ₂ . In addition, O ₂ pulse overestimates stroke volume in the presence of erythrocytosis and underestimates it in the presence of anemia or reduced arterial O ₂ saturation. O ₂ pulse is reduced in patients with impaired ventricular function, severe valvular regurgitation, or pulmonary vascular disease. It is also uniformly reduced in those with Fontan physiology as a consequence of the inability of this circulation to augment systemic ventricular preload during exercise.

The respiratory exchange ratio (RER) is defined as the ratio V̇ co ₂ /V̇ o ₂ (ratio of the volume of CO ₂ produced per minute to the volume of oxygen consumed per minute). A normal resting RER is between 0.67 and 1.0, depending on the precise composition of protein, carbohydrates, and fat in the diet. As exercise intensifies, anaerobic metabolism commences and the lactate threshold is reached; buffering of lactic acid with bicarbonate causes the carbon dioxide production (V̇ co ₂ ) to increase out of proportion to oxygen consumption (V̇ o ₂ ), resulting in an increased RER. An RER of 1.09 or greater is thought to indicate the onset of anaerobic metabolism and to be consistent with a good effort. Because RER increases only if anaerobic metabolism occurs, exercise limitation and low V̇ o ₂ owing to musculoskeletal problems or poor effort are associated with an RER less than this threshold.

The ventilatory anaerobic threshold (VAT) is used to identify the onset of anaerobic metabolism that occurs before V̇ o ₂ peaks and is relatively effort and motivation independent. As aerobic exercise progresses, minute ventilation (V̇ _E ) increases in direct proportion to V̇ co ₂ and V̇ o ₂ . When anaerobic metabolism commences and CO ₂ production increases as lactic acid is buffered, V̇ _E increases accordingly. VAT is the point at which V̇ _E /V̇ o ₂ and V̇ _E /V̇ co ₂ diverge, with V̇ _E increasing in proportion to V̇ co ₂ but out of proportion to V̇ o ₂ . An important characteristic of successful endurance athletes is the ability to reach and sustain effort at an anaerobic threshold that is a large percentage (80%–85%) of peak V̇ o ₂ .

Ventilation efficiency can be assessed with the use of the V̇ _E /V̇ co ₂ slope. This relationship is defined as 863 • V̇ co ₂ /[Pa co ₂ • (1 − V _D /V _T )], where V _D /V _T is the ratio of physiologic dead space to tidal volume. The V̇ _E /V̇ co ₂ slope can be thought of as the number of liters of ventilation required to eliminate 1 L of CO ₂ . Normal children have a V̇ _E /V̇ co ₂ slope of less than 28. To maintain a normal Pa co ₂ during exercise, children with increased V _D /V _T and reduced ventilatory efficiency have a greater than normal increase in V̇ _E and therefore a steeper V̇ _E /V̇ co ₂ slope. Increased V _D /V _T is the consequence of either reduced V _T in the setting of a normal V _D or pulmonary flow maldistribution and subsequent V̇/Q̇ mismatch that increases V _D . The latter is the major source of inefficient ventilation and steepening of the V̇ _E /V̇ co ₂ slope in children with cardiac disease.

In children with PA stenosis, (e.g., repaired TOF), pulmonary hypertension, or increased LA pressure from any cause (e.g., LV systolic or diastolic dysfunction, mitral valve disease), an increase in the V̇ _E /V̇ co ₂ slope is associated with increased mortality. When pulmonary stenosis is corrected in children with TOF, the V̇ _E /V̇ co ₂ slope and peak V̇ o ₂ improve.

Children with Fontan physiology also exhibit an increase in V̇ _E /V̇ co ₂ slope. These children have inherent nonhomogeneous pulmonary perfusion at rest owing to the lack of pulsatile pulmonary blood flow. In addition, there is poor recruitment of the distal pulmonary vasculature during exercise. The presence of a Fontan fenestration further contributes to this increase in the V̇ _E /V̇ co ₂ slope by allowing mixed venous blood high in CO ₂ to be shunted into the systemic circulation. This produces, via central chemoreceptor stimulation, an increase in V̇ _E out of proportion to V̇ co ₂ . Fontan fenestration closure eliminates this right-to-left shunt and reduces the V̇ _E /V̇ co ₂ slope but does not improve the peak V̇ o ₂ . The reason is that the primary limitation to increases in V̇ o ₂ during exercise in Fontan patients is the inherent inability of the pulmonary vascular bed to substantially increase surface area, flow, and preload delivery to the systemic ventricle.

