Principles of Medical Management - Neonatal Cardiology, 3rd Ed.

Neonatal Cardiology, 3rd Ed. Michael Artman

Chapter 11. Principles of Medical Management

■ INTRODUCTION

■ HEART FAILURE

Overview

Heart Failure Syndromes

Diagnosis of Heart Failure

Clinical Assessment of Heart Failure

Severity

Etiology of Heart Failure in Neonates Therapeutic Guidelines

■ NUTRITIONAL THERAPY

Overview

Etiology of Failure to Thrive

Diagnosis

Treatment

■ MISCELLANEOUS MEDICAL PROBLEMS

Infective Endocarditis

Intracardiac and Intravascular Thrombi

■ SUGGESTED READINGS

■ INTRODUCTION

Providing medical care to a newborn with known or suspected cardiovascular disease can be daunting. An understanding of the pathophysiology of these conditions and the application of a few general principles will promote effective care and minimize the chance of iatrogenic misadventures. It is imperative that a concerted team of specialists with expertise in advanced pediatric cardiac care be assembled, including physicians from several specialties (neonatology, cardiology, critical care, cardiac surgery, and anesthesiology), nurses (neonatal, pediatric cardiac intensive care, and pediatric cardiac acute care), and other health care professionals (respiratory therapists, physical therapists, dieticians, pharmacists, social workers, etc.). Effective and ongoing communication is essential for optimizing care and providing a uniform approach to the management of these complex medical patients.

■ HEART FAILURE

Overview

Heart failure in infancy is a syndrome that occurs as a consequence of the inability of the cardiovascular system to meet the metabolic and growth demands of the infant. It is a common feature of congenital cardiovascular disease presenting symptomatically in neonates. Heart failure in neonates and infants is most commonly caused by structural defects that result in decreased systemic output. In contrast to adults, most infants with heart failure have preserved cardiac contractile function but have increased demands on the cardiovascular system with increased myocardial oxygen requirements. The most common conditions associated with heart failure in infants are those in which there is a dominant left-to-right shunt with excessive pulmonary blood flow and increased oxygen demand. Heart failure in neonates can also result from any structural defect that results in decreased systemic blood flow (eg, severe aortic stenosis) or from myocardial dysfunction regardless of the etiology. Occasionally, heart failure occurs in situations in which the heart is structurally normal, but systemic output is very high and is associated with abnormal distribution of flow (eg, a large arteriovenous malformation), severe anemia, or excessive metabolic demands (eg, neonatal thyrotoxicosis).

Pathophysiology

The development and progression of heart failure results from a complex interplay of hemodynamic and neurohormonal factors. As illustrated in Figure 11-1, heart failure is viewed as a clinical syndrome that incorporates hemodynamics and compensatory neurohormonal responses in the overall conceptual framework. It should be noted that the roles of compensatory mechanisms that regulate cardiovascular function have been studied largely in chronic compensated states in adult patients and mature animal models. Although it is likely that developmental differences impact the compensatory physiological responses and the responses to therapy that have been designed for adult patients, the general concepts are likely applicable to infants. Additional clinical and experimental studies are necessary to define the spectrum of pathophysiology of heart failure in preterm and term newborn infants.

Cardiac Dysfunction

Systemic output may be insufficient because of (1) reduced ability to eject blood due to either myocardial contractile dysfunction or obstructed outflow (systolic dysfunction), (2) reduced ability of the heart to receive venous return caused by either myocardial diastolic dysfunction or obstructed inflow (diastolic dysfunction), (3) abnormal distribution of cardiac output, or (4) combinations of the first three factors. Regardless of the primary etiology of heart failure, the interaction between the contractile (inotropic) and relaxation (lusitropic) properties of the heart are altered. End-diastolic intraventricular pressure and volume are determined by preload (venous return), the lusitropic state of the myocytes, and the passive compliance of the nonmyocyte elements of the ventricle. On the other hand, end-systolic ventricular pressure and volume are determined by central impedance and peripheral resistance (which together make up the afterload against which the ventricle pumps) in combination with the inotropic state of the ventricular myocardium. These factors are interrelated, and it is often difficult to separate the primary factors from secondary responses.

Systolic dysfunction. The fundamental problem in systolic dysfunction is impaired ventricular contractility. The healthy heart is able to increase its output in response to an increase in preload (the Frank-Starling relationship) and can maintain stroke volume in the face of an increase in afterload by increasing its contractile state (homeometric autoregulation). The heart with impaired systolic function is incapable of doing either. The ability to increase stroke volume with an increase in preload is diminished, and a small increase in afterload may lead to a marked decline in the output of a ventricle. The corollary to this is that a small decrease in afterload may significantly improve cardiac output in a heart with systolic dysfunction. This forms the basis for the widespread use of vasodilator therapy for heart failure related to systolic dysfunction.

FIGURE 11-1. Interrelationships of various influences on the heart failure syndrome. Much of the theoretical and experimental framework for understanding the pathophysiology of heart failure has been developed in adults, but the general concepts are likely to be applicable (with modification) to infants. This schematic diagram is intended to illustrate the complexities involved in determining and modulating the responses to heart failure. Abbreviations: NPs, atrial natriuretic peptides; SNS, sympathetic nervous system; RAAS, renin-angiotensin-aldosterone system.

Afterload is determined primarily by the impedance of the aortic valve, aorta and the other central elastic arteries, and the resistance of the peripheral arterial vasculature. According to the LaPlace relationship, afterload (end-systolic wall stress) is proportional to both end- systolic pressure and end-systolic volume. As afterload increases, because of either an increase in central impedance (eg, aortic stenosis or coarctation of the aorta) or by an increase in peripheral resistance (eg, vasoconstriction caused by alpha-adrenergic stimulation), the ventricle with systolic dysfunction will not eject as much blood as a normal ventricle. Stroke volume will therefore decrease, and end-systolic volume will increase.

Diastolic dysfunction. Diastolic dysfunction is characterized by either decreased passive ventricular compliance or impaired relaxation. Consequently, increased venous pressure is necessary to sustain adequate ventricular filling, and only small increases in venous return lead to large increases in venous pressure without concomitant increases in stroke volume. This is the basis of the concept of limited preload reserve in diastolic heart failure. That is, abnormal diastolic function may cause symptoms of inadequate cardiac output despite normal systolic function.

