Neonatal Cardiology, 3rd Ed. Michael Artman

Chapter 12. Cardiovascular Drug Therapy

■ GENERAL PRINCIPLES OF PHARMACOLOGICAL THERAPY

■ PHARMACOKINETIC PRINCIPLES

Absorption

Drug Distribution

Body Composition

Metabolism

Excretion

Pharmacogenomics

■ THERAPEUTIC DRUG MONITORING

■ BIOMARKERS

■ DRUG INTERACTIONS

■ CARDIOVASCULAR PHARMACOLOGY

■ POSITIVE INOTROPIC AGENTS

Digoxin

■ ADRENERGIC AGONISTS

Dopamine

Fenoldopam

Epinephrine

Phenylephrine

Norepinephrine Isoproterenol

■ PHOSPHODIESTERASE INHIBITORS

Milrinone

■ DIURETICS

Loop Diuretics

Thiazide Diuretics

Potassium-Sparing Diuretics

■ VASODILATORS

Nitrovasodilators

Pulmonary Vasodilators

Calcium Channel Antagonists

Angiotensin-Converting Enzyme (ACE) Inhibitors

Angiotensin Receptor Blockers a-Adrenergic Receptor Antagonists Neprilysin Inhibitors

■ ALDOSTERONE RECEPTOR ANTAGONISTS

■ HORMONES

Nesiritide

Thryoxine and Triiodothyronine Vasopressin

■ β-ADRENERGIC RECEPTOR BLOCKERS

Propranolol

Atenolol

Esmolol

Carvedilol

■ PROSTAGLANDIN E1

■ SUGGESTED READINGS

■ GENERAL PRINCIPLES OF PHARMACOLOGICAL THERAPY

Although a large number of specific therapeutic agents are available for treatment of patients with cardiovascular disease, most of these drugs have never been rigorously tested in clinical trials conducted in infants and children with heart disease. Testing in the pediatric population has been included relatively recently as a requirement for gaining Food and Drug Administration approval for a new drug. Even so, most drugs currently used to treat infants with cardiac conditions have not been evaluated with respect to pharmacokinetics, efficacy, or safety in this population.

The number of drugs available to treat cardiovascular disorders is enormous. Rather than attempting to maintain extensive knowledge about each specific drug, it is much more practical to understand principles and mechanisms of action according to drug classification. Practical differences among drugs within a given class are often of minimal clinical significance. A useful approach is to understand general mechanisms of action and to become familiar with one or two specific agents within a given class. In this manner, a small “personal” formulary can be developed that greatly simplifies the amount of information necessary to provide appropriate therapy. It is also important to stay current, be alert to new drug developments, and be willing to modify the approach to drug therapy as new information becomes available.

Drug therapy in infants should be founded on sound principles of clinical pharmacology. Ideally, drug administration is justified only if sufficient data exist to indicate that the overall morbidity or mortality of the disease is reduced by therapy and the beneficial effects outweigh the adverse drug effects. However, information regarding basic and clinical pharmacology of many drugs is simply not available in the neonatal population. Drug therapy for infants with cardiovascular disease is therefore usually extrapolated from studies performed in adult patients or older children and is often guided by personal experience, anecdotal reports, tradition, or uncritical acceptance of drug advertising. Medications are often administered on the basis of personal belief that a drug is effective, sometimes even in the face of scientific evidence to the contrary.

The general concept of rational drug therapy (Table 12-1) is to prescribe drugs in an attempt to maximize efficacy and to minimize adverse drug effects. This implies that therapy is tailored to the needs of a particular patient and clinical situation. Nowhere is this more important than in the newborn population. Adverse or toxic effects of a drug in neonates may not become clear until the drug has been marketed for many years. Even though a drug is commercially available and has been used in adults, it may not be safe or effective in a newborn with heart disease.

TABLE 12-1. Guidelines for Rational Drug Therapy

• Reasonable certainty of the diagnosis

• Understanding of the disease pathophysiology

• Knowledge of the clinical pharmacology of the available drugs for the condition

• Individualizing the specific drug and dose for the particular patient

• Defining end points of efficacy and toxicity

• Appropriate monitoring for therapeutic and toxic end points

• Willingness to change therapy if drug efficacy is not apparent or if unacceptable toxicity occurs

Adherence to the general features of rational drug therapy, which avoids prescribing on the basis of personal beliefs, will most certainly improve use of medications. A firm understanding of the pathophysiology of the disease being treated is also necessary to provide effective drug therapy, so it is important to make every attempt to establish a diagnosis with certainty.

Application of drug therapy to a specific neonatal patient should be considered a “therapeutic experiment.” Even if specific information regarding the pharmacology, pharmacodynamics, and pharmacokinetics of a particular drug is available for neonates, an individual patient may not have been exposed to the specific chemical entity to be administered. Furthermore, although the drug may have been tested in neonates with other conditions, the underlying pathophysiology and genetic makeup of a specific patient may affect the response to the medication. If drug administration is approached as a therapeutic experiment in every patient, a heightened awareness of drug efficacy and toxicity is generated. It is imperative to set end points of therapy, to monitor appropriately for such end points, and to observe carefully for adverse drug effects. The approach to rational and age-appropriate drug therapy must be based on a firm understanding of drug metabolism, distribution, receptor/effector ontogeny, and knowledge of the molecular and cellular processes involved in regulation of cardiovascular function in preterm and term neonates.

■ PHARMACOKINETIC PRINCIPLES

Pharmacokinetics defines drug concentrations in mathematical and kinetic terms. Absorption, distribution, metabolism, and excretion all affect the pharmacokinetic profile of a particular drug. Each of these processes can be described in quantitative terms. These principles are especially useful if the pharmacodynamic effects of a particular drug can be related to the concentration of the drug. Fortunately, for most drugs, a close relationship exists between the pharmacodynamic action of the drug and the concentration of the drug at the receptor site of action. Thus, understanding the various factors that influence the overall pharmacokinetic profile of a given drug is important in developing a rational and age-appropriate therapeutic strategy.

Absorption

Drugs are administered by intravenous infusion or by extravascular routes (orally, sublingually, intramuscularly, subcutaneously, rectally, or by inhalation). For extravascular routes of administration, the drug must be absorbed across cell membranes to reach the bloodstream, where distribution subsequently occurs. In selected cases, inhalational therapy provides a high concentration of the drug at the site of action in the lungs (eg, nitric oxide therapy). Most drugs move through membranes by passive diffusion, and therefore drug movement is regulated by the physicochemical properties of the drug, membrane characteristics, pH, and local blood flow.

Drug absorption following intramuscular injection is generally erratic and less reliable than other routes. Perfusion and blood flow to muscle beds is variable and may change rapidly, especially in critically ill newborns. Neonates and preterm infants have relatively little muscle mass, making injection technically difficult. Furthermore, many drugs are insufficiently soluble and are not amenable to intramuscular administration. Thus, intramuscular injections in neonates should be avoided. On the other hand, subcutaneous injection of drugs such as enoxaparin is becoming more common in neonates.

Gastrointestinal Absorption

Diffusion largely drives drug absorption from the gastrointestinal tract. The rate and extent of drug absorption are therefore influenced by gastrointestinal motility, absorptive surface area, pH (which affects ionization of the drug), and gastrointestinal contents. Developmental changes in gastrointestinal characteristics include a relatively greater gastrointestinal surface area (relative to body size), higher gastric pH, delayed gastrointestinal transit time, and the presence of p glucuronidase in the intestinal lumen. Despite important differences in gastrointestinal function, few controlled studies of oral drug bioavailability in neonates are available. A relatively higher gastric pH will reduce the absorption of enterally administered drugs that are poorly ionized. In contrast, the relatively larger surface area of the newborn gastrointestinal tract may potentially increase absorption of many drugs. Gastric emptying and intestinal transit times are often reduced in newborns, especially those with cardiovascular disease who intermittently may have impaired intestinal perfusion. For these reasons, drug absorption varies considerably not only among different patients but even within the same patient at different times.

In addition, drug-metabolizing enzymes and transporters in the intestine can affect the bioavailability of a number of drugs administered orally. Many of these enzymes undergo developmental changes in expression and activity. For example, intestinal expression of CYP3A and CYP1A1 is low at birth and increases with increasing age. The reduced activity at birth results in lower clearance of substrates for these enzymes and higher plasma concentrations of the active compound. Examples of drugs that are metabolized by these pathways include alprazolam, amlodipine, and dexamethasone.

