Park's Pediatric Cardiology for Practitioners, 6th Ed.

Congestive Heart Failure

Definition

Congestive heart failure (CHF) is a clinical syndrome in which the heart is unable to pump enough blood to the body to meet its needs, to dispose of systemic or pulmonary venous return adequately, or a combination of the two.

Cause

The heart failure syndrome may arise from diverse causes. Common causes of CHF are volume or pressure overload (or both) caused by congenital or acquired heart disease and myocardial diseases. Tachyarrhythmias and heart block can also cause heart failure at any age. By far the most common causes of CHF in infancy result from congenital heart defects (CHDs). Beyond infancy, myocardial dysfunctions of various etiologies are important causes of CHF. Among the rare causes of CHF are metabolic and endocrine disorders, anemia, pulmonary diseases, collagen vascular diseases, systemic or pulmonary hypertension, neuromuscular disorders, and drugs such as anthracyclines.

Congenital Heart Disease

Volume overload lesions, such as ventricular septal defect (VSD), patent ductus arteriosus (PDA), and endocardial cushion defect (ECD), are the most common causes of CHF in the first 6 months of life. In infancy, the time of the onset of CHF varies predictably with the type of defect. Table 27-1 lists common CHDs according to the age at which CHF develops. When looking at the table, the following should also be noted.

1. Children with tetralogy of Fallot (TOF) do not develop CHF unless they have received a large systemic-to-pulmonary artery shunt procedure (e.g., too large a Gore-Tex interposition shunt).

2. Atrial septal defect (ASD) rarely causes CHF in the pediatric age group, although it causes CHF in adulthood.

3. Large left-to-right shunt lesions, such as VSD and PDA, do not cause CHF before 6 to 8 weeks of age because the pulmonary vascular resistance does not fall low enough to cause a large left-to-right shunt until this age. The onset of CHF resulting from these left-to-right shunt lesions may be earlier in premature infants (within the first month) because of an earlier fall in the pulmonary vascular resistance in these infants.

Acquired Heart Disease

Acquired heart disease of various causes can lead to CHF. With acquired heart disease, the age at onset of CHF is not as predictable as with CHD, but the following generalities apply:

1. Dilated cardiomyopathy is probably the most common cause of CHF beyond infancy. It may cause CHF at any age during childhood and adolescence. The cause of the majority of dilated cardiomyopathy is idiopathic, but it may be caused by infectious, endocrine, or metabolic disorders; autoimmune diseases; or after antineoplastic treatment (e.g., anthracycline).

2. Doxorubicin cardiomyopathy may manifest months to years after the completion of chemotherapy for malignancies in children.

TABLE 27-1

CAUSES OF CONGESTIVE HEART FAILURE RESULTING FROM CONGENITAL HEART DISEASE

Age of Onset

Cause

At birth

HLHS

 

Volume overload lesions:

 

Severe tricuspid or pulmonary insufficiency

 

Large systemic arteriovenous fistula

First week

TGA

 

PDA in small premature infants

 

HLHS (with more favorable anatomy)

 

TAPVR, particularly those with pulmonary venous obstruction

 

Others

 

Systemic arteriovenous fistula

 

Critical AS or PS

1–4 wk

COA with associated anomalies

 

Critical AS

 

Large left-to-right shunt lesions (VSD, PDA) in premature infants

 

All other lesions previously listed

4–6 wk

Some left-to-right shunt lesions such as ECD

6 wk–4 mo

Large VSD

 

Large PDA

 

Others such as anomalous left coronary artery from the PA

AS, Aortic stenosis; COA, coarctation of the aorta; ECD, endocardial cushion defect; HLHS, hypoplastic left heart syndrome; PA, pulmonary artery; PDA, patent ductus arteriosus; PS, pulmonary stenosis; TAPVR, total anomalous pulmonary venous return; TGA, transposition of the great arteries; VSD, ventricular septal defect.

3. Cardiomyopathies associated with muscular dystrophy and Friedreich’s ataxia may cause CHF in older children and adolescents.

4. Myocarditis associated with Kawasaki’s disease is seen in children 1 to 4 years of age.

5. Patients who received surgery for some types of CHDs (e.g., Fontan operation, surgery for TOF, transposition of the great arteries and other cyanotic defects) may remain in or develop CHF after varying period of time.

6. Viral myocarditis tends to be more common in small children older than 1 year. It occurs occasionally in the newborn period, with a fulminating clinical course with poor prognosis.

7. Acute rheumatic carditis is an occasional cause of CHF that occurs primarily in school-age children.

8. Rheumatic valvular heart diseases, usually volume overload lesions such as mitral regurgitation (MR) or aortic regurgitation (AR), cause CHF in older children and adults. These diseases are uncommon in industrialized counties.

9. Endocardial fibroelastosis, a rare primary myocardial disease, causes CHF in infancy; 90% of cases occur in the first 8 months of life.

Miscellaneous Causes

Miscellaneous causes of CHF includes the following:

1. Metabolic abnormalities (severe hypoxia and acidosis, as well as hypoglycemia and hypocalcemia) can cause CHF in newborns.