Abnormal distribution of cardiac output. Heart failure may be present in neonates despite normal (or near normal) systolic and diastolic cardiac function if systemic blood flow is inadequate to meet the metabolic demands of the neonate. The most common scenario is a structural defect that results in a large left-to-right shunt (eg, large ventricular septal defect, single ventricle with unobstructed pulmonary blood flow, atrioventricular septal defect, large patent ductus arteriosus, or arteriovenous malformation). In this situation, combined ventricular output is high, but because of the large left-to-right shunt, there is excessive pulmonary blood flow. Even though systemic blood flow is usually normal or even increased, metabolic demand is increased far more, driven in large part by an increase in oxygen consumption related to increased work of breathing. In the normal newborn, approximately 20% to 30% of oxygen consumption is related to respiratory work, and it can increase two- to threefold when pulmonary blood flow is elevated. In this setting, which is common in infants with heart failure, compensatory neurohormonal mechanisms are activated, and the heart failure syndrome develops despite normal cardiac pump function. The increased sympathetic state stimulates brown-fat metabolism, which further increases oxygen consumption and contributes significantly to the increased overall metabolic demand.

Neurohormonal Mechanisms

A variety of neurohormonal signaling pathways and physiologic mechanisms are involved in the normal maintenance and regulation of the cardiovascular system. When systemic output is inadequate for whatever reason, a host of compensatory mechanisms are activated in an effort to maintain oxygen delivery to vital organs. Most of the physiological responses result from activation of the sympathetic nervous system and the renin-angiotensin- aldosterone system. In addition to the direct effects of increased sympathetic tone and increased levels of angiotensin and aldosterone, other responses include increases in vasopressin secretion and endothelin levels and perturbations in nitric oxide signaling in the vasculature and myocardium. In the early stages of heart failure, these and other compensatory mechanisms help to maintain cardiac output and oxygen delivery, but with time and disease progression, these processes become deleterious (Figure 11-2).

The compensatory increases in neurohormonal activities initially result in an increase in myocardial contractility, selective peripheral vasoconstriction, sodium and water retention, and maintenance of blood pressure. A new state of cardiovascular homeostasis occurs (compensated heart failure syndrome) with higher sympathetic output and increased activity of the renin-angiotensin- aldosterone system. However, when the heart failure state becomes chronic, the same responses that were beneficial in initially maintaining circulatory homeostasis may begin to accelerate myocardial cell death, increase fibrosis, and exacerbate the hemodynamic abnormalities. Furthermore, excessive activation of vasoconstrictor systems is accompanied by a loss of counterregulatory vasodilator influences (nitric oxide, prostacyclin) that adds to the burden of the failing heart.

FIGURE 11-2. Compensatory neurohormonal mechanisms in heart failure. Contractile dysfunction (or impaired distribution of blood flow) results in activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system. These systems produce an integrated physiological response intended to provide compensatory support of the cardiovascular system. The potentially deleterious effects include hypertrophy, fibrosis, and cell death that further contribute to cardiac contractile dysfunction such that a cycle of progressive deterioration is established. It is essential to interrupt this cycle to provide optimal long-term management of the heart failure syndrome. Abbreviations: SNS, sympathetic nervous system; RAAS, renin-angiotensin-aldosterone system.

Enhanced sympathetic activity occurs in adult patients with systolic dysfunction even before clinical signs appear. A clear association exists between increased sympathetic tone (eg, as reflected by increased plasma norepinephrine concentrations) and increased mortality in adult heart failure patients. Increased plasma levels of norepinephrine and β-receptor down-regulation are also reported in the pediatric population.

Although activation of the sympathetic nervous system and renin-angiotensin-aldosterone system is quite effective for short-term compensation, the adverse consequences of continued activation of these systems eventually overcome the initial benefits. Myocardial oxygen consumption increases due to increases in heart rate, contractility, and wall stress. If excessive, these oxygen demands may exceed oxygen delivery to the myocardium, particularly in the subendocardium.

Hypertrophy initially helps compensate for an acute overload by decreasing wall stress and maintaining stroke volume. This occurs by activation of the hypertrophic response genes, which increases the number of functioning contractile elements within the myocytes but does not increase myocyte numbers. These changes in gene expression also involve proteins external to the contractile elements that control myocardial calcium homeostasis. This may eventually diminish the ability to transport calcium to and from the contractile elements efficiently. Furthermore, hypertrophy increases the overall myocardial oxygen requirement.

Ventricular remodeling describes the structural changes in the myocardium that occur in response to changes in loading conditions. As indicated above, the myocyte compartment of the heart responds by hypertrophy. The nonmyocyte components of the heart also respond to autocrine and paracrine signals (eg, angiotensin II and aldosterone) independent of the hemodynamic status. Aldosterone acts on fibroblasts and promotes collagen synthesis. Increased production of collagen decreases the proportion of the myocyte-to- nonmyocyte component of the ventricular myocardium. This leads to increased stiffness of the ventricular wall and contributes significantly to diastolic dysfunction.

Additionally, increased cardiac interstitial collagen deposition may contribute to reduced capillary density and increased oxygen diffusion distance. Other more direct effects of remodeling include activation of stretchsensitive calcium channels. As a result of membrane deformation, resting intracellular calcium levels increase, promoting activation of the hypertrophic gene response. Increases in loading conditions have also been associated with re-expression of fetal genes, early response genes (c-fos, c-jun, c-myc), and atrial natriuretic peptide, all early markers of cardiac hypertrophy.

In addition to the changes mentioned above, activation of the sympathetic nervous system and the renin- angiotensin-aldosterone system may be toxic to the myocytes. Myocyte necrosis occurs via a variety of cytotoxic mechanisms and may be observed in situations of both acute and chronic myocardial dysfunction. Microscopically, cellular swelling and inflammation characterize necrosis. In addition to necrosis, an increased rate of apoptosis appears to be a common feature of the heart failure syndrome. Apoptosis is an active process that involves activation (or lack of suppression) of genes encoding for programmed cell death. Although data are limited in adult human hearts, the intermediary factors responsible for apoptosis appear to be activated by angiotensin II. Apoptosis appears to be increased in the context of vascular remodeling, hypertension, ischemiareperfusion states, and other circumstances that promote ventricular remodeling. Both necrosis and apoptosis contribute to the progressive loss of myocytes that further diminishes the overall pumping capability of the heart and promotes perpetuation of the cycle of decompensation in heart failure (Figure 11-2).

Systemic Inflammatory Response in Heart Failure

Inflammation is a tightly regulated process that has been studied for many years. The same cascades that are operative in sepsis and autoimmune diseases are activated to varying degrees in the heart failure syndrome. Cytokines are central regulatory molecules involved in the systemic inflammatory response syndrome. Cytokines are produced by a variety of cells and can be categorized as “pro-inflammatory’ or “anti-inflammatory.” Pro-inflammatory cytokines, such as interleukin-1, interleukin-6, and tumor necrosis factor-а, depress myocyte contractile function, activate immune cells, and suppress production of anti-inflammatory cytokines. In contrast, anti-inflammatory cytokines (eg, interleukins-4, -5, and -10) reduce production of pro-inflammatory molecules and play a protective role in some disease states.