Drug Distribution

Distribution refers to the processes involved in partitioning of a drug among the various body tissues and organs. In general, the movements of drugs throughout tissues are reversible from one location to another and are affected by relative concentrations of the drug at various sites. Drug concentrations in various compartments are in turn determined by many factors, including blood flow, physicochemical properties of the drug, pH, composition of body fluids and tissues, drug binding in the plasma, and drug binding to other tissue proteins. The route of administration is an important determinant of drug distribution, especially in the early phases after administration. Following oral administration, the liver is the first major organ to encounter a drug, whereas the heart and lungs will receive the greatest initial concentration of a drug administered intravenously. The free drug concentration is generally the most reliable determinant of the concentration of the drug at the receptor sites. Therefore, binding to plasma proteins can be an important factor in modulating drug distribution, doseresponse relationships, and drug clearance. In general, fundamental age-related differences in the composition of the proteins involved in drug binding diminish binding of drugs to plasma proteins in newborns compared with adults.

Body Composition

Important changes in body composition occur during development that may have profound effects on drug distribution. In a normal full term infant, total body water makes up approximately 75% to 80% of body weight. After birth, there is a rapid fall in total body water and a relative increase in intracellular fluid. By 1 year of age, total body water makes up approximately 60% of body weight. Fat tissue represents only approximately 3% of total body weight in a 28 week gestation premature infant, in contrast to 15% to 28% of the body weight as fat in a term newborn. In newborns, especially premature newborns, the relatively greater proportion of total body water and the lower total body fat content undoubtedly affect the apparent volume of distribution of many drugs.

Apparent volume of distribution is the theoretical volume of fluid into which the total amount of drug administered would have to be diluted to produce the resulting concentration in the plasma. Apparent volume of distribution is influenced by a number of patient variables (including regional perfusion, distribution of fat, muscle and body water, and cell permeability) and drug variables (including protein binding and lipid and water solubility). Many commonly used drugs have a larger apparent volume of distribution in premature and newborn infants (eg, furosemide, theophylline, and aminoglycosides). This becomes especially important when a loading dose is administered since the volume of distribution is a major determinant of an appropriate loading dose.

Metabolism

The two major categories of metabolic or biotransformation reactions are the nonsynthetic (phase I) reactions, such as oxidation, reduction, or hydrolysis, and the synthetic (phase II) reactions, such as sulfation or glucuronidation. Phase I reactions often are followed by a phase II reaction. These processes increase the water solubility of a drug and promote clearance. Most drug metabolism occurs in the liver, but other organs and tissues can contribute significantly to drug metabolism (blood, lungs, gastrointestinal tract, and kidneys). In addition to facilitating more rapid drug clearance, biotransformation may result in either toxic or therapeutically active metabolites. Hepatic metabolism is generally reduced in newborns compared with adults, but this does not uniformly apply to all drugs. In the neonatal period, most phase l and phase II reaction rates are diminished and are more readily saturated. As a result, neonates generally exhibit reduced clearance rates and longer half lives for drugs that are eliminated by biotransformation. However, drug metabolism may change rapidly in the first few months after birth, necessitating appropriate dosage adjustments. Table 12-2 highlights selected aspects of neonatal drug metabolism.

TABLE 12-2. General Features of Drug Metabolism in Neonates

• Drug metabolism and clearance vary according to gestational age and are often variable even among patients of comparable gestation.

• Biotransformation processes are slower than in adults.

• Elimination is slower compared with adults.

• Novel biotransformation pathways may exist in neonates.

• Esterase activity is reduced compared with adults.

Some drugs, such as angiotensin-converting enzyme inhibitors, are administered in the form of a prodrug. Prodrugs are inactive dosage forms (usually salts or esters) that must be hydrolyzed to release the active form of the drug. Hydrolysis and esterase activity may be quite variable in newborns. Relatively little information is currently available regarding the potential impact of age related differences in de-esterification.

Excretion

Renal excretion is the major pathway for the elimination of most drugs and drug metabolites. Maturation of renal function is well characterized, and much of it occurs after birth. Changes in renal function that occur with gestational age, chronological age, and underlying disease state must be considered for every drug that is eliminated principally via the kidneys. Since congenital heart disease may be associated with reduced renal perfusion, renal function must be monitored in these patients.

Pharmacogenomics

Developmental pharmacogenomics involves both development and genetic constitution as determinants of drug disposition and/or drug response. In adults, genotypephenotype relationships are largely constant. In contrast, during the perinatal period, numerous processes affecting either pharmacokinetics (eg, drug-metabolizing enzymes and transporters) or pharmacodynamics (eg, receptor expression and signal transduction) are developmentally regulated and undergo changes in expression and activity. This adds further complexity to the genotype-phenotype relationship.

Defining the developmental expression and functional activity of genes involved in determining drug responses is essential for understanding the genotype-phenotype relationship. This is an emerging field, and the effect of normal and abnormal ontogeny on the genotype-phenotype relationships for drug-metabolizing enzymes, transporters, and/or receptor expression has not been investigated during development. If genotype and phenotype are concordant, genotyping can theoretically be used to predict the activity of a drug-metabolizing enzyme or transporter (ie, the phenotype). This has been demonstrated for the cytochrome P450 enzyme, CYP2D6, for which an “activity score” predictive of enzyme activity was constructed following consideration of over 25 different allelic variants and their functional consequences. The potential clinical utility of genotype-derived activity scores will be realized if the score can be shown to predict drug clearance.

Developmental changes in the functional capacity of drug-metabolizing enzymes and transporters are not the only variables affecting the genotype-phenotype relationship. Evidence continues to emerge regarding the impact of the changing intestinal microbiome on drug absorption, metabolism, and regulation of enzyme and transporter expression. For example, breast milk has a different effect on the developmental acquisition of CYP1A2 activity than does formula. Additional investigation is needed to provide further insights into postnatal changes in drug responses. Such insights are essential in order to improve the precision with which drugs are administered to newborns and infants with cardiovascular diseases.

■ THERAPEUTIC DRUG MONITORING

Rational use of therapeutic drug monitoring can be very helpful in adjusting drug dosing, especially in critically ill newborns. The capability to measure the plasma concentration of the most commonly used drugs is widely available. However, a clear relationship between the plasma drug concentration and the pharmacodynamic or toxic effects must be present to provide maximal benefit.

Although guidelines are available for “therapeutic” drug concentrations for many cardiovascular drugs, these values are derived largely from adult population studies. An individual infant may be more or less sensitive to the therapeutic and toxic effects of a specific drug. Some patients will obtain a beneficial effect at steady state plasma concentrations lower than the therapeutic threshold listed by the laboratory. In these cases, increasing the dosage simply to achieve a laboratory value within the therapeutic range is not necessary and could be harmful. Conversely, maintaining a higher-than-usual steady state plasma concentration to achieve efficacy is acceptable if toxicity is absent. Therapeutic drug monitoring is especially useful for antiarrhythmic drugs in complex patients, critically ill patients receiving multiple drugs, or infants with impaired renal and/or hepatic function.

■ BIOMARKERS

Biomarkers are biological molecules that serve as a sign or signal of a normal or abnormal process associated with a given disease or condition. The National Institutes of Health defines a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes or pharmacologic responses to a therapeutic intervention.” Given the difficulties in correlating pharmacokinetics with pharmacodynamics in neonates, measurement of a biomarker to assess the impact of both disease and development on drug responses (including toxicity) in neonatal patients holds great promise.

However, in contrast to studies in adults where multiple biomarkers have been validated and are increasingly used to support drug development, relatively little information is available for pediatric patients. Children have been called “biomarker orphans” because of the challenges in biomarker development in this population, including the need for invasive and repeated sampling, the lack of disease burden relative to adults, and the potential impact of developmental changes per se on a given biomarker. Examples of this latter challenge include understanding how the ontogeny of renal function influences biomarkers used to assess renal injury (eg, NGAL and KIM-1), developmental differences in disease expression, and age-dependent differences in the activity of drug-metabolizing enzymes used as biomarkers to predict drug clearance.

Despite the overall lag in biomarker development for infants and children, some progress has been made recently. For example, protein or peptide biomarkers are being used in a variety of pediatric diseases, including cancer, asthma, biliary atresia, bronchopulmonary dysplasia, nephrotic syndrome, acute renal injury, traumatic brain injury, juvenile idiopathic arthritis, and eosinophilic gastroduodenititis. Although work is ongoing, practical application of biomarkers is very limited in neonates with cardiovascular diseases.