Fontan Physiology

Francis Fontan, a French cardiac surgeon, described a new treatment for complex cardiac malformations with only one ventricle in 1971. To decrease the chronic volume overload for the single ventricle and normalize oxygenation, he separated the systemic and pulmonary circulations by directly connecting the systemic venous return (SVC and IVC) to the PA, without a pumping chamber. This created a circulation wherein pulmonary blood was driven solely by a nonpulsatile pressure gradient across the pulmonary vascular bed, with the single ventricle being the sole source of kinetic energy. All other shunt connections were interrupted. The original indication was tricuspid atresia, but over the years the classic Fontan technique has been modified in many ways and is now used for various complex cardiac lesions with single ventricle physiology, such as HLHS, double-inlet RV, and pulmonary atresia with intact septum (see also Chapters 17 and 23 ).

It is impossible to create a Fontan circulation at birth; high PVR and small vessel sizes prevent adequate pulmonary blood flow. In the neonatal period, palliative procedures such as stage I Norwood operation with aortic arch reconstruction, atrial septostomy, and aortopulmonary shunts (modified Blalock-Taussig shunt) or the Sano modification of the Norwood procedure (RV-to-PA conduit) aim for balanced systemic and pulmonary blood flows, allowing the infant to grow for several months despite cyanosis and volume load on the ventricle. At the age of 3 to 6 months, an intermediate procedure called the bidirectional Glenn operation or superior cavopulmonary anastomosis, is performed. The SVC is connected directly to the PA, providing nonpulsatile pulmonary blood flow, whereas the IVC remains connected to the heart. As a result, the volume load on the ventricle is significantly reduced, but oxygenated and deoxygenated blood still mix and the saturations remain in the low 80% range. By the age of 1 to 5 years, most of these children are ready for the Fontan circulation. With adequate growth and maturation of the pulmonary vascular bed, the resistance should be small enough to allow the complete separation of the systemic and pulmonary flows. The IVC is now also connected to the PA, most often via a lateral tunnel in the atrium or an extracardiac conduit, with or without a small fenestration (small opening in the baffle or conduit connecting the systemic venous return with the common atrium of the single ventricle). The fenestration can provide a residual right-to-left shunt in case of sudden increases in PVR, maintaining ventricular preload and function. This seems to facilitate the adaptation to the new loading conditions, shorten the recovery time, and decrease the incidence of early complications. The fenestration often occludes spontaneously, or it is closed during a cardiac catheterization and hemodynamic evaluation with a special device ( Fig. 18.9 ; see also Fig. 17.11, Fig. 17.12, Fig. 17.13 ).

The Fontan operation has dramatically improved the mortality rates for children with single ventricles, but the success comes at a price: chronic systemic venous hypertension and congestion have been implicated in a multitude of potential early and long-term complications, including arrhythmias, residual right-to-left shunts, coagulopathies with increased risk for thrombosis and stroke, lymphatic dysfunction with pleural effusions, and protein-losing enteropathy. Late cardiac failure and poor functional outcome remain risks for patients with Fontan circulations. The anatomy of the single ventricle and the type of Fontan connection influence the duration of freedom from complications. Children with systemic RVs and the classic atriopulmonary Fontan procedure (RA directly anastomosed to the PA) tend to have a shorter duration of freedom from complications than those with systemic LVs and newer Fontan modifications ( E-Figs. 18.2 and 18.3 ).

Inherent limitations of the Fontan circulation, such as altered control of cardiac output with decreased hemodynamic response to stress and reduced exercise tolerance, have been documented ( Fig. 18.10 ). Even at rest, cardiac output is usually only 70% (range, 50%- 80%) of normal for body surface area. Cardiac output is classically determined by four factors: preload, contractility, HR, and afterload. Over a physiologic range, cardiac output improves with increased preload, contractility, and HR and with decreased afterload. For the Fontan circulation, the determinants of cardiac output are more complex ( Fig. 18.11 ). The classic determinants of cardiac output are less effective, while other factors, such as transpulmonary gradient and PVR, must be considered. The following mechanisms regulate cardiac output in children with Fontan physiology.