Although oversimplified, several clinical conditions, such as septic shock, are thought to result from an imbalance in these two systems with an unchecked pro- inflammatory response triggered by an inciting event (eg, bacterial infection). An emerging concept in heart failure is that similar immune system derangements contribute significantly to the pathophysiology and progression of the heart failure syndrome. The triggering mechanisms that initiate the systemic inflammatory response syndrome in heart failure and the potential of specific therapeutic strategies remain to be fully characterized. It is important to note that nearly all of this work has been performed in adult patients and mature animal models and that relatively little is known regarding the role of the systemic inflammatory response in neonates with heart failure.

Heart Failure Syndromes

As is evident from the preceding discussion, it is important to think of heart failure as a syndrome that is defined as a disorder of the cardiovascular system, not merely acute pump failure resulting in inadequate oxygen delivery. Heart failure develops as a consequence of compensatory hemodynamic and neurohormonal mechanisms that become overwhelmed or exhausted in response to inadequate systemic blood flow. The signs and symptoms of heart failure result from these compensatory physiological responses and are related to the acuity of the disease process. Based on these concepts, the following definitions provide a framework for understanding and characterizing heart failure in neonates.

Shock

Shock is defined as a state of acute circulatory dysfunction with completely overwhelmed and inadequate physiological compensatory mechanisms. These infants are lethargic, exhibit poor perfusion, are often hypotensive and tachycardic, and generally appear quite ill. Blood pressure may be difficult to measure noninvasively. Additionally, blood pressure may be maintained at normal or near normal levels until the terminal stages of shock in infants. Thus, it is important to not rely solely on blood pressure as an indicator of the presence shock in newborns. However, confirmed hypotension in a neonate is an important finding and should prompt immediate intervention. Shock can result from a variety of noncardiac causes in neonates (eg, sepsis, severe anemia). However, cardiogenic shock may also be a presenting feature of left-sided obstructive lesions (such as critical aortic stenosis, interrupted aortic arch or hypoplastic left heart syndrome, or perinatal cardiomyopathy). Less commonly, coronary artery anomalies, such as coronary ostial stenosis, anomalous left coronary artery arising from the pulmonary artery (usually does not present until after 2 months of age), and perinatal myocardial infarction caused by paradoxical venous emboli crossing into the left atrium through the foramen ovale, may present with neonatal cardiovascular collapse. Since the normal physiologic responses are inadequate to maintain circulatory homeostasis, shock must be treated immediately to avoid death.

Acute Heart Failure Syndrome (Decompensated State)

Acute decompensated heart failure occurs when physiological and neurohormonal compensatory mechanisms are activated, but the responses are insufficient to maintain normal systemic circulation. The development of symptoms or the worsening of a previously compensated state marks the beginning of decompensation and onset of the acute heart failure syndrome. Additional myocardial injury, increased metabolic demands (eg, as a result of infection), or changes in loading conditions may trigger decompensation from a stable compensated state. Symptoms of fluid retention develop or progress because of peripheral vasoconstriction and sodium retention. Respiratory distress secondary to pulmonary venous congestion and hepatic distention caused by fluid retention and/or right ventricular dysfunction are common manifestations of decompensated heart failure syndrome in neonates. Infants with acute heart failure are symptomatic with restlessness, irritability, tachypnea, tachycardia, diminished peripheral perfusion, and decreased urine output. Without intervention, infants in a decompensated state will continue to deteriorate, often rapidly. It is important to recognize acute decompensated heart failure so that appropriate therapy can be provided urgently.

Chronic Heart Failure Syndrome (Compensated State)

The chronic heart failure syndrome is defined as a stable balance between inadequate systemic blood flow and activation of compensatory hemodynamic and neurohormonal responses. These patients may exhibit few, if any, symptoms of “congestive” heart failure since activation of compensatory mechanisms, primarily the sympathetic nervous system and the renin-angiotensin-aldosterone system, maintains circulatory homeostasis. Often, the only noticeable finding in an infant is failure to thrive because caloric intake is often reduced and metabolic demand is increased because of enhanced sympathetic activity. The patient may demonstrate respiratory distress caused by elevated pulmonary venous pressures, but it is often subtle. This sustained activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system ultimately contributes to progressive (and often silent) deterioration of ventricular function. Chronic heart failure is a common manifestation of many types of structural cardiac defects in neonates resulting from the abnormal distribution of blood flow or abnormal ventricular function.

Diagnosis of Heart Failure

Neonates represent a unique population in terms of cardiopulmonary function, clinical presentation, and approaches to management. Knowledge of these developmental differences is important in order to understand the pathophysiology of heart failure in neonates and to develop age-appropriate approaches to therapy. Heart failure is a clinical syndrome that must be diagnosed by a comprehensive history and physical examination. No single test can be performed to diagnose the presence of the heart failure syndrome. For example, an echocardiogram can be very helpful in defining cardiac anatomy, ventricular function, and pulmonary artery pressure, but it does not provide a diagnosis of heart failure. An infant may have no clinical evidence of heart failure despite the presence of a large ventricular septal defect or echocardiographic evidence of decreased ventricular systolic function. Conversely, heart failure may be present in the setting of a structurally normal heart and normal ventricular function but with inadequate effective output because of, for example, severe anemia or a large cerebral arteriovenous malformation.

The prenatal and perinatal history may provide clues as to possible acquired causes of heart failure, such as neonatal myocarditis or severe anemia caused by placental bleeding. However, the neonatal history is generally much more informative. Often, the most prominent manifestation of the heart failure syndrome in newborn and young infants is related to the respiratory system. Infants with heart failure are frequently tachypneic, especially with feeding. The feeding history reveals decreased oral intake and prolonged feeding times because of tiring during feeding and increased respiratory effort during oral feeding. Diaphoresis with feeding and emesis are commonly present. These symptoms are exacerbated by a concomitant viral respiratory infection, which may be the reason that the infant is brought to medical care. Infants with chronic heart failure generally exhibit failure to thrive with decreased growth velocity. Unfortunately, the signs and symptoms may be nonspecific as other neonatal illnesses present similarly to heart failure.

Infants with heart failure often appear apathetic and uninterested in their environment and are frequently characterized as irritable. The physical examination often shows tachycardia and tachypnea, even at rest. It is unusual to hear a gallop in newborn infants, even in the presence of severely depressed ventricular function. In infants with a left-to-right shunt, the presence of a diastolic inflow rumble indicates a large shunt with markedly increased pulmonary blood flow. Absence of a heart murmur does not exclude cardiovascular disease. For example, an infant with coarctation of the aorta may have severe obstruction leading to left ventricular dysfunction yet not have a murmur.

The lungs are usually clear to auscultation. With advanced heart failure, there may be diffuse inspiratory crackles or rales, but this is a rare finding. Neonates are more susceptible to atelectasis than older children and adults because of differences in pulmonary function. Functional residual capacity, or the volume of gas present in the lungs at the end of a normal expiration, is the balance between the inward recoil of the lung and the outward recoil of the chest wall. In neonates, the chest wall generates little outward recoil, making the relaxation volume of the thorax smaller than that of the adult. Closing capacity, or the point at which small conducting airways begin to collapse, exceeds functional residual capacity, resulting in the neonatal lung being more susceptible to atelectasis. Furthermore, failure to thrive, a common feature of chronic heart failure in infants, leads to respiratory muscle weakness that can compromise alveolar stability and pulmonary compliance.