■ DRUG INTERACTIONS

Drug interactions represent an often-neglected source of potential morbidity. In contrast to adult patients with multiorgan system diseases and multiple-drug therapies, neonates are generally managed with a limited number of medications. However, potential adverse drug interactions exist among the most commonly used cardiovascular drugs in newborns. Table 12-3 lists some of the most commonly used cardiovascular drugs in the neonatal period and the clinically relevant drug-drug interactions that might occur with their use. This is a selected and limited listing. Additional references should be consulted when using other drug combinations. Many hospital pharmacies automatically survey for potential drug interactions, but even if they do not, hospital pharmacists are generally an excellent source of information regarding drug interactions.

TABLE 12-3. Common Cardiovascular Drug Interactions in Neonates

Drug	Interaction	Effect
Digoxin	Amiodarone	Reduced digoxin clearance (decrease digoxin dose)
	Amphotericin B	Hypokalemia (digoxin toxicity; monitor serum K+)
	Diuretics	Hypokalemia (digoxin toxicity; monitor serum K+)
	Flecainide	Reduced digoxin clearance (decrease digoxin dose)
	Spironolactone	Possible reduced digoxin clearance (monitor digoxin level)
Furosemide	Aminoglycosides	Increased nephro- and ototoxicity
Adenosine	Theophylline; Caffeine	Diminished adenosine effect (increase adenosine dose)
ACE inhibitors	Furosemide	Potential for renal dysfunction
	Spironolactone	Hyperkalemia

■ CARDIOVASCULAR PHARMACOLOGY

As understanding of the cellular and molecular aspects of cardiovascular diseases in adult patients has increased, cardiovascular drug therapy has expanded considerably in the past few decades. Many drugs are marketed for the treatment of heart failure and hypertension. In contrast, far less attention has been directed toward the immature heart and cardiovascular system. Although there are relatively few developmental studies, in almost every study published to date, drugs developed for adults affect contractile function in a qualitatively or quantitatively different fashion in immature myocardium. As described in Chapter 2, the fundamental processes involved in contraction, relaxation, and calcium regulation undergo maturational changes in the perinatal period. Important age-related differences exist in virtually all of the cellular components and signaling pathways that are involved in the mechanism(s) of action of conventional pharmacological agents. As a result, the responses to these drugs in the immature cardiovascular system are often poorly understood and may be unpredictable and suboptimal.

This chapter presents an overview of drugs that are most commonly used to treat cardiovascular diseases in neonates. Emphasis is on the management of heart failure since acute and compensated heart failure are common problems in this patient population. Dosage guidelines for commonly used cardiovascular drugs are presented in Table 12-4. Antiarrhythmic agents are discussed in Chapter 10.

■ POSITIVE INOTROPIC AGENTS

The three major classes of inotropic agents currently used in infants include cardiac glycosides, β-adrenergic agonists and phosphodiesterase inhibitors. In every case, important developmental differences influence the responses to drugs from among these classes. For example, age-related changes occur in β-adrenergic receptor/ effector coupling, G protein distribution, adenylyl cyclase activity/isoform expression, cAMP-dependent protein kinase activity, and expression and distribution of cyclic nucleotide phosphodiesterases and protein phosphatases. Little is known regarding the determinants of the matu- rational changes in responses to cardiac glycosides (such as digoxin). Nonetheless, these drugs are widely used in the neonatal population, even though documentation of their efficacy and safety is inadequate.

Digoxin

Digoxin is the cardiac glycoside used in neonates. The primary mechanism of action of digoxin is related to inhibition of sarcolemmal Na+-K+ ATPase activity (Figure 12-1). This inhibition produces a slight increase in intracellular sodium concentration. This change in the transsarcolemmal sodium gradient affects sodium-calcium exchange activity, which causes an increase in intracellular calcium concentration. As a result, more calcium is available for delivery to and from the contractile proteins, and contractility increases. In addition to direct myocardial effects, digoxin slows cardiac conduction and heart rate, making this agent also useful in treating supraventricular tachycardia.

Digoxin is readily absorbed from the gastrointestinal tract. In general, this is the preferred route of administration, but digoxin may be administered intravenously if necessary. Peak serum levels occur approximately 30 to 90 minutes after an oral dose. During the initial phase of distribution, the drug is distributed to tissue-binding sites. Following distribution and tissue binding, digoxin is excreted by the kidneys with a half-life of approximately 20 hours in infants (compared with 40 hours in older children). The half-life is increased in premature infants due to slower renal elimination. The clearance of digoxin is directly related to renal function, and the dosage must be adjusted in patients with impaired or immature renal function.

Because digoxin has a large volume of distribution, therapy may be started with administration of a loading dose. The loading dose (digitalization dose) is generally divided over 12 to 24 hours (one-half total loading dose initially; one-quarter 6 to 12 hours later; one-quarter 12 to 24 hours after the initial dose). It should be recognized, however, that administration of a loading dose is associated with a higher incidence of toxic effects in newborns. Rarely is digoxin required as an emergency, and other drugs are available that can be given intravenously until digoxin reaches steady-state levels (approximately 5 days after starting maintenance therapy). Thus, it is reasonable in most cases to begin maintenance dose therapy without a loading dose. Digoxin may be given once daily based on pharmacokinetic studies in infants. This may simplify the medical regimen, and, in general, once-a-day dosing improves compliance. However, many pediatric cardiologists prescribe twice-a-day dosing of digoxin to neonates and infants, based on historical convention.

FIGURE 12-1. Cellular mechanism of action of digoxin. Digoxin inhibits the plasma membrane sodium pump (Na+-K+- ATPase). This results in a slight increase in intracellular sodium concentration, which then influences the activity of the sodiumcalcium exchanger (NCX). The net effect within the myocyte is an increase in intracellular calcium with more calcium delivered to the contractile protein complex. This provides a positive inotropic effect. However, digoxin binds to sodium pumps ubiquitously distributed throughout the body. The overall response to digoxin therapy in heart failure involves changes in neurohormonal activity mediated by the actions of digoxin in other organs besides the heart (see text for more details).

Although digoxin concentration in the blood can be readily measured, routine monitoring of serum digoxin levels is not necessary. In addition, the presence of endogenous digoxin-like immunoreactive substances in infants may confound interpretation of serum digoxin concentrations in newborns. If drug concentration monitoring is performed, trough serum concentrations should be used to guide adjustments in therapy. Because of the lack of relationship between higher serum levels and a greater therapeutic effect, the target serum digoxin levels should range between 1 and 2 ng/mL in neonates, similar to infants and older children. The major indication for obtaining a serum digoxin concentration is in cases of known or suspected digoxin toxicity. This occurs most commonly in cases of accidental overdose and in complicated patients with renal failure or those taking medications that may interfere with digoxin clearance. Newborns and infants are less prone to arrhythmias induced by digoxin than are adults with ischemic heart disease.

The major indication for digoxin is heart failure with impaired myocardial contractile function. Numerous studies in adult patients have confirmed the beneficial effects of digoxin for congestive heart failure. However, controversy exists regarding the magnitude of the positive inotropic effect of digoxin in newborns with heart disease. No randomized, prospective, controlled clinical trials of digoxin have been performed in this population. Thus, recommendations are based largely on inferences drawn from adult studies and animal experiments.

The efficacy of digoxin for infants with heart failure due to a large left-to-right shunt is even more controversial. Most infants with intracardiac left-to-right shunts have normal systolic ventricular function and likely do not benefit from a positive inotropic agent. Manipulation of loading conditions with diuretics is a more rational approach and should be used initially. However, some patients who are very tachycardic because of sympathetic nervous system stimulation may be benefit from digoxin. Consistent with this approach, digoxin has been shown to exert important neurohormonal modulating effects in adult patients with congestive heart failure (Table 12-5). These effects may provide substantial benefits, even in the absence of measurable objective changes in cardiac function. However, the neurohormonal effects of digoxin remain to be studied in neonates with heart disease and may include beneficial noncardiac effects, such as a decrease in oxygen consumption by suppressing brown-fat metabolism.