2. Endocrinopathy such as hyperthyroidism.

3. Supraventricular tachycardia (SVT) causes CHF in early infancy.

4. Complete heart block associated with structural heart defects causes CHF in the newborn period or early infancy.

5. Severe anemia may be a cause of CHF at any age. Hydrops fetalis may be a cause of CHF in the newborn period and severe sicklemia at a later age.

6. Bronchopulmonary dysplasia seen in premature infants causes predominantly right-sided heart failure in the first few months of life.

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FIGURE 27-1 Effects of anticongestive medications on the Frank-Starling relationship for ventricular function. In persons with normal heart, cardiac output increases as a function of ventricular filling pressure (preload; see the upper curve). In patients with heart failure, the normal relationship between cardiac output (or stroke volume) and filling pressure (preload) is shifted lower and to the right such that a low-output state and congestive symptoms may coincide. Congestive symptoms (dyspnea, tachypnea) may appear even in normal hearts if the filling pressure reaches a certain point. At one extreme, the addition of a pure inotropic agent, such as digoxin, primarily increases the stroke volume with minimal impact on filling pressure (so that the patient may still have congestive symptoms). Conversely, the addition of a diuretic primarily decreases the filling pressure (with improved congestive symptoms) but without improving cardiac output. Clinically, it is common to use multiple classes of agents (usually a combination of inotropic agents. diuretics, and vasodilators) to produce both increased cardiac output and decreased filling pressure. (Adapted from Cohn JN, Franciosa JS. Vasodilator therapy of cardiac failure [first of two parts], N Engl J Med 1977; 297:27-31).

7. Primary carnitine deficiency (plasma membrane carnitine transport defect) causes progressive cardiomyopathy with or without skeletal muscle weakness that begins at 2 to 4 years of age.

8. Acute coronary pulmonale caused by acute airway obstruction (such as seen with large tonsils) can cause CHF at any age but most commonly during early childhood.

9. Acute systemic hypertension, as seen in acute postinfectious glomerulonephritis, causes CHF in school-age children. Fluid retention with poor renal function is important as a cause of hypertension in this condition.

Pathophysiology

Cardiac output is determined by preload, afterload, myocardial contractility, and heart rate. Cardiac output is proportional to filling pressure (preload) and inversely proportional to the resistance against which the heart pumps (afterload).

Preload

According to the Frank-Starling law, as the ventricular end-diastolic volume (or preload) increases, the healthy heart increases cardiac output until a maximum is reached and cardiac output can no longer be augmented (see Figure 27-1, which appears in the section on Management in this chapter). This is a built-in property of the heart that normally allows it to pump out automatically whatever amount of blood flows into the heart. When the left ventricular (LV) end-diastolic pressure reaches a certain point, however, pulmonary congestion develops with congestive symptoms (tachypnea and dyspnea). Congestive symptoms occur even with a normally functioning myocardium if the end-diastolic pressure is greatly increased, such as seen with infusion of a large amount of fluid or blood. An increase in the stroke volume is also achieved in the failing heart when the preload is increased but the failing heart does not achieve the same level of maximal cardiac output as seen in the normal heart. The increased stroke volume obtained in this manner increases the myocardial oxygen consumption.

Afterload

Afterload is the force that resists myofibril shortening during systole, which contributes to total myocardial wall stress (or tension). A decrease in afterload increases cardiac output, and an acute increase in afterload results in decreases in stroke volume and ejection fraction. Indices of afterload include aortic pressure, total systemic vascular resistance, arterial impedance, and myocardial peak wall stress. Afterload reducing increases cardiac output without increasing oxygen consumption.

Wall Stress

According to the law of Laplace, wall tension is the product of pressure and radium.

image

The Laplace law, although an oversimplification, emphasizes the following two points: (1) the bigger the LV and the greater the radius, the greater the wall stress, and (2) at any given radius (LV size), the greater the pressure developed in the LV, the greater the wall stress. Thus, dilated ventricles require more tension in the wall and thus increased oxygen demand to generate the same pressure. A relationship exists between wall stress and preload as well as afterload. Preload can be defined as the wall stress at the end of diastole. The afterload, being the load on the contracting myocardium, is the wall stress during LV ejection.

The increased wall tension in the dilated ventricle leads to ventricular hypertrophy that tends to keep the wall tension low. Well-trained athletes develop cardiac hypertrophy, which helps reduce wall stress, according to Laplace’s law. A failing heart will also hypertrophy to reduce the increase in wall stress, but the hypertrophy in the failing heart is abnormal because it occurs as part of ventricular remodeling secondary to neurohormonal compensatory mechanisms. (Cardiac remodeling is defined as genomic expression resulting in molecular, cellular, and interstitial changes that are manifested clinically as changes in size, shape, and function of the heart after cardiac injury.) Although hypertrophy may tend to lower wall tension, abnormally hypertrophied ventricles may interfere with synthesis of some of the contractile proteins and leads to collagen damage, including fibrosis. It is also possible that capillary growth does not keep up with the growth of the muscle fibers, causing difficulties in supplying energy.

Compensatory Mechanisms

In the early stages of heart failure, various compensatory mechanisms are evoked to maintain normal metabolic function. Among the compensatory responses are the activation of the sympathetic nervous system and the renin–angiotensin–aldosterone system. Although these responses are an attempt to preserve cardiovascular homeostasis and thus beneficial initially, chronic stimulation of these systems may be deleterious in the natural history of myocardial dysfunction.