The liver is usually enlarged. Jugular venous distension is almost never seen because the liver is very compliant in young infants. The size of the liver is used as a guide to the severity of fluid overload or right ventricular dysfunction. The presence of hepatomegaly in a critically ill infant may differentiate heart failure from sepsis. This is extremely important when considering the need for rapid fluid replacement, which may be harmful in a patient with heart failure. Neonates rarely exhibit peripheral edema unless there is hypoproteinemia or renal failure. The extremities may be cool with diminished cutaneous perfusion if systemic cardiac output is markedly compromised.

Biomarkers

Given that heart failure is a dynamic clinical syndrome with involvement of neurohormonal, genetic, biochemical, and inflammatory mediators, a variety of biomarkers may provide useful information for the diagnosis, risk stratification, and monitoring of infants with heart failure. Biomarkers of inflammation, oxidative stress, protease activity, neurohormonal activation, myocyte injury, matrix remodeling, and other pathways have been reported or are currently being studied in adults with heart disease. Most of the heart failure biomarkers that have been studied in adults have not been fully characterized in neonates and young children. Two biomarkers that have been evaluated in children are norepinephrine and b-type natriuretic peptide (BNP). Norepinephrine levels correlate reasonably well with clinical assessments of heart failure severity in infants and children. BNP has been shown to be elevated in newborns with patent ductus arteriosus, and other studies suggest that BNP levels can discriminate between heart disease and respiratory disease in children. However, additional studies are required to determine the utility of measuring levels of norepinephrine, BNP, or other newer biomarkers (such as N-terminal pro-BNP) for risk stratification and monitoring the response to therapy in infants with cardiovascular disease.

Clinical Assessment of Heart Failure Severity

In most clinical settings, assessment of the severity of heart failure in neonates and infants is subjective and may vary among clinicians. For routine cases, a subjective assessment is adequate if the clinician pays careful attention to signs and symptoms of heart failure, including growth of the infant. However, in complicated cases and certainly for clinical trials comparing heart failure therapies, outcomes, or quality of life, a more quantitative assessment of heart failure severity is necessary.

Heart failure severity in adults and adolescents is commonly graded according to the New York Heart Association classification, which uses functional capacity as a marker of heart failure severity. Because this approach is not applicable to infants, an alternative scoring system was developed by Ross and colleagues (originally published in 1992 and revised in 2012; see “Suggested Readings”). The Ross Classification has been used in several heart failure studies in infants and has been modified for use in older children. The New York University Pediatric Heart Failure Index was developed in an effort to further discriminate among early stages of disease and to detect more subtle changes in heart failure severity. However, neither the Ross Classification nor the New York University Pediatric Heart Failure Index is considered to be sufficiently sensitive for early stages of disease. Additional work is necessary to develop a more accurate and sensitive method of measuring heart failure severity in infants.

Etiology of Heart Failure in Neonates

Heart failure in newborn and young infants may be caused by many different conditions. The age at onset may be helpful in narrowing the differential diagnosis.

Table 11-1 provides guidelines to the most likely etiologies based on the time of onset of the heart failure syndrome. It is important to formulate an appropriate differential diagnosis so that the evaluation can be focused on the most likely causes of heart failure, as this will expedite the diagnostic work-up. Accurate diagnosis is essential for devising an appropriate and individualized approach to treatment.

Heart failure presenting immediately at birth is rare and is generally attributed to heart muscle dysfunction caused by birth asphyxia with myocardial ischemia, neonatal sepsis, hypoglycemia, or severe anemia or polycythemia. Fetal and neonatal arrhythmias (either sustained tachycardia or bradycardia) are much less common causes of heart failure at birth, although they may cause hydrops fetalis, a presentation of heart failure in the fetus. Least common are congenital cardiovascular defects that may present with heart failure at birth (Ebstein anomaly with severe tricuspid regurgitation, absent pulmonary valve syndrome, or large systemic arteriovenous malformations).

Heart failure beginning in the first week of life is most likely associated with a structural defect involving the left heart (critical aortic stenosis, severe coarctation or interrupted aortic arch, hypoplastic left heart syndrome). Less common are other forms of congenital structural defects and heart muscle dysfunction. Renal disorders that cause profound renal failure or neonatal systemic hypertension may present in the first week of life with signs of heart failure. Similarly, certain endocrine abnormalities may cause heart failure in neonates during the first week or two after birth.

Previously well newborns who develop heart failure in the first 2 to 8 weeks of life are most likely to have a structural defect that results in a left-to-right shunt. These infants are generally asymptomatic until pulmonary vascular resistance and blood hemoglobin concentration fall postnatally and the magnitude of pulmonary blood flow becomes sufficiently large to cause signs and symptoms of heart failure due to maldistribution of blood flow (pulmonary overcirculation with or without inadequate systemic blood flow). Other forms of congenital cardiovascular malformations can present in the first 2 weeks to 2 months of life, including complex defects, such as various forms of single ventricle, obstructive lesions that are not critical at birth but gradually produce symptoms, cardiomyopathies, and, rarely, heart failure due to severe pulmonary problems.

Therapeutic Guidelines

Normalization of altered hemodynamics remains the primary objective during the acutely decompensated phase of heart failure. The effective long-term treatment of the heart failure syndrome requires attention to the neurohormonal derangements involved in the pathophysiology of heart failure.

The treatment objectives for a neonate with heart failure may be somewhat different than those for an adult patient. Often, heart failure in infants with structural cardiovascular defects is managed for a relatively short period of time until surgical or catheter-based intervention is undertaken. For example, an infant with left ventricular failure as a result of severe aortic stenosis will be treated medically until stabilized and then referred for definitive therapy. However, heart failure may persist in some of these infants because of pre-existing myocardial injury or incomplete relief of structural abnormalities (eg, residual aortic stenosis and aortic insufficiency after aortic valvuloplasty).

This chapter presents a general approach to management of heart failure in newborn and young infants. Additional details of the basic and clinical pharmacology of the various drugs and drug classes are presented in Chapter 12.

Shock and Acute Heart Failure (Decompensated State)

The management of shock and acutely decompensated heart failure requires immediate “normalization” of the altered hemodynamics. The therapeutic approach consists primarily of intravenous administration of diuretics, inotropic agents, and vasodilators. In addition, the therapeutic and deleterious effects of other therapies, such as oxygen, ventilation (spontaneous vs. assisted) and the need to maintain patency of the ductus arteriosus patency, must be considered on an individual basis, depending on the specific anatomy and pathophysiology. Additional details regarding the initial treatment of symptomatic newborns with congenital cardiovascular defects are presented in Chapter 5.