TABLE 12-5. Neurohormonal Effects of Digoxin

• Restores baroreceptor sensitivity

• Increases vagal tone

• Decreases central sympathetic outflow

• Decreases myocardial response toβ-adrenergic receptor stimulation

• Decreases plasma norepinephrine

• Decreases activation of the renin-angiotensin- aldosterone system

Digoxin has a narrow therapeutic window, and one must always be alert to the potential for digoxin toxicity. Common signs and symptoms of systemic toxicity in adults (anorexia, vomiting, visual disturbances, and central nervous system disturbances) may be especially difficult to recognize in infants. Digoxin toxicity should be suspected in any neonate receiving digoxin who manifests apathy toward feeding or feeding intolerance. Cardiac toxicity in infants is often manifest as high-degree atrioventricular block (second or third degree) with resulting bradycardia. Prolongation of the PR interval is an expected consequence of digoxin effect and is not a sign of toxicity. In addition to atrioventricular block, virtually any type of arrhythmia can be produced by digoxin toxicity. Unless toxicity is suspected, it is not necessary to routinely obtain an electrocardiogram (ECG) or measure the heart rate prior to administration of digoxin. Drugs that may predispose to digoxin toxicity include diuretics (hypokalemia) and amiodarone (reduced elimination of digoxin). Treatment of acute digoxin toxicity requires hemodynamic and ECG monitoring, temporary cardiac pacing if necessary, normalization of serum potassium levels, and antiarrhythmic drug therapy. In cases of lifethreatening arrhythmias, specific Fab antibody fragments should be administered intravenously.

■ ADRENERGIC AGONISTS

The responses to adrenergic agonists are mediated by specific receptors. Although grossly oversimplified, a convenient scheme for understanding the predominant actions of adrenergic agonists is to consider that the heart contains mainly β₁-, the lungs contain β2-, and the vasculature contains β₂- and a-adrenergic receptors. Stimulation of β1-adrenergic receptors in the mature heart increases rate, contractility, relaxation, and conduction. These events are mediated by G-protein-coupled stimulation of adenylyl cyclase, generation of cAMP, activation of cAMP-dependent protein kinase, and phosphorylation of key regulatory proteins involved in calcium regulation (Chapter 2). Stimulation of P₂-adrenergic receptors in the lungs produces bronchodilation and modest pulmonary vasodilation. Systemic vasoconstriction results from activation of a-adrenergic receptors. In contrast to most of the vascular bed, skeletal muscle vasculature contains β₂- adrenergic receptors, which promote vasodilation when activated. Dopaminergic receptors in the splanchnic and renal vascular beds produce vasodilation in response to dopaminergic agonists (eg, dopamine).

Age-dependent changes in receptor expression, receptor-effector coupling, kinase activities, substrate availability, phosphatase activities, and cAMP hydrolysis by phosphodiesterases all contribute to age-related variability in responsiveness to adrenergic agonists. Loading conditions, volume status, and responsiveness of the peripheral vasculature can also influence the responses to these agents, especially in critically ill infants. Therefore, adrenergic agonists must be carefully titrated, and appropriate hemodynamic monitoring is required. Drugs in this class undergo rapid metabolism and are administered by continuous intravenous infusion. Comparison of the relative effects on β, a, and dopaminergic receptor subtypes for various drugs is presented in Table 12-6.

Dopamine

Dopamine is an endogenous catecholamine precursor of norepinephrine with direct cardiac β₁-adrenergic agonist effects. In addition, dopamine indirectly stimulates P₁ receptors by promoting the release of norepinephrine from presynaptic sympathetic nerve terminals within the myocardium. Unlike the other related catecholamines, dopamine exhibits specific dopaminergic receptor ago- nism (dopamine DA₁ receptor agonist). Dopamine has little or no effect on β₂-adrenergic receptors, but at higher concentrations, it stimulates a_j-adrenergic receptors.

At low to moderate doses, the major action of dopamine is to increase contractility (β₁ effect) and to dilate the renal vascular bed (DA₁ effect). At higher rates of infusion, a₁ receptor stimulation becomes more pronounced, and vasoconstriction occurs. In addition, the renal vasodilating effect is overcome at higher concentrations.

Dopamine has gained considerable popularity for use in newborns. Dopamine is indicated in neonates with depressed cardiac output related to impaired contractile function. At conventional doses, dopamine has little effect on pulmonary vascular resistance. High rates of infusion may increase systemic vascular resistance because of a1- mediated vasoconstriction. Extreme vasoconstriction with peripheral gangrene is associated with use of moderate or high doses in critically ill patients with circulatory insufficiency. Dopamine has minimal effect on heart rate, but high concentrations may induce sinus tachycardia and provoke arrhythmias. Dopamine clearance is slowed in the presence of hepatic or renal dysfunction. Dopamine should ideally be infused through a central catheter, but if the drug must be administered in a peripheral vein, care should be employed to avoid extravasation. Careful hemodynamic monitoring is imperative to titrate the dosage to the desired hemodynamic responses. Dopamine should not be mixed with sodium bicarbonate because alkaline solutions inactivate the drug.

Fenoldopam

Like dopamine, fenoldopam is a selective DA₁ agonist, but, in contrast, fenoldopam is more potent than dopamine and does not stimulate a- or β-adrenergic receptors at conventional dosages. This pharmacologic profile results in dilation of the renal and splanchnic beds, increased renal blood flow and glomerular filtration rate, and diuresis. Fenoldopam is used primarily for treating hypertension in adults, but some centers have used intravenous fenoldopam in neonates in an effort to promote diuresis. Potential advantages of fenoldopam include rapid titration and few side effects beyond excessive hypotension. However, the limited published results in oliguric neonates and in newborns immediately after cardiac surgery do not provide compelling evidence for a dramatic benefit from fenoldopam infusion. Additional prospective studies will be needed to determine if fenoldopam should play a role in the management of neonates with heart disease.

Epinephrine

Epinephrine is an endogenous catecholamine produced by the adrenal medulla that has extremely potent effects on a- and β-adrenergic receptors. Hemodynamic responses are dose dependent. At low concentrations, the predominant effects are increased heart rate, contractility, and systolic blood pressure due to β1-adrenergic stimulation. As the dose increases, diastolic blood pressure may decline slightly due to β₂-adrenergic effects in the peripheral vascular beds. At higher doses, a-adrenergic effects become prominent and pronounced vasoconstriction occurs.

The major indication for epinephrine is for patients with cardiovascular collapse associated with low cardiac output who have failed to respond adequately to milrinone and dopamine. Epinephrine must be infused cautiously with careful hemodynamic monitoring. The initial infusion rate should be at the lower end of the recommended dosage and then gradually increased as needed. The major life-threatening toxic effect of epinephrine is the induction of ventricular arrhythmias, but this is uncommon in neonates. Epinephrine increases myocardial oxygen consumption because of its prominent inotropic and chronotropic effects. High doses may produce myocardial ischemia, especially in cases involving either coronary artery anomalies or significant ventricular hypertrophy. Tissue ischemia can occur because of peripheral vasoconstriction, especially with high rates of infusion. Urine output should be monitored carefully. Because subcutaneous infiltration at peripheral infusion sites may result in cutaneous necrosis, epinephrine should be administered via a central catheter.

Phenylephrine

Phenylephrine is an a₁-adrenergic receptor agonist with relatively little effect on other adrenergic receptors. The hemodynamic effects of phenylephrine are related primarily to vasoconstriction and increased systemic vascular resistance. There may be a reflex decrease in heart rate. Phenylephrine is administered by continuous intravenous infusion. Administration of phenylephrine in neonates is indicated in conditions such as septic shock, where the primary goal of therapy is to promote vasoconstriction. Phenylephrine is also used acutely during hypercyanotic episodes in cardiovascular defects, such as tetralogy of Fallot, to increase systemic vascular resistance, reduce right-to-left shunting, and promote an increase in pulmonary blood flow and thereby improve systemic oxygenation.

Norepinephrine

Norepinephrine is an endogenous catecholamine that has β1- and a-adrenergic agonist effects, but in contrast to epinephrine and isoproterenol, norepinephrine does not stimulate β₂ receptors (at conventional concentrations). Infusion of norepinephrine increases systolic and diastolic blood pressure, systemic vascular resistance, and contractility. Heart rate may remain unchanged or even decrease by virtue of the opposing effects of norepinephrine on myocardial β1 receptors and reflex baroreceptor activation with vasoconstriction. The prominent a-adrenergic effects of norepinephrine result in systemic vasoconstriction and may reduce renal perfusion and urine output.