1. One major compensatory mechanism for increasing cardiac output is an increase in sympathetic tone secondary to increased adrenal secretion of circulating epinephrine and increased neural release of norepinephrine. The initial beneficial effects of adrenergic stimulation include increased heart rate and myocardial contractility with a resulting increase in cardiac output. However, chronic adrenergic stimulation eventually leads to adverse myocardial effects, including increased afterload, hypermetabolism, arrhythmogenesis, and direct myocardial toxicity.

a. Catecholamines are toxic to cardiac muscle, perhaps by producing calcium overload or by inhibiting the synthesis of contractile proteins.

b. High catecholamine levels decrease the density of β-adrenergic receptors on the surfaces of the myocardial cell, which may be the major cause of the functional loss of the catecholamine-mediated positive inotropic response.

In clinical settings, the reduction of adrenergic stimulation by the use of β-adrenergic blockers has resulted in clinical improvement in patients with dilated cardiomyopathy, in whom increased levels of catecholamines have been shown to be present.

2. The reduced blood flow to the kidneys in patients with CHF causes a marked increase in renin output, and this in turn causes the formation of angiotensin II. Angiotensin II leads to a further increase in reabsorption of both water and salt from the renal tubules. Angiotensin II may cause a trophic response in vascular smooth muscle (with vasoconstriction) and myocardial hypertrophy. Angiotensin II also promotes myocardial fibrosis. Thus, although a hypertrophic response is adaptive by attempting to restore wall stress to normal, angiotensin II plays a maladaptive role in CHF by initiating fibrosis and altering ventricular compliance.

Thus, the reasons for using β-adrenergic blockers and angiotensin-converting enzyme (ACE) inhibitors in the treatment of CHF are to block the maladaptive role of adrenergic and renin–angiotensin–aldosterone systems.

Diagnosis

The diagnosis of CHF relies on several sources of clinical findings, including history, physical examination, chest radiographs, and echocardiographic studies. No single test is specific for CHF. In addition to physical findings discussed later, cardiomegaly on a chest film (or echocardiographic study) is nearly a prerequisite sign of CHF. An electrocardiogram (ECG) is perhaps the least important test for the diagnosis of CHF, although it may help identify the cause of heart failure. Echocardiographic studies are most helpful noninvasive study that confirms the diagnosis of heart failure and estimates the severity of heart failure. It may also help identify the cause of heart failure.

Plasma levels of natriuretic peptides, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), are increased in most adult patients with heart failure. They are important makers of heart failure and may help distinguish dyspnea caused by heart failure and pulmonary disease in adult patients. ANP is stored mainly in the RA and is released when the atrial distending pressure increases. BNP is stored in ventricular myocardium and appears to be released when the ventricular filling pressure increases. Both peptides exhibit vasodilating effects and natriuretic effects on the kidneys and counteract the water-retaining effects of the renin–angiotensin–aldosterone system. The plasma levels of these peptides are elevated in newborns and in the first weeks of life but decrease to the levels observed in normal adults. Increased levels of BNP and the N-terminal segment of its prohormone (NT-ProBNT) have been reported in most children with either pressure or volume overload cardiac lesions compared with the levels seen in normal children (Nir et al, 2005). However, the usefulness of the levels of these peptides appears limited because an appropriate reference range has not been established. The levels of these peptides are different depending on the commercial testing kits used.

History

1. Poor feeding of recent onset, tachypnea that worsens during feeding, poor weight gain, and cold sweat on the forehead suggest CHF in infants.

2. Older children may complain of shortness of breath, especially with activities, early fatigability, puffy eyelids, or swollen feet.

Physical Examination

Physical findings of CHF may be classified as follows, depending on their pathophysiologic mechanisms. The more common findings are in italics.

1. The following are found as compensatory responses to impaired cardiac function:

a. Tachycardiagallop rhythm, and weak and thready pulses are common.

b. Cardiomegaly is almost always present. Chest radiographs are more reliable than physical examination in demonstrating cardiomegaly.

c. There are signs of increased sympathetic discharges (e.g., growth failureperspiration, cold and wet skin).

2. Pulmonary venous congestion (from left-sided failure) results in the following manifestations:

a. Tachypnea is common and is an early manifestation of CHF in infants.

b. Dyspnea on exertion (equivalent to poor feeding in small infants) is common in children.

c. Orthopnea may be seen in older children.

d. Wheezing and pulmonary crackles are occasionally audible.

3. Systemic venous congestion (caused by right-sided failure) results in the following:

a. Hepatomegaly is common, but it is not always indicative of CHF. A large liver may be palpable in conditions that cause hyperinflated lungs (asthma, bronchiolitis, during hypoxic spells) and in infiltrative liver disease. Conversely, the absence of hepatomegaly does not rule out CHF; hepatomegaly may be absent in (early) left-sided failure.

b. Puffy eyelids are common in infants.

c. Distended neck veins and ankle edema, which are common in adults, are not seen in infants.

d. Splenomegaly is not indicative of CHF; it usually indicates infection.