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  Preload: The RV usually provides the kinetic energy to distend the pulmonary vasculature and create a preload reservoir for the LV, thereby enabling an increase in cardiac output up to fivefold or greater with exercise. The lack of a pre-pulmonary pump leads to a significant decrease in available pulmonary blood volume and, consequently, reduced or absent LV preload reserve.

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  Contractility: During the staged palliation, the single ventricle typically develops from a volume-overloaded and dilated ventricle to a hypertrophied, underfilled ventricle. Although the contractile response to β-adrenergic stimulation seems to be preserved, the resulting increase in cardiac output is diminished, most likely owing to limited preload reserve.

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  Heart rate and rhythm: Within the physiologic range, atrial pacing at different HRs does not alter cardiac output because there is a simultaneous decrease in stroke volume. Normalization of HR increases the reduced cardiac output associated with severe bradycardia or tachycardia. During exercise testing, Fontan patients demonstrate chronotropic incompetence, a blunted HR response to exercise. This is likely the result of autonomic dysfunction or abnormal reflex control. In contrast to the HR, cardiac rhythm is of utmost importance. Ectopy or loss of atrioventricular (AV) synchronization compromises ventricular filling and decreases the transpulmonary gradient.

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  Afterload: The Fontan circulation is characterized by increased afterload, which is a physiologic response to decreased cardiac output and occurs because a single ventricle is ejecting into two large resistance beds (systemic and pulmonary vascular) arranged in series. Autonomic regulation and activation of various endocrine systems increase the systemic venous resistance and help to maintain adequate perfusion pressures and venous tone. Because of the limited preload reserve, attempts at afterload reduction often result in significant hypotension. On the other hand, excessive afterload, such as that which occurs with residual aortic arch obstruction, is poorly tolerated.

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  Transpulmonary flow: Transpulmonary flow is directly proportional to the gradient between the systemic venous pressure (usually between 10 and 15 mm Hg, rarely >20 mm Hg) and the preventricular atrial pressure, which is determined by the functional status of the AV valve, the ventricle, the rhythm, and the potential presence of outflow obstruction. Transpulmonary flow is inversely proportional to the resistance over the Fontan circuit. This resistance is largely determined by PVR, but mechanical obstruction such as stenosis or thrombosis may also play a role. The geometry of the cavopulmonary connections is also important in that turbulent flow produces energy loss and a reduction in effective driving pressure. It has been suggested that PVR is the key determinant of transpulmonary flow, delivery of pulmonary venous flow to the systemic ventricle, and, consequently, cardiac output ( Fig. 18.12 ).

  

In conclusion, the Fontan circulation can be described as a serial circulation with a single kinetic energy pump. Increased systemic venous pressures are necessary to create the transpulmonary pressure gradient that drives flow across the pulmonary vascular bed; however, these increased pressures simultaneously increase the ventricular afterload. Cardiac output depends on an adequate preload and low PVR. Decreased cardiac output at rest and limited exercise tolerance are characteristics of the Fontan circulation.

Physiology of the Transplanted Heart

According to the International Society for Heart and Lung Transplantation (ISHLT), children younger than 18 years of age account for about 13% of all heart transplantations. Every year, approximately 450 cardiac transplants in children are reported to this voluntary registry, mainly from centers in Europe and North America. Major indications are cardiomyopathies, CHD, and a growing number of retransplantations, especially in older children. The median survival time (the time at which 50% of recipients are still alive) has improved over the years, mainly because of reduced early posttransplant mortality. Survival time is currently 20.6 years for infants, 17.2 years for children aged 1 to 5 years, 13.9 years for children aged 6 to 10 years, and 12.4 years for teenagers. Ninety-four percent of transplant recipients describe a normal functional status with no limitations during physical activity.

As survival continues to improve, more and more children with transplanted hearts will present to operating rooms and sedation suites for diagnostic studies and general procedures. A basic understanding of the physiologic changes in the transplanted heart and the implications of current immunosuppressive therapy are important for safe management.