Norepinephrine is rarely used as a positive inotropic agent because of the associated increases in systemic vascular resistance and myocardial oxygen demand and decreases in in renal blood flow. Norepinephrine may be useful in gravely ill patients with cardiovascular collapse associated with profound peripheral vasodilation, such as hyperdynamic septic shock. Some infants exhibit little vascular tone following cardiopulmonary bypass surgery, and norepinephrine may be helpful temporarily in supporting systemic blood pressure. Adverse effects of norepinephrine include arrhythmias, tissue ischemia secondary to extreme vasoconstriction, and skin necrosis if cutaneous infiltration occurs. Norepinephrine should be administered through a central venous catheter.

Isoproterenol

Isoproterenol is a synthetic catecholamine with potent nonselective β-adrenergic agonism and no significant effect on a-adrenergic receptors. Isoproterenol increases cardiac contractility and heart rate (β1 effect) and reduces systemic vascular resistance due to dilation of skeletal muscle, renal, and splanchnic beds (β₂ effect).

Bradycardia caused by atrioventricular block or sinus node dysfunction is the only indication for isoproterenol in young infants. These patients may be managed temporarily by infusing isoproterenol until pacing can be instituted (either a temporary pacing catheter or a permanent pacemaker).

Although isoproterenol increases myocardial contractility and therefore increases cardiac output, this agent causes a much greater increase in heart rate than milrinone, dobutamine, or dopamine. The increase in contractility and heart rate may produce excessive myocardial oxygen requirements and impaired time for diastolic filling. This and other major adverse effects, including sinus tachycardia and both atrial and ventricular arrhythmias, preclude the use of isoproterenol for treatment of neonates and infants with low cardiac output syndrome related to decreased ventricular function.

■ PHOSPHODIESTERASE INHIBITORS

A family of phosphodiesterase enzymes with distinct properties and subcellular distributions controls the degradation of intracellular cAMP and cGMP. Drugs that selectively inhibit cAMP phosphodiesterase activity exert a positive inotropic effect in mature myocardium that is mediated by elevated cAMP and activation of protein kinase A (Chapter 2). Experimental studies in immature animals indicate significant age-related changes in expression of various phosphodiesterase isoenzymes. For example, newborn rabbit myocardium is insensitive to the effects of selective inhibitors of phosphodiesterase type 3 (eg, milrinone) because of a relative lack of this enzyme. Development of the phosphodiesterase system in human myocardium has not been characterized, but virtually every immature mammalian species studied to date exhibits little or no positive inotropic response to milrinone. Despite these observations, milrinone has gained widespread usage in the pre- and postoperative management of infants with ventricular dysfunction. Whether the apparently beneficial hemodynamic responses are due primarily to increased contractility or to pulmonary and systemic vasodilation is unclear.

Milrinone

Milrinone is a second-generation phosphodiesterase inhibitor that is commonly used in neonates, infants, and children with heart disease. The clinical benefits of milrinone in infants with low cardiac output after cardiac surgery may be due to systemic and pulmonary vasodilation. Additionally, species differences between humans and animals and the relative maturity of the human myocardium at birth may result in milrinone-induced increases in ventricular contractility. Milrinone has lower clearance in infants than in older children and is associated with the development of thrombocytopenia in newborns and older infants. The use of milrinone is restricted to intravenous administration. Published experience with milrinone in neonates is relatively limited, but it seems to be effective and well tolerated. Importantly, milrinone is not arrhythmogenic.

■ DIURETICS

Diuretics remain a mainstay of anticongestive therapy in adults and are used mainly to improve symptoms associated with a congested circulatory state. However, diuretics do not improve the neurohormonal alterations that contribute to the heart failure syndrome. Aggressive diuresis can actually promote activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (Chapter 11). The clinical response to a diuretic depends on effective delivery of salt and water to the renal tubule. Hypovolemia, decreased renal blood flow, reduced glomerular filtration rate, or sodium depletion may reduce diuretic efficacy. Diuretics can be classified according to their pharmacological effects at various sites within the nephron (see below). Relative potency and adverse effects vary among the different classes.

Loop Diuretics

These agents are potent diuretics and have been widely used in the neonatal intensive care unit for a variety of indications, including heart disease. The most commonly used drug is furosemide, but ethacrynic acid and bumetanide are also available. Loop diuretics inhibit chloride-sodium-potassium cotransport in the thick ascending limb of the loop of Henle. This reduces reabsorption of chloride, sodium, and potassium and increases net excretion of free water.

Furosemide

Furosemide exerts many effects, some of which are mediated through stimulation of renal prostaglandins. Furosemide increases renal blood flow, enhances renin release, and reduces renal vascular resistance. It has diuretic and nondiuretic pulmonary effects and appears to reduce pulmonary transvascular fluid filtration.

Major clinic indications for furosemide in newborns with heart disease include acute and chronic management of congestive circulatory states and diuresis following cardiac surgery. Furosemide may be administered orally or intravenously. The drug is primarily excreted unchanged by the kidneys, and the dosage must be adjusted in renal failure or in infants with immature renal function. In preterm infants, the plasma half-life is approximately 20 hours, compared with 8 hours in term infants and 1 hour in adults.

Adverse effects of furosemide include excessive contraction of extracellular volume, electrolyte imbalances, and ototoxicity. Hyponatremia in older patients with congestive heart failure is generally due to excess total body water rather than decreased total body sodium. However, in newborn infants with limited sodium intake, chronic or excessive use of furosemide may promote excessive sodium excretion and contribute to hyponatremia. Hypokalemia is a relatively common side effect of therapy with loop diuretics, and serum potassium should be monitored, especially in the acute care setting. Potassium supplementation is often required in the perioperative period for infants with significant congenital heart disease. In the chronic phase of furosemide therapy, potassium-sparing agents, such as spironolactone (see below) or ACEI drugs, may obviate the need for supplementation. Hypochloremic metabolic alkalosis is a common occurrence with furosemide therapy, and, if severe, chloride supplementation is required. Hypocalcemia and hypomagnesemia are usually not significant clinically, but one must be alert to these potential complications, especially in the immediate postoperative period.

With standard dosage regimens in infants with normal renal function, the risk of ototoxicity is minimal. However, if renal dysfunction is present or if other ototoxic medications are administered concomitantly (such as aminoglycosides), the risk of ototoxicity increases. The dosage of furosemide must be reduced in preterm infants because of immature renal function.

Bumetanide

Bumetanide is a loop diuretic for which fewer data are available in newborns. It is generally reserved for use in infants who have not responded adequately to conventional diuretic regimens. Bumetanide can be administered orally or intravenously. In contrast to furosemide, bumetanide is partially metabolized in the liver with approximately 50% excreted unchanged in the urine. Thus, the dosage should be reduced in cases of hepatic dysfunction. Bumetanide is more potent than furosemide and requires careful attention to dosing. The indications and potential complications are similar to those described for furosemide.

Thiazide Diuretics

Thiazides exert their diuretic effect primarily by inhibiting sodium and chloride transport in the distal convoluted tubule of the nephron. Thiazide diuretics have been available for many years, and there is broad experience with these agents. Hydrochlorothiazide and chlorothiazide are the primary thiazide diuretics used in newborn patients with cardiovascular abnormalities. They are generally used chronically for outpatient management of congested circulatory states but may be useful in the inpatient setting for patients with more advanced heart failure. In this situation, a thiazide diuretic may be used in combination with a loop diuretic and/or a potassium-sparing diuretic.

Hydrochlorothiazide and Chlorothiazide

These two drugs are close structural analogs with similar mechanism of action, diuretic efficacy, and side effects. The main differences relate to dosage, absorption, and excretion. Following oral administration, a diuretic effect is generally noted within 60 minutes and may persist as long as 12 to 24 hours. Hydrochlorothiazide is more potent than chlorothiazide.

Adverse effects of thiazides include hypokalemia, hyperuricemia, and hypercalcemia. Nonrenal effects of thiazide diuretics that have been described in older patients and adults include carbohydrate intolerance and adverse effects on plasma cholesterol and triglycerides. The extent and implications of potential disturbances in cholesterol, lipoproteins, and triglycerides have not been determined in neonates.

Metolazone

Metolazone is an orally available sulfonamide derivative that blocks sodium reabsorption in the distal and proximal convoluted tubule. It exhibits several thiazide properties, although it does not have a classic thiazide structure. In general, metolazone is reserved for short-term treatment of edematous states that are resistant to conventional therapy with loop diuretics or thiazides. The combination of metolazone and furosemide can be synergistic and promote marked diuresis. Metolazone is given orally once a day or every other day. The major adverse effects of metolazone include significant volume depletion and severe electrolyte disturbances. Careful monitoring of the patient is essential.