Radiography

The presence of cardiomegaly should be demonstrated by chest radiographs. The absence of cardiomegaly almost rules out the diagnosis of CHF. The only exception to this rule is when the pulmonary venous return is obstructed; in such cases, the lung parenchyma will show pulmonary edema or venous congestion.

Electrocardiography

Electrocardiography helps determine the type of heart defect causing heart failure but is not helpful in determining whether CHF is present.

Echocardiography

Echocardiographic studies may confirm enlargement of ventricular chambers and impaired LV systolic function (decreased fractional shortening or ejection fraction) as well as impaired diastolic function by the use of Doppler techniques. A more important role of echocardiography may be its ability to determine the cause of CHF. Echocardiography is also helpful in serial evaluation of the efficacy of therapy. Normal echocardiographic values for LV diastolic and systolic dimensions are found in Table D-1 in Appendix D.

Tissue Diagnosis

Endomyocardial biopsy obtained during cardiac catheterization offers a new approach to specific diagnosis of the cause of CHF, such as inflammatory disease, infectious process, or metabolic disorder. When viral myocarditis is suspected, the polymerase chain reaction provides a means of isolating the offending viral agent from biopsy specimens. In a patient with dilated cardiomyopathy, evaluation of biopsy specimens, including genetic analysis, may provide data permitting the diagnosis of specific metabolic causes, such as carnitine deficiency.

Management

The treatment of CHF consists of (1) elimination of the underlying causes, (2) treatment of the precipitating or contributing causes (e.g., infection, anemia, arrhythmias, fever), and (3) control of heart failure state. Eliminating the underlying causes is the most desirable approach whenever possible. Surgical correction of CHDs is such an approach. Every patient with CHF should receive maximal medical treatment, but continuing with long-term anticongestive measures is unwise when the heart defect can be safely repaired through surgery. The heart failure state is controlled by the use of multiple drugs, including inotropic agents, diuretics, and afterload-reducing agents, along with general supportive measures.

Treatment of Underlying Causes or Contributing Factors

1. When surgically feasible, surgical correction of underlying CHDs and valvular heart disease is the best approach for complete cure.

2. If hypertension is the underlying cause of CHF, antihypertensive treatment should be given.

3. If arrhythmias or advanced heart block is the cause of or contributing factor to heart failure, antiarrhythmic agents or cardiac pacemaker therapy is indicated.

4. If hyperthyroidism is the cause of heart failure, this condition should be treated.

5. Fever should be controlled with antipyretics.

6. When there is a concomitant infection, it should be treated with appropriate antibiotics.

7. For anemia, a packed cell transfusion is given to raise the hematocrit to 35% or higher.

General Measures

General support to improve congestive symptoms and nutritional support are important.

1. A “cardiac chair” or “infant seat” is used to keep infants in a semiupright position to relieve respiratory distress.

2. Oxygen (40%–50%) with humidity is administered to infants with respiratory distress if pulse oximetry indicates compromise of blood oxygenation.

3. Adequate calories and fluid should be provided to permit appropriate weight gain. Infants in CHF need significantly higher caloric intakes than recommended for average children. The required calorie intake may be as high as 150 to 160 kcal/kg/day for infants in CHF. Compounding this problem is that these infants typically cannot take in needed calories even for normal growth owing to tachypnea, increased work of breathing, diminished strength of sucking, and difficulty with coordination of sucking and swallowing.

a. Increasing caloric density of feeding may be required and it may be accomplished with fortification of feeding (Table 27-2).

b. Frequent small feedings are better tolerated than large feeding in infants.

c. If oral feedings are not well tolerated, intermittent or continuous nasogastric (NG) feeding is indicated. To promote normal development of oral-motor function, infants may be allowed to take calorie-dense oral feeds throughout the day and then be given continuous NG feeds overnight.

d. Salt restriction in the form of a low-salt formula and severe fluid restriction are not indicated in infants. Use of diuretics has replaced these measures.

e. Parents should be taught proper feeding techniques.

TABLE 27-2

INCREASING CALORIC DENSITY OF FEEDINGS

image


MCT, Medium-chain triglyceride.

TABLE 27-3

DIURETIC AGENTS AND DOSAGES

image

IV, Intravenous; PO, oral.

4. In older children, salt restriction (<0.5 g/day) and avoidance of salty snacks (chips, pretzels) and table salt are recommended. Bed rest remains an important component of management. The availability of a television screen and computer games for entertainment ensures bed rest in older children.

5. If respiratory failure accompanies cardiac failure, intubation and positive-pressure ventilation are occasionally required. Respiratory failure usually signifies that surgical intervention will be needed for CHDs when the patient is stabilized.

6. Daily weight measurement is essential in hospitalized patients.

Drug Therapy

Three major classes of drugs are commonly used in the treatment of CHF in children: inotropic agents, diuretics, and afterload-reducing agents. Rapid-acting inotropic agents (dopamine, dobutamine) are used in critically or acutely ill infants and children. Diuretics are usually used with inotropic agents. Afterload-reducing agents, such as ACE inhibitors, have gained popularity because they can increase cardiac output without increasing myocardial oxygen consumption. Recently, low-dose β-adrenergic blockade has been added to the treatment of dilated cardiomyopathy with encouraging results.