Rational Use of Vasoactive Drugs

Many factors influence the selection of appropriate inotropic and vasopressor therapies, including the clinical situation, underlying cardiac abnormalities, and perfusion requirements of other organs. The major goal is to improve tissue oxygenation. Oxygen delivery is principally dependent on cardiac output and oxygen content. In addition to an increased cardiac output (i.e., optimal HR, preload, contractility, and afterload), adequate hemoglobin concentration and oxygen saturation values are important components. On the other hand, a careful balance of pulmonary and systemic blood flows can be crucial for certain congenital heart defects.

Catecholamines and catecholamine-like agents remain the most commonly used inotropic and vasoconstrictor drugs. It is likely that improvements in cardiac output in neonates in response to drugs such as dopamine or dobutamine are the result of increases in both HR and contractility. Some evidence exists in infants and young children after cardiac surgery that the increases in cardiac output produced by dopamine and dobutamine may be more related to a positive chronotropic effect than to an increase in the intrinsic contractile state. With few exceptions, drugs that primarily increase afterload, such as α-adrenergic agonists, have limited use in children. Large increases in afterload without corresponding improvements in contractile state are often poorly tolerated by infants and children, particularly in the context of significant underlying contractile dysfunction.

Practical Considerations for the Use of Vasoactive Agents

Commonly used drugs, their doses, and a summary of their effects on selected cardiac functions are presented in Table 18.8 ; most of this information has been empirically derived from studies in adults. Limited direct information regarding the effects of commonly used vasoactive drugs in children at different ages and in various pathophysiologic states is available. Neonates, infants, and small children demonstrate unique responses to inotropic and vasoactive drugs primarily because of age-specific pharmacokinetics; differences in receptor types, number, and function; and a variability in drug delivery. Important variations in the volume of distribution and measured plasma concentrations have been observed in children receiving inotropic agents. As much as a 10-fold range in plasma concentration has been reported for a given infusion rate.

TABLE 18.8

Inotropics and Vasopressors

Agent	Intravenous Dose	Comments
Dopamine	2–20 µg/kg per minute infusion	Primary effects at β 1 , β 2 , and dopamine receptors, somewhat related to dose; lower doses (2–5 µg/kg per minute) can increase contractility and can also have a direct dopaminergic receptor effect to increase splanchnic and renal perfusion; increasing doses increase contractility via β-effects and increase likelihood of α-mediated vasoconstriction; effects depend on endogenous catecholamine stores.
Dobutamine	2–20 µg/kg per minute infusion	Relatively selective β 1 stimulation; also potential β 2 stimulation, tachycardia, and vasodilation, especially at higher doses (>10 µg/kg per minute); may be less potent than dopamine, especially in immature myocardium; no significant α-adrenergic effects; tachydysrhythmias perhaps more likely than with dopamine; effects are independent of endogenous catecholamine stores.
Epinephrine	0.02–2.0 µg/kg per minute infusion	Primary β-effects to increase contractility and vasodilation at lower doses (0.02–0.10 µg/kg per minute); increasing doses (>0.1 µg/kg per minute) are accompanied by increased contractility and increased α-mediated vasoconstriction; may be best choice to augment contractility and perfusion, especially in situations of severely compromised ventricular function, shock, or anaphylaxis.
Isoproterenol	0.05–2.0 µg/kg per minute infusion	Pure, nonselective β-agonist; significant inotropic, chronotropic (β 1 and β 2 ), and vasodilatory (β 2 ) effects; may be an effective pulmonary vasodilator in some children; tachycardia and increased myocardial oxygen consumption may be dose limiting; tachydysrhythmias may also occur; bronchodilator.
Norepinephrine	0.05–2 µg/kg per minute infusion	Primary effects on α 1 -, α 2 -,and β 1 -receptors, no significant clinical effects on β 2. Increased systemic blood pressure and cardiac output (α 1 and β 1 ) as well as improved pulmonary blood flow (α 2 ). Less tachycardia. Mainly used for treatment of septic shock and pulmonary hypertension.
Phenylephrine	1–10 µg/kg bolus, 0.1–0.5 µg/kg per minute infusion Preterm and term infants may require as much as a 30 µg/kg bolus (see Chapter 17 )	Pure α-mediated vasoconstriction; no increase in contractility.
Vasopressin	0.0003–0.002 U/kg per minute	Induces intense vasoconstriction via V 1a receptors in the vascular endothelium. May cause vasodilation via V 2 receptors in specific tissues (release of nitric oxide and vasodilating prostaglandins). Used for the treatment of vasodilatory shock, refractory hypotension, and pulmonary arterial hypertension. Careful when programming syringe pumps: multiple dosing forms (U/minute, U/kg per hour, U/kg per minute, or mU/kg per minute).
Amrinone	0.75–1 mg/kg repeated twice, maximum 3 mg/kg Neonates and infants may require loading doses of 2–4 mg/kg and infusions of 10 µg/kg per minute	Increases cyclic adenosine monophosphate by phosphodiesterase inhibition; positive inotropy, positive lusitropy, and smooth muscle vasorelaxation; hypotension; reversible thrombocytopenia.
Milrinone	50–75 µg/kg loading dose, 0.5–1.0 µg/kg per minute infusion	Similar to amrinone (antiplatelet effects may be less).
Calcium chloride Calcium gluconate	10–20 mg/kg per dose (slowly) 30–60 mg/kg per dose (slowly)	Positive inotropic and direct vasoconstricting effects; inotropy is significant only if ionized calcium is low and/or ventricular function is depressed by other agents; can slow sinus node; increases electrophysiologic abnormalities from hypokalemia and digoxin.
Digoxin	Total digitalizing dose (TDD):	TDD given in divided doses: TDD followed by TDD q8–12 hour × 2; increases cardiac contractility; slows sinus node and decreases atrioventricular (AV) node conduction; long half-life (24–48 hours) that is prolonged by renal dysfunction; numerous drug interactions; toxicity includes supraventricular tachycardia, AV block, ventricular dysrhythmias; symptoms include drowsiness, nausea, vomiting; toxicity exacerbated by hypokalemia.
	Premature: 20 µg/kg
	Neonate (1 mo): 30 µg/kg
	Infant (<2 yr): 40 µg/kg
	Child (2–5 yr): 30 µg/kg
	Child (>5 yr): 20 µg/kg
	Maintenance: 2.5–5 µg/kg q12 hour