Potassium-Sparing Diuretics

Spironolactone competitively inhibits aldosterone at the distal tubule. By blocking aldosterone effects, spironolactone reduces potassium loss in the urine. The diuretic effect is relatively weak compared with the loop or thiazide diuretics. In most cases, spironolactone is used in combination with either furosemide or hydrochlorothiazide to ameliorate the potassium-losing effects of these agents.

The major adverse effect of spironolactone is hyperkalemia. In most patients, this is not a significant problem, but the risk is increased in patients with excessive potassium intake (eg, when coadministered with a potassium supplement), renal dysfunction, or hepatic dysfunction. Care should be exercised if spironolactone is used in combination with an angiotensin-converting enzyme inhibitor because of the propensity for hyperkalemia. Similarly, if coadministration of a potassium supplement is necessary, serum potassium levels must be monitored carefully.

■ VASODILATORS

The major indications for the use of vasodilators in infants with heart disease are (1) impaired ventricular function, (2) semilunar valve regurgitation, (3) systemic hypertension, and (4) pulmonary hypertension. The selection of a specific drug depends on the primary goal of therapy, underlying or associated conditions, and whether the treatment is acute or chronic. Vasodilators can be categorized in several ways. One classification groups the drug classes according to their major mechanism of action. Table 12-7 presents the major mechanisms of action and a representative drug for each class. Knowledge of the mechanism of action of a given drug provides a framework for understanding the pharmacology and therapeutic applications. Understanding the mechanism of action allows the clinician to intelligently employ new drugs within a class expeditiously. Another method of classification is to group drugs according to their predominant site of action. As outlined in Table 12-7, vasodilators can be considered as predominantly venous, arteriolar, or balanced (comparable effects on arterioles and venules). Depending on the goal of therapy, one may select an agent that has predominant effects on venous capacitance, arteriolar resistance, or both.

TABLE 12-7. Vasodilator Mechanisms and Sites of Action

Predominant Mechanism	Drug Examples	Predominant Site of Action
Nitrovasodilator	Nitroglycerin	Venous
Calcium channel antagonist	Nifedipine	Arteriolar
ACE inhibitor	Captopril	Mixed
Angiotensin receptor blocker	Losartan	Mixed
Natriuretic peptide	Nesiritide	Mixed

Nitrovasodilators

Relaxation of vascular smooth muscle by drugs in this class is mediated by nitric oxide. Nitric oxide activates guanylyl cyclase, resulting in increased formation of cGMP in vascular smooth muscle cells and activation of cGMP-dependent protein kinase. The net effect is relaxation of vascular smooth muscle tone and vasodilation.

Nitroprusside

Nitroprusside is an extremely potent vasodilator. Hemodynamic responses to nitroprusside result from decreases in venous and arteriolar tone. Nitroprusside reduces systemic vascular resistance, pulmonary vascular resistance, and atrial pressures and may indirectly increase cardiac output. Heart rate may increase slightly in response to nitroprusside.

Nitroprusside is used for treating hypertensive emergencies because it is a potent vasodilator with a rapid onset of action and titratable effects. Nitroprusside is sometimes administered to pediatric cardiac surgical patients in the immediate postoperative period. In addition, it may be effective acutely in children with left ventricular dysfunction or mitral regurgitation. With proper monitoring and dosing, nitroprusside appears to be safe and effective in neonates.

Nitroprusside is rapidly metabolized and must be administered by continuous intravenous infusion.

It is subject to photochemical degradation, so solutions must be freshly prepared and protected from light during infusion. Because of the rapid onset of action and rapid metabolism, the desired hemodynamic effect can be achieved by careful dose titration. The major adverse effects of nitroprusside are a direct extension of its powerful vasodilator activity. Careful hemodynamic monitoring is imperative in order to avoid significant hypotension.

Nitroprusside is metabolized to thiocyanate and cyanide. Toxic effects in older patients include tachycardia, tachypnea, vomiting, headache, fatigue, anorexia, and disorientation. These signs and symptoms are difficult to detect in newborns. Although red blood cell cyanide and serum thiocyanate concentrations must be monitored in infants receiving long-term or high-dose nitroprusside therapy, the precise relationships between cyanide or thiocyanate concentrations and clinical toxicity are not entirely clear. Chronic thiocyanate toxicity may affect thyroid function, and this must be considered in neonates.

Pulmonary Vasodilators

Nitric Oxide

Nitric oxide is an endothelium-derived relaxing factor that is administered as an inhaled gas. This agent causes rapid pulmonary vasodilation but does not affect the systemic vasculature because it is rapidly inactivated by hemoglobin. Therapy with nitric oxide plays a central role in the management of infants with persistent pulmonary hypertension of the newborn and has dramatically reduced morbidity and mortality from this potentially lethal condition. This agent can also be extremely beneficial in the perioperative period for neonates with pulmonary arterial hypertension associated with congenital cardiovascular disease. Because it is preferentially distributed to better-aerated areas of the lungs, its local vasodilatory effects can match ventilation and perfusion, leading to improved oxygenation. Determination of the effectiveness of nitric oxide therapy includes evaluation of oxygenation and pulmonary artery pressure. Echocardiography may be helpful in assessing pulmonary artery pressure noninvasively. Methemoglobin levels should be monitored regularly in patients receiving high concentrations or prolonged therapy.

Sildenafil

Sildenafil is a potent and selective inhibitor of cyclic nucleotide phosphodiesterase type 5. This isoform is the predominant phosphodiesterase that metabolizes cGMP in the lung vasculature. Inhibition of this phosphodiesterase results in pulmonary vasodilation and increased efficacy of inhaled nitric oxide. Sildenafil can be administered enterally, intravenously, or as an aerosol, but most of the published experience in infants to date has been with the oral and intravenous forms. Orally administered sildenafil has been shown to be effective in treating persistent pulmonary hypertension in newborns and is well tolerated. The primary use of sildenafil in neonates with cardiac disease is for those patients with acute or chronic pulmonary hypertension who have responded well to inhaled nitric oxide. Additional studies are needed in infants with heart disease to define optimal dosing and pharmacokinetics and to further clarify the role of sildenafil in the immediate postoperative period.

Calcium Channel Antagonists

Calcium channel antagonists block the opening of calcium channels in vascular smooth muscle, thereby promoting vasodilation. However, these drugs also block L-type calcium channels in the heart. Experiments in animals suggest that the immature heart is more sensitive to the negative inotropic effects of calcium channel blockers, but these agents are effective for controlling blood pressure in neonates and infants after cardiac surgery.

Calcium channel antagonists are categorized into three major chemical classes: dihydropyridines (nifedipine), benzothiazepines (diltiazem), and phenylalkylamines (verapamil). Drugs of the dihydropyridine class exhibit the most pronounced vasodilation and should be selected if that is the primary goal of therapy. Many different dihydropyridine calcium channel antagonists are commercially available in the United States. Most of the published pediatric experience is limited to nifedipine, but the clinically important differences among the various dihydropyridines are slight. In young infants, nifedipine is used primarily to treat pulmonary hypertension associated with bronchopulmonary dysplasia. Oral verapamil is used rarely for treatment of older infants with arrhythmias or hypertrophic cardiomyopathy but is contraindicated in neonates and young infants because of the risk of cardiovascular collapse.

Angiotensin-Converting Enzyme (ACE) Inhibitors

ACE inhibitors play a central role in the management of systemic hypertension and congestive heart failure in adults. However, relatively few rigorous clinical trials have been performed to support the widespread use of ACE inhibitors in infants and children. Despite the relative paucity of data, anecdotal reports and clinical experience support the beneficial effects of these drugs, especially in the short term.

ACE inhibitors block the conversion of angiotensin I to angiotensin II by inhibiting activity of the converting enzyme. In addition, ACE inhibitors reduce the inactivation of vasodilatory bradykinins and diminish production of aldosterone. These concepts are illustrated in Figure 12-2. More recently, it has become apparent that tissue angiotensin-generating systems may be important in local control of cardiac, renal, and vascular function.

Hemodynamic effects of ACE inhibitors include a reduction in systemic vascular resistance and systemic blood pressure. Because patients with congestive heart failure also respond with venodilation, these drugs are classified as balanced vasodilators. Results from studies of the chronic use of ACE inhibitors in adults with heart failure have confirmed significant improvements in survival, reduction in hospitalizations, and improvements in quality of life. ACE inhibitor therapy does not promote neurohormonal activation. The results of ACE inhibitor therapy for heart failure in adult patients is so compelling that administration of an ACE inhibitor is currently recommended even for patients with asymptomatic left ventricular dysfunction.