Diuretics

Diuretics remain the principal therapeutic agent to control pulmonary and systemic venous congestion. Diuretics only reduce preload and improves congestive symptoms, but do not improve cardiac output or myocardial contractility (see Fig. 27-1). Patients with mild CHF may improve rapidly after a dose of fast-acting diuretics, such as ethacrynic acid or furosemide, even without inotropic agents. Table 27-3 shows dosages of commonly available diuretic preparations. There are three main classes of diuretics that are commercially available.

1. Thiazide diuretics (e.g., chlorothiazide, hydrochlorothiazide), which act at the proximal and distal tubules, are no longer popular.

2. Rapid-acting diuretics, such as furosemide and ethacrynic acid, are the drugs of choice. They act primarily at the loop of Henle (“loop diuretics”).

3. Aldosterone antagonists (e.g., spironolactone) act on the distal tubule to inhibit sodium-potassium exchange. The serum aldosterone level is significantly increased in patients with persistent CHF, contributing to fluid and salt retention. Patients with increased levels of circulating aldosterone have a diminished response to diuretic agents because aldosterone increases tubular reabsorption of sodium and water at a site distal to the sites of action of other diuretic agents (thiazides or furosemide). Aldosterone antagonists have value in preventing hypokalemia produced by other diuretics and thus are used in conjunction with a loop diuretic. However, when ACE inhibitors are used, spironolactone should be discontinued to avoid hyperkalemia.

TABLE 27-4

SUGGESTED STARTING DOSAGES OF CATECHOLAMINES

Drug

Dosage and Route

Side Effects

Epinephrine (Adrenalin)

0.1–1 μg/kg/min IV

Hypertension, arrhythmias

Isoproterenol (Isuprel)

0.1–0.5 μg/kg/min IV

Peripheral and pulmonary vasodilatation

Dobutamine (Dobutrex)

2–8 μg/kg/min IV

Little tachycardia and vasodilatation, arrhythmias

Dopamine (Intropin)

5–10 μg/kg/min IV

Tachycardia, arrhythmias, hypertension or hypotension

   

Dose-related cardiovascular effects (μg/kg/min):

   

Renal vasodilatation: 2–5

   

Inotropic: 5–8

   

Tachycardia: >8

   

Mild vasoconstriction: >10

   

Vasoconstriction: 15–20

IV, Intravenous.

Side effects of diuretic therapy

Diuretic therapy alters the serum electrolytes and acid–base equilibrium.

1. Hypokalemia is a common problem with diuretic therapy except when used with spironolactone. It is more profound with potent loop diuretics. Hypokalemia may increase the likelihood of digitalis toxicity.

2. Hypochloremic alkalosis may result because the loss of chloride ions is greater than the loss of sodium ions through the kidneys, with a resultant increase in bicarbonate levels. Alkalosis also predisposes to digitalis toxicity.

Rapidly Acting Inotropic Agents

In critically ill infants with CHF, in those with renal dysfunction (e.g., infants with coarctation of the aorta), or in postoperative cardiac patients with heart failure, rapidly acting catecholamines with a short duration of action are preferable to digoxin. This class of agents includes dopamine, dobutamine, isoproterenol, and epinephrine. These agents possess inotropic and vasodilator actions and thus are useful in acute situations. Dobutamine has fewer chronotropic effects than dopamine. Dopamine in high doses causes α-receptor stimulation with vasoconstriction and reduction of renal blood flow. There is an added beneficial effect when an inotropic agent has vasodilating action as in dopamine. Inotropic agents in general increase the contractile property of the myocardium toward the normal curve (see Fig. 27-1). Dosages for intravenous drip of these catecholamines are suggested in Table 27-4.

Amrinone is a noncatecholamine agent that exerts its inotropic and vasodilator effects by inhibiting phosphodiesterase. Thrombocytopenia is a side effect; the drug should be discontinued if the platelet count falls below 150,000/mm3. Amrinone is useful in patients with severe CHF (dilated cardiomyopathy) who have received prolonged treatment with β-stimulants (see Appendix ETable E-2 for dosage).

Digitalis Glycosides

Usage of digoxin

The popularity of digoxin in the treatment of heart failure has waxed and waned. Until the early 1980s, there were only two classes of drugs available to treat CHF; cardiac glycosides and diuretics (thiazide diuretics, loop diuretics, or aldosterone antagonist). During that period of time, open heart surgeries carried a high mortality rate in small infants with CHDs; thus, maximum pharmacologic efforts were made using digoxin and diuretics to delay the surgeries in small infants with heart failure from CHDs.

Afterload-reducing agents, mainly ACE inhibitors, became available in the 1980s. At that time, it became apparent that many infants with large left-to-right shunt lesions had congestive symptoms, but their LV systolic function remained normal, the so-called pulmonary overcirculation state. With increasing popularity of ACE inhibitors and new understanding of pathophysiology of congestive symptoms (with normal LV systolic function) in infants with large left-to-right shunt lesions, the benefits of digoxin in these infants were questioned, and the use of digoxin became controversial. Salutary effects of combined use of diuretics and afterload-reducing agents, without digoxin, were reported. Thereafter, the use of digoxin in small infants with congestive symptoms from large left-to-right shunt lesions gradually lost popularity.