Chronic Heart Failure Syndrome (Compensated State)

Treatment of adult patients with compensated congestive heart failure is directed at modifying or interrupting the excessive neurohormonal activity. Treatment objectives include reduction of morbidity and hospitalization, increased long-term survival, and improved quality of life (reduction in symptoms and improved weight gain). Drugs such as ACEi, angiotensin receptor blockers, aldosterone antagonists, and β-adrenergic receptor blockers have all emerged as important agents in the treatment of adult patients with heart failure. Whether and to what extent these processes play a role in newborn and young infants with inadequate systemic output remain to be determined. However, based on studies in adults and animals, it is reasonable to predict that similar mechanisms are operative in human neonates with heart failure, although there may be both qualitative and quantitative age-related differences. Additional research is needed to characterize the neurohormonal responses to heart failure and to heart failure therapy in preterm and term infants.

General approaches to the management of heart failure in neonates include improving myocardial contractile function, altering loading conditions, modulating neurohormonal activation, nutritional therapy, surgical or catheter-based intervention, mechanical circulatory support, and heart transplantation. The major classes of drugs used to treat chronic heart failure in infants are inotropes, diuretics, vasodilators, and neurohormonal modulators.

Inotropic agents. Drugs that act via cyclic AMPdependent mechanisms (eg, β-adrenergic agonists and phosphodiesterase inhibitors) may acutely improve hemodynamics. However, in clinical trials conducted in adult patients, chronic administration of β-agonists or phosphodiesterase inhibitors does not improve symptoms or exercise tolerance. Furthermore, treatment with these drugs increases mortality and morbidity in the long term in adult patients with ischemic heart disease. In contrast, milrinone (a phosphodiesterase inhibitor) is commonly used to treat cardiac dysfunction and decompensation in children. The long-term effects of β-agonists or phosphodiesterase inhibitors in infants and young children have not been studied. Inotropic therapy is utilized in acute or decompensated heart failure and as a bridge to surgery, catheter intervention, or cardiac transplant. It is not recommended for long-term treatment of chronic heart failure.

Although digoxin is often thought of as a positive inotropic agent in infants, the effect on contractility is modest at best. In addition, digoxin may improve symptoms even in the absence of a measurable change in cardiac contractile function. For these reasons, beneficial effects of digoxin therapy, if they exist, in chronic heart failure are likely attributable largely to neurohormonal modulation (see below and Chapter 12).

Diuretics. Diuretics produce symptomatic improvement in neonates with pulmonary congestion. By reducing preload, diuretics also decrease wall stress, a potent stimulus for myocardial remodeling. However, diuretics should not be used in the management of patients without signs or symptoms related to pulmonary congestion. Furthermore, when used alone, diuretics may have deleterious effects because of neurohormonal activation (stimulation of the sympathetic nervous system and activation of the renin-angiotensin-aldosterone system) caused by intravascular volume depletion.

Three classes of diuretics are commonly used for the treatment of congestion related to heart failure in infants. Loop diuretics, mainly furosemide, are potent drugs that retain their effectiveness even at very low glomerular filtration rates. The neonatal response to these loop diuretics is reduced because of immaturity of renal secretory mechanisms. Thiazide diuretics (eg, hydrochlorothiazide, chlorothiazide) act in the distal tubules. They are less potent than loop diuretics and are more affected by low cardiac output and thus low glomerular filtration rate. Potassium-sparing diuretics (eg, spironolactone) also act in the distal tubules. Spironolactone diminishes myocardial fibrosis by blocking aldosterone receptors in the myocardium. Potassium-sparing diuretics should be used with caution in infants being treated concomitantly with an angiotensin-converting enzyme inhibitor because of the potential for hyperkalemia.

Diuretic therapy is commonly initiated with a loop diuretic. However, in resistant cases, a thiazide diuretic is added. This combination impairs postdiuretic sodium retention and blocks the adaptive processes that develop during chronic loop diuretic therapy. When a thiazide is combined with a loop diuretic, the thiazide should be given approximately 30 to 60 minutes before the loop diuretic to permit transport in the downstream segment to be blocked fully before it is flooded with solute from the thick ascending limb. This strategy will optimize the natriuretic response.

Vasodilators. Vasodilators are used in the treatment of heart failure in children with impaired ventricular function, semilunar valve regurgitation, or left-to-right shunts. In situations of depressed cardiac contractile function, the administration of a vasodilator may reduce impedance to ejection and improve cardiac output. In an infant with a large left-to-right shunt at the ventricular or arterial level, the magnitude of the shunt is dependent on the relative ratio of systemic to pulmonary vascular resistance. Cardiac contractile function is generally normal or only mildly depressed. Most arteriolar dilators preferentially decrease systemic vascular resistance. Thus, left ventricular output to the systemic circulation increases and the magnitude of left-to-right shunt decreases. However, it is important to note that systemic vascular resistance is low in the normal newborn and in those with large left-to-right shunts who have warm and well perfused extremities. The benefit of vasodilators in these infants is questionable. Moreover, the reduction in left-to-right shunt volume depends on the reactivity of the pulmonary vascular bed as well. If the pulmonary vascular resistance is normal or only mildly elevated (which is commonly the case), then a reduction in systemic vascular resistance by arteriolar dilatation results in increased systemic output and reduction of left-to-right shunt. However, if the pulmonary vascular resistance is elevated and also decreases in response to drug therapy (a less common scenario), there may not be any overall change in the magnitude of the left-to-right shunt. Surgical repair of the defect should be considered for infants with heart failure due to a large left-to-right shunt if growth cannot be improved with medical management.

Angiotensin-converting enzyme inhibitors (ACEi) are widely used for treating chronic heart failure in adults. The preference of ACEi over older classes of vasodilators is related to the effects of different classes of vasodilators on neurohormonal activation. Arteriolar dilators (eg, hydralazine, nifedipine) promote activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system, resulting in reflex tachycardia and sodium and water retention; these responses are deleterious in the long-term treatment of adults with the heart failure syndrome. In contrast, treatment with an ACEi avoids the deleterious effects of activation of the renin-angiotensin-aldosterone system. Their use has been shown to significantly improve long-term survival in adult patients with chronic congestive heart failure. It is advisable to begin patients on relatively low doses and then increase the dose to target levels as tolerated. Reduction of diuretic doses to increase circulating blood volume may be necessary if the patient becomes hypotensive after administration of angiotensin-converting enzyme inhibitors. Because of the favorable effects on neurohormonal modulation (see below and Chapter 12), treatment with an ACEi is recommended even for asymptomatic adults with objective evidence of depressed cardiac function. Currently, it is not known whether such therapy will have the same long-term beneficial effects in infants as has been shown in adults.