FIGURE 12-2. Effects of angiotensin converting enzyme inhibitors. ACE inhibitors block the conversion of angiotensin I to angiotensin II, thereby reducing vasoconstriction and aldosterone production mediated by angiotensin II. In addition, the degradation of bradykinin is inhibited by ACE inhibitors. This action promotes vasodilation.

Many ACE inhibitors that are commercially available in the United States are similar with regard to their mechanism of action but differ slightly in their pharmacokinetic and metabolic profiles. Most of the published experience in the pediatric population is with captopril and enalapril.

Captopril

Captopril reduces systemic vascular resistance and increases venous capacitance, resulting in increased cardiac output and a reduction in cardiac filling pressures in children with congestive heart failure. Pulmonary vascular resistance generally declines, and heart rate is usually minimally affected. Mild to moderate diuresis occurs as a result of increased renal blood flow and a reduction in aldosterone formation.

Captopril is administered orally, and peak plasma concentrations occur 1 to 2 hours after a single oral dose. Although the plasma half-life is short (2 to 3 hours), the duration of the clinical effect is usually 6 to 8 hours. Captopril is therefore administered three times a day. Approximately 50% is excreted in the urine unchanged, and clearance is reduced in patients with impaired renal function.

Initial pediatric experience with captopril was for the treatment of systemic hypertension. Subsequently, captopril was shown to be very effective in the management of congestive heart failure in infants and children with dilated cardiomyopathy. Captopril is generally well tolerated in most infants, but significant hypotension may occur in volume-depleted patients or in patients with extremely high basal renin activity. When starting captopril therapy for congestive heart failure in infants, the first dose should be low and the blood pressure carefully monitored. If the drug is tolerated, then the dosage can be escalated over a few days.

Adverse effects include neutropenia, proteinuria, and oliguria, especially in children with underlying renal disease. Less serious side effects include rash, taste impairment, and minor gastrointestinal disturbances. A dry, nonproductive cough is a well-described feature of ACE inhibitor therapy in adults, but this does not seem to be a major problem in neonates. In general, potassium supplements and potassium-sparing diuretics should not be administered concomitantly to patients receiving captopril because of the risk of hyperkalemia.

Enalapril

The mechanism of action, hemodynamics, and clinical indications for enalapril are similar to those described above for captopril. Enalapril differs from captopril in that enalapril is a prodrug that must be deesterified to form the active agent, enalaprilat. Enalaprilat is commercially available for parenteral administration. Enalapril has a slower onset of action and longer half-life than captopril. Generally, enalapril is administered once or twice per day, facilitating compliance. Enalapril has been shown to be effective in the management of infants with congestive heart failure and systemic hypertension. The overall incidence of side effects due to enalapril appears to be lower than that reported for captopril. Because enalapril has a longer duration of action, hypotension may be prolonged if overdose occurs.

Angiotensin Receptor Blockers

Angiotensin receptors exist as distinct subtypes (AT1, AT2) that serve to couple angiotensin with specific intracellular responses. Because local tissue production of angiotensin may occur that is not ACE dependent, more complete local inhibition of the angiotensin pathway can theoretically be achieved by direct blockade of AT receptors. Recently, a number of selective AT₁ receptor blockers have been released for the treatment of heart failure and hypertension in adults. These agents are particularly useful in adult patients who develop coughing when taking ACE inhibitors. This side effect is much less common in infants and children. The prototype is losartan. Experience with these agents in infants is extremely limited.

a-Adrenergic Receptor Antagonists

Phentolamine

Phentolamine is a competitive antagonist of a-adrenergic receptors, but it is nonselective and blocks a1 and a₂ receptors. Blockade of presynaptic a₂-adrenergic receptors may contribute to the tachycardia and arrhythmias that occur at high doses of phentolamine. Administration of phentolamine to patients with low cardiac output produces a decrease in systemic vascular resistance with a resultant increase in cardiac output. Although phen- tolamine is classified as a mixed vasodilator, the effects on venous capacitance are minimal compared with other mixed vasodilators. Phentolamine reduces pulmonary vascular resistance and pulmonary arterial pressure.

Published experience with phentolamine in children is limited to short-term intravenous administration. In general, phentolamine is effective and well tolerated in infants and children. Adverse effects include significant sinus tachycardia, arrhythmias, and excessive hypotension.

The major application of phentolamine in neonates is in the period immediately after cardiac surgery.

Neprilysin Inhibitors

Sacubitril is a prodrug that is activated by esterases to form sacubitrilat. Sacubitrilat inhibits the activity of neprilysin, 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, in a fixed-dose combination with the angiotensin receptor blocker valsartan, was recently shown to provide substantial benefit in adults with heart failure. This is an emerging new class of drugs that hold considerable promise for the treatment of heart failure. However, the safety and efficacy of neprilysin inhibitors in neonates remains to be determined and is the subject of investigation.

■ ALDOSTERONE RECEPTOR ANTAGONISTS

Enhanced activity of the renin-angiotensin system with increased synthesis of aldosterone is a hallmark of congestive heart failure. Aldosterone likely is involved in the pathogenesis of a variety of deleterious responses observed in the heart failure syndrome. Aldosterone plays an important role in promoting the abnormal collagen production and interstitial fibrosis that occurs in chronic congestive heart failure. Therapy with ACE inhibitors has been assumed to block both angiotensin II and aldosterone production. However, recent data in adults suggest that aldosterone production may “escape” despite the appropriate use of an ACE inhibitor. An escape of aldosterone production has several potentially important consequences, including sodium retention, potassium and magnesium loss, excessive myocardial collagen production, ventricular hypertrophy, myocardial norepinephrine release, endothelial dysfunction, and a decrease in serum high-density lipoprotein cholesterol. Administration of the aldosterone antagonist, spironolactone, to patients with heart failure treated with conventional therapy (including an ACE inhibitor) results in increased diuresis and symptomatic improvement. Spironolactone has been used for years as a potassium-sparing diuretic in infants with heart failure. Whether additional benefit is derived from inhibiting the other effects of aldosterone in infants remains to be determined.

■ HORMONES

Nesiritide

Nesiritide is a recombinant B type natriuretic peptide that is given by intravenous infusion. In adult patients with heart failure, it has been shown to produce vasodilation, increase glomerular filtration rate, inhibit renal sodium reabsorption, and promote diuresis. Studies in children suggest nesiritide may increase urine output and reduce levels of neurohormonal markers of heart failure. Some centers use nesiritide acutely for infants with low cardiac output following cardiac surgery and for infants with severely depressed cardiac function due to cardiomyopathy. Additional studies are needed to determine the safety and efficacy of nesiritide in neonates with heart disease.

Thryoxine and Triiodothyronine

A number of neuroendocrine changes occur in heart failure (Chapter 11), during critical illness, and following surgical procedures. Thyroid hormone secretion is reduced in critically ill adults and children following cardiac surgery. These changes in thyroid hormone levels are referred to as “nonthyroidal illness syndrome” and generally have not been thought to represent true hypothyroidism. However, this concept is controversial, and some authorities suggest that these patients may have acquired true central hypothyroidism as a consequence of their critical illness or surgical procedure. Some centers routinely administer either thyroxine or triiodothyronine in the postoperative period if thyroid-stimulating hormone is elevated, circulating thyroid hormone levels are reduced, and the infant exhibits persistent or refractory low cardiac output. However, little published information exists regarding the safety, efficacy, and long-term effects of thyroid hormone administration to neonates in the early postcardiac surgery period. Additional studies are required to determine the significance of these changes in thyroid hormone levels and the role, if any, of routine thyroid hormone therapy in this setting.

Vasopressin

Vasopressin is a potent vasoconstrictor that acts directly on the vasculature via V1 receptors and indirectly by potentiating the vasoconstrictor effects of catecholamines. The responses to vasopressin are preserved in the presence of acidosis or hypoxia. Cardiopulmonary bypass is known to evoke a systemic inflammatory response that can result in low cardiac output and vasodilatory shock. The first line of therapy in this setting is infusion of catecholamines, such as dopamine or norepinephrine. However, shock persists in some infants despite maximal supportive therapy. This clinical syndrome mimics that seen in patients with septic shock, which has been associated with depressed levels of vasopressin in adults and children. Based on results from studies demonstrating a beneficial effect of vasopressin infusion in patients with vasodilatory septic shock, several investigators have administered vasopressin to infants with vasodilatory shock following cardiopulmonary bypass. In general, the reported results are favorable, and it appears that vasopressin can be an effective adjunct to more conventional therapy in this setting. However, additional studies are required to more fully define the indications, safety, and efficacy of vasopressin in infants with heart disease.