TABLE 27-5

ORAL DIGOXIN DOSAGE FOR CONGESTIVE HEART FAILURE

Age

Total Digitalizing Dose (μg/kg)

Maintenance Dose (μg/kg/day)

Premature infants

20

5

Newborn infants

30

8

<2 yr

40–50

10–12

>2 yr

30–40

8–10

 The maintenance dose is 25% of the total digitalizing dose in two divided doses. The intravenous dose is 75% of the oral dose.

Adapted from Park MK: The use of digoxin in infants and children with specific emphasis on dosage. J Pediatr 108:871-877, 1986.

However, studies have shown that digoxin improves symptoms in these infants with pulmonary overcirculation, perhaps because of other actions of digoxin (Berman et al, 1983). In addition to inotropic action, digoxin also has parasympathomimetic action with slowing of heart rate, reducing sinoatrial firing, and slowing the atrioventricular (AV) conduction. Several earlier studies have shown that digoxin reduces circulating norepinephrine, renin, and aldosterone levels. Digoxin is a diuretic agent as well. Thus, digoxin can increase inotropy without increasing myocardial oxygen consumption. Research has shown that myocardial oxygen consumption is increased in the normal heart by the positive inotropic action of glycosides; oxygen consumption is actually reduced or remains constant in the failing heart (Braunwald, 1985). Therefore, some cardiologists still favor the use of digoxin in infants with CHF from large-shunt lesions. A usual approach may be that a diuretic and an afterload-reducing agent are initially started, and digoxin is added later if further improvement is needed.

With regard to the patients with dilated LV with decreased systolic function, such as those with dilated cardiomyopathy, inotropic agents clearly increase the cardiac output (or contractile state of the myocardium), thereby resulting in an upward and leftward shift of the ventricular function curve relating cardiac output to filling volume of pressure (see Fig. 27-1). When inotropic agents are used with a vasodilator or a diuretic, a much greater improvement is seen both in the contractile state and in congestive symptoms than when a single class of agent was used (see Fig. 27-1). Thus, the use of a combination of inotropic agents, diuretics, and vasodilators has become popular.

Dosage of digoxin

The total digitalizing dose and maintenance dosages of digoxin in treating CHF by oral and intravenous routes are shown in Table 27-5. A higher dose may be needed in treating SVT, in which the goal of treatment is to delay AV conduction. The maintenance dose is more closely related to the serum digoxin level than is the digitalizing dose, which is given to build a sufficient body store of the drug and to shorten the time required to reach the pharmacokinetic steady state.

The pediatric dosage of digoxin is much larger than the adult dosage on the basis of body weight. Pharmacokinetic studies indicate that infants and children require larger doses of digoxin than adults to attain comparable serum levels, primarily because of a larger volume of distribution and, less important, a more rapid renal clearance, including tubular secretion. The volume of distribution of digoxin is 7.5 L/kg in neonates, 16 L/kg in infants and children, and 4 L/kg in adults. Much higher concentrations of digoxin are found in the myocardium and skeletal muscles from young patients.

How to digitalize

Loading doses of the total digitalizing doses are given over 12 to 18 hours followed by maintenance doses. This results in a pharmacokinetic steady state in 3 to 5 days. The intravenous route is preferred over the oral route, particularly when dealing with infants in severe heart failure. The intramuscular route is not recommended because absorption of the drug from the injection site is unreliable. When an infant is in mild heart failure, the maintenance dose may be administered orally without loading doses; this results in a steady state in 5 to 8 days.

BOX 27-1 Electrocardiographic Changes Associated with Digitalis

Effects

Shortening of QTc, the earliest sign of digitalis effect

Sagging ST segment and diminished amplitude of T wave (the T vector does not change)

Slowing of heart rate

Toxicity

Prolongation of PR interval: sometimes a prolonged PR interval is seen in children without digitalis, making a baseline ECG mandatory; the prolongation may progress to second-degree AV block

Profound sinus bradycardia or sinoatrial block

Supraventricular arrhythmias, such as atrial or nodal ectopic beats and tachycardias (particularly if accompanied by AV block), which are more common than ventricular arrhythmias in children

Ventricular arrhythmias such as ventricular bigeminy and trigeminy, which are extremely rare in children, although they are common in adults with digitalis toxicity; isolated PVCs, which are not uncommon in children, is a sign of toxicity

AV, Atrioventricular; ECG, electrocardiographic; PVC, premature ventricular contraction.

The following is a suggested step-by-step method of digitalization:

1. Obtain a baseline ECG (rhythm and PR interval) and baseline levels of serum electrolytes. Changes in ECG rhythm and PR interval are important signs of digitalis toxicity (see later discussion). Hypokalemia and hypercalcemia predispose to digitalis toxicity.

2. Calculate the total digitalizing dose (see Table 27-5).

3. Give half the total digitalizing dose immediately followed by one fourth and then the final fourth of the total digitalizing dose at 6- to 8-hour intervals.

4. Start the maintenance dose 12 hours after the final total digitalizing dose. Obtaining an ECG strip before starting the maintenance dose is advised.