Investigators from the Pediatric Heart Network studied enalapril in infants with single ventricle and found no benefit on somatic growth, ventricular function, or heart failure severity compared to placebo. Enalapril is currently not recommended for neonates with a single ventricle. Additional studies are needed to determine the safety, efficacy, and impact of maturational changes in the renin-angiotensin-aldosterone system on drug responses to ACEi in infants.

A new class of vasodilators work by inhibiting nepri- lysin, a neutral endopeptidase that degrades vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin. Thus, inhibition of neprilysin increases the levels of these peptides, resulting in vasodilation and an increase in sodium excretion (diuresis). Sacubitril is a neprilysin inhibitor that was studied as a fixed-dose combination with the angiotensin receptor blocker valsartan in a large study of heart failure in adults. The results were striking and demonstrated considerable benefit in adults with heart failure. This emerging class of drugs holds considerable promise for the treatment of heart failure. However, the role of neprilysin in the pathophysiology of heart failure in infants and the safety and efficacy of neprilysin inhibitors in neonates remain to be determined.

The pulmonary vasodilator sildenafil is being used in infants and neonates with severe heart failure, especially in the presence of decreased ventricular function or significant tricuspid regurgitation. The rationale is that in the setting of decreased left ventricular function, left atrial hypertension increases pulmonary vascular resistance, and sildenafil therapy might be beneficial by reducing right ventricular afterload. Similarly, with significant tricuspid regurgitation, the pulmonary vasodilator effect of sildenafil may improve effective right ventricular output. However, experience with slidenafil in these settings is largely anecdotal, and more definitive studies are necessary to determine the safety and efficacy of sildenafil in neonatal heart failure.

Neurohormonal modulation. As described above, the heart failure syndrome is characterized by generalized increases in sympathetic efferent discharge, activation of the renin-angiotensin-aldosterone system, and stimulation of mediators of myocardial remodeling. Treatment of chronic heart failure is directed at “resetting” this neurohormonal imbalance. Drugs currently used for this purpose in adults include digoxin, ACEi, β-adrenergic receptor blockers, aldosterone antagonists, and angiotensin receptor blockers.

Many of these drugs have not been studied in neonates with heart failure. Even old drugs, such as digoxin, have not been studied in appropriately designed prospective clinical trials of heart failure in infants and children. Although the neurohormonal responses to digoxin have not been defined in infants, the beneficial effects of digoxin in infants with heart failure due to a left-to-right shunt and apparently normal cardiac contractility suggest that neurohormonal modulation by digoxin may play a role in this population as well. Case series and uncontrolled trials of ACEi (mainly captopril or enalapril) in infants and children with left-to-right shunts or dilated cardiomyopathy describe beneficial hemodynamic and clinical responses, but additional studies are needed.

A large body of evidence has accumulated to support the use of β-blockers in the treatment of the heart failure syndrome in adults. Third-generation β-blockers, such as bucindolol and carvedilol, have added vasodilator properties that appear to provide a more favorable hemodynamic profile. Carvedilol also has antioxidant properties that are thought to provide an added cardioprotective benefit against the deleterious effects of oxygen free radicals.

Clinical studies have confirmed increased sympathetic nervous system activity in infants and children with heart failure due to both congenital and acquired causes. There have been several reports of beneficial responses to β-blockers in children, but these studies are uncontrolled or retrospective. Results from the only published randomized controlled trial of β-blocker therapy (carvedilol) in children with heart failure were reported in 2007. This study failed to show a beneficial effect of carvedilol on a composite measure of heart failure outcomes. However, event rates were lower than expected, the study population was heterogeneous, and the trial may have been underpowered. Furthermore, the improvement rate among placebo-treated patients was higher than predicted, and trough carvedilol concentrations in the blood were lower than expected (based on adult studies). Additionally, the high proportion of infants and toddlers may have impacted the overall results, as this age-group tends to have high spontaneous improvement rates. β-blocker therapy is being used in neonates and infants with impaired ventricular function, but further studies are necessary.

Spironolactone, an aldosterone receptor antagonist, decreases myocardial fibrosis that occurs as part of cardiac remodeling in heart failure in adult patients. However, these responses to heart failure and to therapeutic interventions have not been formally studied in infants and children. Although spironolactone has been used routinely as a potassium-sparing diuretic in infants with heart failure, it is not known whether these additional beneficial effects occur in this population.

Angiotensin receptor blockers eg, losartan, valsartan irbesartan, and candesartan) have been tested in adult patients with heart failure. These drugs have comparable benefit to ACEi but cause fewer side effects. There is little experience in infants with heart failure largely because ACEi rarely produce bradykinin-mediated side effects (eg, cough) in this age-group.

In summary, despite an enlarging body of evidence in adult patients related to the favorable effects of drugs targeted at the neurohormonal derangements observed in heart failure, much less information is available to support the use of these drugs in infants. However, it is important to recognize that neurohormonal activation and its pharmacological modulation are likely important in the chronic heart failure syndrome in newborn and young infants. Based on our current understanding of pathophysiology, a general approach to medical therapy for the chronic heart failure syndrome in infants is presented in Figure 11-3. Infants with refractory heart failure and failure to thrive despite medical management should undergo surgical repair or palliation (if a surgical approach is possible) without further delay.

FIGURE 11-3. General therapeutic approach to newborn and young infants with chronic compensated heart failure syndrome. This algorithm is based on currently available evidence. The rationale and additional details are provided in the text.

Emerging Therapies

In addition to neprilysin inhibitors, a number of newly developed agents are undergoing clinical trials in adults with chronic heart failure. Agents that appear to hold the most promise include ivabradine (sinus node slowing), serelaxin (recombinant human relaxin-2; vasodilator action), ularitide (synthetic form of the human natriuretic peptide urodilatin), and omecamtiv mecarbil (cardiac-specific myosin activator). None of these agents has been studied in infants or children, but if safety and efficacy are demonstrated in adults, trials in children may be forthcoming.

Device Therapy

Use of extracorporeal membrane oxygenation and ventricular assist devices is discussed in Chapter 13.

■ NUTRITIONAL THERAPY

Overview

Nutritional therapy is an important component of the comprehensive management of infants with cardiovascular disease. Acute and chronic malnutrition is common in infants with congenital and acquired cardiovascular disease and may be related to the complexity of the medical condition. For example, 80% of infants with complex single ventricle exhibit chronic malnutrition. When faced with a newborn with significant structural cardiovascular disease, caretakers may focus on the acute medical and surgical aspects of the condition and not give the nutritional aspects of neonatal care sufficient priority. Early attention to nutritional needs may ultimately have important positive influences on overall growth, well-being, and long-term outcome. Failure to establish adequate growth in an infant awaiting surgical repair or palliation should be considered a failure of medical therapy and constitutes an indication for surgical intervention, including heart transplantation if other operative intervention is not available.