■ β-ADRENERGIC RECEPTOR BLOCKERS

β-blockers can be classified as first generation, nonselective for β1 and β₂ blockade (eg, propranolol); second generation with relative selectivity for β1 receptors (eg, metoprolol and atenolol); and third-generation drugs (selective or nonselective) with potentially important ancillary properties (eg, carvedilol and bucindolol). β-blockers are not interchangeable, therapy must be carefully initiated and monitored, and published experience in pediatric patients is limited. The most commonly used β-blockers in infants are propranolol, atenolol, and esmolol.

Propranolol

Propranolol was the first commercially available β-adrenergic blocker in the United States. Subsequently, many β-blockers have been developed and are available for commercial use. However, propranolol has been most widely used, and there is published experience with this drug in pediatric patients. Propranolol is available for oral or intravenous administration, but if intravenous β-blocker therapy is necessary, the short-acting β-adrenergic blocker esmolol (see below) should be used because of the risk of severe hypotension and bradycardia associated with intravenous propranolol.

Propranolol is used in infants for management of supraventricular tachycardia, some forms of ventricular arrhythmias, treatment of congenital long QT syndromes, and hypertrophic cardiomyopathy. In the past, propranolol was sometimes used in an attempt to reduce the frequency and severity of hypercyanotic episodes in infants with tetralogy of Fallot. Now most patients undergo surgical correction or palliation if hypercyanotic episodes occur. Some infants with critical pulmonary stenosis may benefit from a short course of propranolol after relief of pulmonary valve stenosis until the infundibular hypertrophy regresses.

Propranolol is well absorbed after an oral dose, although it undergoes extensive first-pass hepatic metabolism, reducing the bioavailability to approximately 30% to 40%. Class-dependent effects of β-adrenergic blockers include depression of contractility, atrioventricular block, bronchospasm, and sleep disturbances. Propranolol should be avoided if possible in infants with significant pulmonary disease. Chronic use of propranolol in infants appears to be safe and well tolerated. However, infants are at risk for developing hypoglycemia if their oral intake is restricted because of other illnesses or other conditions. Blood glucose should be monitored in infants receiving propranolol who are unable to feed normally.

Atenolol

Atenolol is relatively selective for β₁-adrenergic receptors. This agent has the advantage of requiring only once- or twice-a-day administration because of a longer half-life (8 to 10 hours) and is now used commonly instead of propranolol. Fewer central nervous system effects occur with atenolol than with propranolol because atenolol does not cross the blood-brain barrier, but the clinical implications in neonates and young infants are unclear. An atenolol suspension can be prepared by many pharmacies, and this drug is well tolerated.

Esmolol

Esmolol is a β-selective adrenergic blocker with a short plasma half-life (approximately 5 to 10 minutes). The indications and precautions for esmolol are similar to those described for propranolol. The major difference is that, because of the short half-life, esmolol is administered by continuous intravenous infusion. Thus, the dose is easier to titrate, and if adverse effects occur, the duration of toxicity will be quite short. Esmolol is generally used for short periods of time in acute care settings (ie, cardiac catheterization laboratory, postoperative recovery unit, neonatal intensive care nursery).

Carvedilol

Carvedilol is a third-generation β-adrenergic receptor blocker that blocks β₁- , β₂-, and а1-adrenergic receptors.

In addition, it exhibits antioxidant, anti-inflammatory, and antiapoptotic activities. Experience with carvedilol in infants with heart failure is described in Chapter 11. Although promising, additional studies are necessary to define the potential role of carvedilol in managing neonates with heart disease.

■ PROSTAGLANDIN E₁

Prostaglandin E₁ (PGE₁) is used to dilate the ductus arteriosus in newborns with cardiac defects in which maintaining adequate pulmonary or systemic blood flow is dependent on a patent ductus arteriosus. The common indications for PGE₁ therapy include pulmonary atresia, critical pulmonary stenosis, transposition of the great arteries, coarctation of the aorta, interrupted aortic arch, critical aortic stenosis, and hypoplastic left heart syndrome. Administration of PGE₁ should be strongly considered very early in the management of infants in whom a ductus-dependent cardiac defect is suspected. A good example is the infant with signs of congenital cardiovascular disease who is born at a center without tertiary care cardiac services. In this case, it is advisable to begin PGE₁ therapy before transport and more definitive delineation of the cardiac status. This can be lifesaving, and, conversely, withholding therapy can be disastrous if the ductus arteriosus closes in a patient with a ductus- dependent defect. Although not entirely benign, PGE₁ can be administered safely with the proper precautions noted below, and if the infant is subsequently found not to have significant structural heart disease, the infusion can be discontinued.

PGE₁ has a short half-life and must be given by continuous intravascular infusion. Although the intravenous route is preferred, it can be given via an umbilical arterial catheter if necessary. Because these infants are critically dependent on the infusion for maintaining ductus patency, a reliable intravenous line is essential. Thus, the use of a central venous (eg, umbilical venous) catheter is recommended whenever possible. In addition to effects on the ductus arteriosus, PGE₁ dilates the systemic and pulmonary vascular beds. Thus, a potential side effect is hypotension. In these cases, reduction of the dose is generally sufficient to reverse the fall in blood pressure. If this is not possible, small fluid boluses (5 to 10 mL/kg) are often effective. Another potentially serious adverse effect is apnea. Administration of a high dose or an inadvertent bolus of PGE₁ will most certainly induce apnea. Thus, whenever PGEj is administered, personnel and equipment necessary to support ventilation must be available. Infusion pumps with a continuous action should be used, and the intravenous line containing the drug must not be flushed. Additional side effects include fever, irritability, edema, and cutaneous flushing.

■ SUGGESTED READINGS

Drug Dosage Reference

Taketomo CK, Hodding JH, Kraus DM. Pediatric and Neonatal Dosage Handbook. 22nd ed. Hudson, OH: Lexi- Comp, Inc.; 2015.

General Principles of Pediatric Clinical Pharmacology

Hines RN. The ontogeny of drug metabolizing enzymes and implications for adverse effects. Pharmacol Ther. 2008;118:250-267.

Kearns GL, Artman M. Functional biomarkers: an approach to bridge pharmacokinetics and pharmacodynamics in pediatric clinical trials. Curr Pharm Des. 2015;21(39):5636-5642.

Neville KA, Becker ML, Goldman JL, Kearns GL. Developmental pharmacogenomics. Pediatr Anesth. 2011;21:255-265.

Wagner J, Kearns GL, Artman M. Pharmacology. In: Allen HD, Driscoll DJ, Shaddy RE, Penny DJ, Cetta F, Feltes TF, eds. Moss and Adams’ Heart Disease in Infants, Children and Adolescents, Including the Fetus and Young Adult. 9^th ed. Philadelphia, PA: Wolters Kluwer; 2016:1831-1853.

Pharmacology of Specific Drugs and Drug Classes

Giesinger RE, McNamara PJ. Hemodynamic instability in the critically ill neonate: an approach to cardiovascular support based on disease pathophysiology. Semin Perina- tol. 2016;40(3):174-188.

Gupta S, Donn SM. Neonatal hypotension: dopamine or dobutamine? Semin Fetal Neonatal Med. 2014;19:54-59.

Mastropietro CW. Arginine vasopressin and paediatric cardiovascular surgery. OA Crit Care. 2013;1(1):1-7.

Ricci Z, Stazi GV, Di Chiara L, et al. Fenoldopam in newborn patients undergoing cardiopulmonary bypass: controlled clinical trial. Interact Cardio Vasc Thorac Surg. 2008;7:1049-1053.

Samiee-Zafarghandy S, Smith PB, van den Anker JN. Safety of sildenafil in infants. Pediatr Crit Care Med. 2014;15(4):362-368.

Shih JL, Agus MSD. Thyroid function in the critically ill newborn and child. Curr Opin Pediatr. 2009;21:536-540.

Steinhorn RH, Kinsella JP, Pierce C, et al. Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension. JPediatr. 2009;155:841-847.