Monitoring for digitalis toxicity by ECG

Digitalis toxicity is best detected by monitoring with ECGs, not serum digoxin levels, during the first 3 to 5 days after digitalization. Box 27-1 lists signs of digitalis effects and toxicity. In general, whereas the digitalis effect is confined to ventricular repolarization, toxicity involves disturbances in the formation and conduction of the impulse. One should assume that any arrhythmia or conduction disturbance occurring with digitalis is caused by digitalis until proved otherwise.

Serum digoxin levels

Therapeutic ranges of serum digoxin levels for treating CHF are 0.8 to 2 ng/mL. Levels obtained during the first 3 to 5 days after digitalization tend to be higher than those obtained when the pharmacokinetic steady state is reached. Blood for serum digoxin levels should be drawn at least 6 hours after the last dose or just before a scheduled dose; samples obtained earlier than 6 hours after the last dose will give a falsely elevated level.

Determining serum digoxin levels frequently and using those levels for therapeutic goals are neither justified nor practical; occasional determination of the levels is adequate. Determination of the serum digoxin levels is useful in evaluating possible toxicity (see later section), determining the patient’s compliance, and detecting abnormalities in absorption and excretion is mandatory in managing accidental overdoses.

Serum digoxin levels may be elevated when administered concomitantly with other drugs such as quinidine, verapamil, amiodarone, beta-blockers, tetracycline, and erythromycin. Lower serum levels have been noted with rifampin, kaolin-pectin, neomycin, and cholestyramine.

BOX 27-2 Factors That May Predispose to Digitalis Toxicity

High Serum Digoxin Level

High-dose requirement, as in treatment of certain arrhythmias

Decreased renal excretion

Premature infants

Renal disease

Hypothyroidism

Drug interaction (e.g., quinidine, verapamil, amiodarone)

Increased Sensitivity of Myocardium (without High Serum Digoxin Level)

Status of myocardium

Myocardial ischemia

Myocarditis (rheumatic, viral)

Systemic changes

Electrolyte imbalance (hypokalemia, hypercalcemia)

Hypoxia

Alkalosis

Adrenergic stimuli or catecholamines

Immediate postoperative period after heart surgery under cardiopulmonary bypass

Digitalis toxicity

Digitalis toxicity may result during treatment with digoxin or from an accidental overdose of digoxin. With the relatively low dosage recommended in Table 27-5, digitalis toxicity is unlikely to develop. However, one should beware of possible digitalis toxicity in every child receiving digitalis preparations. Patients with conditions listed in Box 27-2 are more likely to develop toxicity. The diagnosis of digitalis toxicity is a clinical decision and usually is based on the following clinical and laboratory findings:

1. The patient has a history of accidental ingestion.

2. Noncardiac symptoms appear in digitalized children; these symptoms include anorexia, nausea, vomiting, diarrhea, restlessness, drowsiness, fatigue, and visual disturbances in older children.

3. Heart failure worsens.

4. ECG signs of toxicity probably are more reliable and appear early (see Box 27-1).

5. An elevated serum level of digoxin (>2 mg/mL) is likely to be associated with toxicity in a child if the clinical findings suggest digitalis toxicity.

Afterload-Reducing Agents

Vasoconstriction that occurs as a compensatory response to reduced cardiac output seen in CHF may be deleterious to the failing ventricle. Vasoconstriction is produced by a rise in sympathetic tone and circulating catecholamines and an increase in the activity of the renin–angiotensin system. Reducing afterload tends to augment the stroke volume without a great change in the contractile state of the heart and therefore without increasing myocardial oxygen consumption (see Fig. 27-1). When a vasodilator is used with an inotropic agent, the degree of improvement in the inotropic state as well as in congestive symptoms is much greater than when a vasodilator alone is used. Combined use of an inotropic agent, a vasodilator, and a diuretic produces most improvement in both inotropic state and congestive symptoms (Fig. 27-1).

Afterload-reducing agents now occupy a prominent role in the treatment of infants with CHF secondary to a large left-to-right shunt lesions (e.g., VSD, AV canal, PDA). Infants with large left-to-right shunts have been shown to benefit from captopril and hydralazine. Beneficial effects of afterload-reducing agents are also seen in dilated cardiomyopathy, Adriamycin-induced cardiomyopathy, myocardial ischemia, postoperative cardiac status, severe MR or AR, and systemic hypertension. These agents usually are used in conjunction with diuretics and often with digitalis glycosides for a maximal benefit.

Afterload-reducing agents may be divided into three groups based on the site of action: arteriolar vasodilators, venodilators, and mixed vasodilators. Dosages of these agents are presented in Table 27-6.

1. Arteriolar vasodilators (hydralazine) augment cardiac output by acting primarily on the arteriolar bed, with resulting reduction of the afterload. Hydralazine often is administered with propranolol because it activates the baroreceptor reflex, with resulting tachycardia.

2. Venodilators (nitroglycerin, isosorbide dinitrate) act primarily by dilating systemic veins and redistributing blood from the pulmonary to the systemic circuit (with a resulting decrease in pulmonary symptoms). Venodilators are most beneficial in patients with pulmonary congestion but may have adverse effects when preload has been restored to normal by diuretics or sodium restriction.