Substantial pharmacodynamic variability (i.e., variability in the serum concentration required to produce the desired effect) can also be observed. Some of these differences are related to receptor maturation and function. For example, it appears that β-adrenergic receptors have a high density in the term neonate and young infant but their coupling to adenyl cyclase may be incomplete. In addition to developmental changes, which are to some extent controlled by thyroid hormone, β-receptor, and adenyl cyclase activities are diminished in response to sustained administration of exogenous β-agonists and also as a result of increased endogenous catecholamine concentrations, which are often seen as a complication of moderate to severe heart failure and other forms of severe stress (e.g., sepsis).

In the neonatal myocardium, chronic catecholamine exposure may upregulate adrenergic receptor number or function, or both, perhaps mimicking the normal developmental program of increasing sympathetic nervous system activity as term approaches. With further maturation in early postnatal life, β-adrenergic receptor density declines. The impacts of various pathophysiologic states on these processes have been incompletely identified. For example, congestive heart failure, cardiopulmonary bypass (CPB), and ischemic reperfusion all lead to decreased β-receptor and adenyl cyclase expression and activity. On the other hand, the myocardium of infants with TOF exhibits increased β-receptor density and greater receptor-stimulated adenyl cyclase activity with increased gene and protein expression.

One must pay particular attention to technical issues when administering vasoactive infusions to infants. Infusions are often specifically prepared as very concentrated, nonstandardized solutions to minimize the amount of volume infused; hence, the potential for dose or concentration error is substantial. One study at a tertiary care children's hospital demonstrated that the actual concentration of prepared solutions varied significantly. Because of the high concentration of these drugs relative to the child's size, small errors (either in calculation or in infusion pump flow rate) can have a large impact on the actual amount of drug delivered. The extremely small infusion rates can also lead to a delay in drug delivery and effect (see Chapters 8 and 52 ). Confirming that the pump drive mechanism is actually delivering drug at the distal end of the infusion tubing, connecting the infusion tubing as close to the child as possible, and using a carrier infusion to “push” the medication at a constant rate are important steps to ensure the safety and effectiveness of drug infusions. The rate of the carrier infusion is also crucial. Most standard infusion setups require rates in excess of 5 mL/hour to effect rapid (less than ~10 minutes) changes in the concentration of drug delivered to the infant and therefore preclude all attempts of fluid restriction.

Vasoactive Drugs