Etiology of Failure to Thrive

Inadequate growth may result from a variety of factors. Infants born with congenital heart defects have a higher incidence of chromosomal abnormalities. Patients with trisomy 21, deletion 22q11 (DiGeorge) syndrome, or Turner syndrome do not have normal linear growth. Many infants born with congenital cardiovascular disease are appropriately grown for gestational age, but the incidence of intrauterine growth retardation in infants with congenital cardiovascular disease is around 5% to 15%. The role of intrauterine growth retardation in longterm growth failure is not always clear, however. In addition, other factors, such as maternal alcohol and drug consumption and cigarette smoking, may play a role in intrauterine growth retardation. Extracardiac congenital anomalies that may contribute to postnatal failure to thrive include gastroschisis, malrotation, and other intestinal abnormalities. Intestinal malabsorption does not commonly play an important role in poor weight gain in patients with cardiac disease. However, mild malabsorption may occur as a result of impaired intestinal perfusion and/or bowel wall edema and may contribute to poor weight gain when combined with other factors.

In general, the most common cause for failure to thrive in infants with heart failure is a combination of decreased caloric intake and increased energy expenditure. Infants with heart failure simply do not feed well. Newborn and young infants with heart failure tire easily and may be unable to suckle effectively. Fatigue may also result from chronic hypoxia and diminished energy reserves. In addition, pronounced tachypnea may interfere with feeding in young infants, as they are unable to coordinate sucking, swallowing, and breathing. The increased work of breathing causes increased intra-abdominal pressure, which may explain the higher frequency of vomiting in these infants, another cause of decreased caloric intake. Discoordination of sucking and swallowing, delayed gastric emptying, vomiting, and increased total energy expenditure all contribute to growth failure in neonates with cardiovascular disease. Although resting energy expenditure may be normal or only slightly elevated, total energy expenditure is significantly increased in infants with heart failure due to increased energy requirements associated with the work of breathing and feeding.

Diagnosis

Failure to thrive is the chief symptom among infants with many types of cardiovascular disease, especially chronic heart failure. Diminished growth velocity is obvious from plotting the infant’s length, weight, and head circumference on a growth chart. Weight is affected earliest and most severely, then length is suppressed, and only with severe failure to thrive is head growth impaired. A number of biochemical markers have been used to assess nutritional status. Serum albumin is widely used, and hypoalbuminemia has been associated with increased

length of hospital stay and risk of death. Prealbumin has a half-life of 2 days, and serum concentrations correlate better with positive nitrogen balance than do albumin or transferrin levels. Additional testing for other etiologies of failure to thrive is not necessary in these infants unless there is a marked discrepancy between the apparent clinical severity of heart failure and the severity of growth failure.

Treatment

Calorie and protein requirements of infants with cardiovascular disease are generally greater than those of normal infants. Normal infants require 100 to 120 kcal/kg/d for optimal growth. Infants with cardiovascular disease may require 120 to 160 kcal/kg/d to maintain appropriate weight gain (approximately 30 g/d in term neonates). Standard infant formulas and breast milk contain 20 kcal/ oz. Infants with significant heart failure may not be able to tolerate the fluid load necessary to provide sufficient calories. In this setting, formula (or fortified breast milk) with a higher caloric density should be employed. Fluid requirements must be individualized and may change, depending on the course of the disease and changes in diuretic therapy. In general, sodium restriction is not recommended for neonates with heart failure since provision of less than 2 mEq/kg/d may result in hyponatremia and growth impairment.

The caloric density of standard infant formula or breast milk may be increased to 24 to 30 kcal/oz using either of two general methods (formula greater than 30 kcal/oz can be used, but this often produces an osmotic diarrhea). One method is to prepare concentrated or powdered formula with less water. This has the advantage of being relatively simple but carries the disadvantage of high solute (and sodium) load. In a similar fashion, breast milk can be supplemented with powdered formula. Generally, infants will tolerate formula or breast milk concentrated to 24 to 27 kcal/oz. If the caloric density required exceeds 27 kcal/oz, then the concentration method should not be used to further increase caloric density. Instead, the alternative method of adding supplements to formula or breast milk should be employed to increase the caloric density. Several commercial breast milk fortifiers are available that have been developed for preterm infants. Caloric density should not be increased abruptly, as that is likely to produce emesis and/or diarrhea. Instead, caloric density should be increased by 3 kcal/oz every 24 hours as tolerated (defined as minimal emesis and no diarrhea).

Thus, it will take about 3 days to incrementally advance an infant from 20 to 30 kcal/oz.

Increasing the caloric content of infant formula or breast milk may increase the respiratory quotient if all of the added calories are in the form of a glucose polymer. Infants with chronic heart failure are prone to contraction alkalosis (secondary to diuretic therapy), which, if combined with an increased carbohydrate load, may lead to either inadequate ventilation or even greater caloric expenditure from excessive use of respiratory muscles.

Comprehensive nutritional therapy not only includes provision of sufficient calories and nutrients but also involves attention to specific feeding problems and educational efforts to ensure the family’s ability to provide specialized care at home. It is often helpful to enlist the assistance of nutritionists and social workers for infants with especially difficult or demanding nutritional needs. In addition, occupational and physical therapists with special expertise in infant oral-motor feeding techniques may provide invaluable advice and practical assistance.

If an infant is failing to thrive despite attention to feeding issues and increased caloric density, it may be necessary to intensify nutritional support by providing nasogastric or orogastric feeds or feeding via a gastrostomy tube. Occasionally, a fundoplication is necessary when a gastrostomy tube is placed if the infant has persistent emesis despite maximal gastroesophageal reflux therapy. The most effective method of improving nutritional status is by 24-hour continuous enteral feeding. If the infant is at home, it is easier for the family if the feeding is for a total of 18 to 20 hours per day to allow time for bathing, formula preparation, travel, and so on. The disadvantage to strict tube feeding and completely avoiding oral feeding is that this approach may contribute to poor oral-motor function and delay progression of adequate oral intake. It is therefore recommended that tube feeding be combined with strategies to maintain oral-motor feeding skills.

Several approaches can be used to combine oral feeding with tube feeding to provide adequate caloric intake and maintain oral-motor feeding skills. One approach is to allow the infant to feed by nipple for a restricted period of time (generally 10, 15, or 20 minutes) and then administer the remainder of the prescribed volume via the nasogastric tube. It is very important that the parents and the nursing staff observe the strict limit on nippling time. Another commonly used approach is to encourage ad libitum oral feeding of calorically enriched formula (or breast milk) throughout the day (8 to 12 hours) and then provide the balance of the daily nutritional needs by continuous feeding at night.

Regardless of the specific regimen used, it is of utmost importance that infants receive all of their prescribed feedings each day, or they will not gain weight well. This must be emphasized to parents and to nursing staff. In addition, parents should be informed that solid foods provide fewer calories per volume as compared to the 24- to 30-kcal/oz formula. As such, it is often recommended that the introduction of solid foods be delayed in infants with moderate to severe growth failure.