3. Mixed vasodilators include ACE inhibitors (captopril, enalapril), nitroprusside, and prazosin. These agents act on both arteriolar and venous beds. ACE inhibitors are popular in children with chronic severe CHF, but sodium nitroprusside is used primarily in acute situations such as after cardiac surgery under cardiopulmonary bypass, especially in patients who had pulmonary hypertension and those with postoperative rises in pulmonary artery pressure. When nitroprusside is used, blood pressure must be monitored continuously. ACE inhibitors reduce systemic vascular resistance by inhibiting angiotensin II generation and augmenting the production of bradykinin.

TABLE 27-6

DOSAGES OF VASODILATORS

image

BID, Twice a day; GI, gastrointestinal; IV, intravenous; PO, oral; QD, once a day; QID, four times a day; TID, three times a day.

Other Drugs

β-Adrenergic blockers

Beneficial effects of β-adrenergic blockers were reported in adult patients with dilated cardiomyopathy. Recent studies suggest that adrenergic overstimulation often seen in patients with chronic CHF may have detrimental effects on the hemodynamics of heart failure by inducing myocyte injury and necrosis rather than being a compensatory mechanism, as traditionally thought. Small-scale, uncontrolled pediatric studies have shown similar beneficial effects of β-adrenergic blockers in some children with chronic CHF who were symptomatic despite being treated with standard anticongestive drugs (digoxin, diuretics, ACE inhibitors).

In 1999, Shaddy et al reported on the use of metoprolol in children. Metoprolol was added to standard anticongestive medicines in patients with chronic CHF from dilated cardiomyopathy. Metoprolol increased LV fractional shortening and ejection fraction and improved symptoms. The starting dose was 0.1 to 0.2 mg/kg per dose twice a day and slowly increased over a period of weeks to a dose of 1.1 mg/kg/day (range, 0.5–2.3 mg/kg/day) (Shaddy et al, 1999).

Carvedilol, when added to standard medical therapy for CHF, has been shown to be beneficial in children with dilated cardiomyopathy (Bruns et al, 2001). The patients included in the study were those with idiopathic dilated cardiomyopathy, chemotherapy-induced cardiomyopathy, postmyocarditis myopathy, or muscular dystrophy and those who had chronic heart failure after surgeries for CHDs (e.g., Fontan or Senning operation). The initial dose was 0.09 mg/kg twice daily, and the dose was increased gradually to 0.36 and 0.75 mg/kg as tolerated, up to the maximum adult dose of 50 mg/day. Side effects of the drug include dizziness, hypotension, and headache (also see the discussion of dilated cardiomyopathy).

Carvedilol and metoprolol have been studied most often. There is a theoretical advantage of carvedilol over metoprolol. Carvedilol is a nonselective beta-blocker that inhibits β1-, β2-, and α1-adrenoceptors with additional vasodilatory and antioxidant properties. Metoprolol is a selective β1- (and β2- at high dose) adrenoceptor blocker that does not have vasodilator or antioxidant properties (Foerster et al, 2008). The improvement in the LV fractional shortening appeared slightly better with carvedilol than with metoprolol.

However, β-adrenergic blockers should not be given to those with decompensated heart failure. Their use should be deferred until reestablishment of good fluid balance and stable blood pressure and should be started with a small dose and gradually increased. Contraindications to the use of β-adrenergic blockers include symptomatic bradycardia or heart block, significant hypotension, active asthma, and severe bronchial disease.

Although earlier noncontrolled studies have implied effectiveness of carvedilol and other β-adrenoceptors in the treatment of pediatric heart failure, a more recent, 26 multicenter large-scale, prospective, randomized trials on 150 patients did not reach the same conclusion (Shaddy et al, 2007). In that study, the patients were divided into three groups; placebo group and low and high doses of carvedilol groups (0.4 mg and 0.8 mg/kg/day, respectively). All patients were on standard treatment with ACE inhibitors and diuretics. The study found no significant differences among the three groups in terms of symptoms and echocardiographic indices over the 6-month period of follow-up. However, it has found a surprising number of patients showing spontaneous improvement in all three groups. It also found a trend to better outcome in patients who have morphologic LVs (as seen in patients with tricuspid atresia).

Carnitine

Carnitine, which is an essential cofactor for transport of long-chain fatty acids into mitochondria for oxidation, has been shown to be beneficial in some cases of cardiomyopathy, especially those with suggestive evidence of disorders of metabolism (Helton et al, 2000). Most of these patients had dilated cardiomyopathy. The dosage of L-carnitine was 50 to 100 mg/kg/day, given twice a day or three times a day orally (maximum daily dose, 3 g). It improved myocardial function, reduced cardiomegaly, and improved muscle weakness. Animal studies suggest potential protective and therapeutic effects on doxorubicin-induced cardiomyopathy in rats.

Surgical Management

If medical treatment with the previously mentioned regimens does not improve CHF caused by CHDs within a few weeks to months, one should consider either palliative or corrective cardiac surgery for the underlying cardiac defect when technically feasible.

Cardiac transplantation is an option for a patient with progressively deteriorating cardiomyopathy despite maximal medical treatment.