■ MISCELLANEOUS MEDICAL PROBLEMS

Infective Endocarditis

Overview

Neonates with cardiac structural defects are at risk for infective endocarditis, although the incidence is low. The most common presentation is that of unexplained fever, often in the setting of indwelling intravascular catheters. Newborns without structural cardiovascular disease may also acquire infective endocarditis related to the presence of intravascular catheters. The organisms most frequently recovered in cases of neonatal infective endocarditis include coagulase-positive and coagulase-negative staphylococci, fungi (Candida species), and Gram-negative organisms. This pattern is different from that observed in older children and adults with infective endocarditis.

Diagnosis

The diagnosis of infective endocarditis in newborns can be difficult and requires thoughtful and comprehensive assessment. Unexplained fever requires a thorough evaluation for sources of fever. Blood cultures are an essential part of the diagnostic work-up. Studies in adult patients demonstrate that the bacteremia of endocarditis is continuous, so cultures can be taken anytime (it is not necessary to wait for a “fever spike”). Because the number of viable organisms in the blood may be relatively low, it is helpful to obtain two or three separate sets of blood cultures drawn several hours apart. Since staphylococci are common causes of both neonatal endocarditis and false-positive contamination of culture specimens, it is imperative that strict attention be paid to maintain sterile techniques during procurement of the specimens. Laboratory findings include leukocytosis and elevated acute-phase reactants (C-reactive protein and erythrocyte sedimentation rate). Urinalysis and culture should be performed, as bacteria or fungi may be isolated from the urine. In addition, there may be proteinuria or hematuria, consistent with an inflammatory process.

Echocardiography plays an important role in determining the presence or absence of structural cardiac defects. Furthermore, ultrasound can be used to image the tips of intravascular catheters in an effort to determine whether there is evidence of a vegetation or thrombus on the catheter or adjacent tissue. However, it is important to stress that echocardiography is not diagnostic of either the presence or the absence of infective endocarditis. In other words, even in the setting of a completely normal echocardiogram, endocarditis may be present. Conversely, a “positive echocardiogram” does not necessarily indicate the presence of infection. Thus, the echocardiogram cannot exclude endocarditis. Echocardiography is very helpful in the setting of positive blood cultures and a definite intracardiac or intravascular mass (vegetation) observed echocardiographically. Serial echocardiograms can be used to monitor progress and resolution of the vegetation.

A common clinical problem arises when an infant with congenital cardiovascular disease and an indwelling central catheter or PICC line develops signs and symptoms of infection. The question arises as to whether this represents an infected catheter or true endocarditis. It is helpful to obtain cultures drawn through the catheter and from a separate site. If the culture from the catheter is positive in the absence of a positive peripheral culture, then an infected catheter (and not endocarditis) is most likely. If both the culture drawn through the catheter and the peripheral culture are positive, the situation is less clear, and the source of bacteremia could be the catheter, endocarditis, or some other source. In this case, some centers compare the time it takes for the cultures from the catheter and a peripheral site to become positive. If the two cultures are positive simultaneously, then bacteremia is not likely to be from the catheter; if the culture from the catheter becomes positive more quickly than the peripheral culture, then the catheter is considered as the source of the infection, and removal is advised. If evidence of ongoing infection persists even after the infected catheter is removed, then a reassessment for the possibility of endocarditis is warranted. In some cases, removal of the catheter is not feasible. There have been reports of successful treatment without removing the catheter, but this often requires prolonged therapy and is not recommended as the first choice if the catheter is thought to be the source of the infection.

Therapy

Appropriate targeted treatment of infective endocarditis requires identification of the responsible organism. The importance of obtaining proper cultures prior to initiating antimicrobial therapy cannot be underestimated. Culture-negative endocarditis in neonates is exceedingly rare, so a broad-spectrum approach to therapy is generally not necessary. When there is a high index of suspicion and culture results are pending, it is reasonable to initiate therapy directed at the most likely organism (eg, staphylococci). Therapy should be modified once culture and sensitivity results are available.

Treatment of fungal endocarditis in neonates can be an extremely challenging clinical problem. These infants often have multiple sites of infection and require a prolonged course of antifungal therapy. If there is evidence of an infected intracardiac or intravascular thrombus, then surgical intervention may be necessary. This is especially important in the setting of an infected prosthetic material (such as a shunt or intracardiac patch). It is difficult to resolve a fungal infection of a prosthetic material without removal of the infected prosthesis.

Endocarditis Prophylaxis

Prophylaxis of infective endocarditis should follow the guidelines recommended by the American Heart Association (see “Suggested Readings”). Infants with congenital cardiovascular disease undergoing cardiac surgery should receive antibiotic prophylaxis directed toward staphylococci (a cephalosporin or vancomycin), but treatment should be restricted to the perioperative period (no longer than 48 hours postoperatively). There is no evidence that a longer course of antibiotic “prophylaxis” for cardiac surgical patients is beneficial, and, indeed, there may be an increased incidence of acquired infections with other organisms (especially in neonates).

Infants undergoing cardiac catheterization generally receive endocarditis prophylaxis only when a device, stent, or other foreign body is implanted. Routine circumcision does not require endocarditis prophylaxis. Similarly, prophylaxis is not indicated for most infants with unrepaired congenital cardiovascular disease undergoing unrelated surgical procedures. Current American Heart Association guidelines should be followed for infants with structural cardiac defects who require invasive diagnostic or surgical procedures.

Intracardiac and Intravascular Thrombi

Formation of a clot at the tip of an indwelling catheter is an extremely common phenomenon. Similarly, a thrombus may form on the wall of the atrium at the site where a catheter tip is located. These situations can present a challenge as to the proper course of therapy. Ultrasound can be very helpful in defining the location, extent, and size of such thrombi. In many cases, there is no need for any specific intervention. If a large mobile mass is observed, then it may be appropriate to administer heparin in an attempt to prevent extension of the clot. Heparin is not thrombolytic, but it may prevent enlargement and allow normal thrombolytic processes to resolve the clot. Removal of the indwelling catheter may be necessary for complete resolution. There is a risk of embolization when there is a large mobile thrombus. Most infants will have a patent foramen ovale, so the risk of systemic embolization exists. However, significant embolic complications appear to be quite rare, although relatively few data are available. Risks of heparin therapy must be considered, especially in critically ill neonates and preterm infants.

If a catheter becomes occluded, it is important not to forcibly flush a clotted catheter, as this can cause embolization. Dissolution of the clot can be attempted by filling the catheter with a small volume (equal to the catheter volume) of tissue plasminogen activator at a concentration of 1 mg/mL. The catheter is clamped for 5 to 15 minutes, and then the contents are aspirated. If the clot cannot be dissolved, then removal of the catheter is recommended.