Treating symptoms of “congestion” is critical to the management of heart failure in both the acute and the chronic setting (1). Diuretics are recommended for patients with symptoms of heart failure and evidence of volume overload. Although these are the most common agents used in the long-term management of heart failure, there is a lack of studies that demonstrate long-term benefits of diuretic treatment. Indeed, data from animal models of cardiomyopathy indicate that furosemide activates the renin-angiotensin-aldosterone system (RAAS) and accelerates the decline of myocardial function (5). Furthermore, a retrospective study of adult heart failure patients identified the use of increased loop diuretic dose as an independent predictor of mortality (6). Loop and thiazide diuretics remain the most commonly used diuretics. In adults, aldosterone antagonists, such as spironolactone, have been shown to improve mortality when added to standard heart failure management (7), though there may be an increase in hyperkalemia (8,9). These agents have not been well studied in children, but pediatric use is expanding, likely secondary to the increased use in adults.

Angiotensin-converting enzyme (ACE) inhibitors were the first agents to demonstrate improved survival in adults with symptomatic heart failure. These medications decrease the formation of angiotensin II, block the activation of the RAAS, and decrease adrenergic activity (10). Prospective randomized controlled trails of various agents within this class have demonstrated improvement in symptoms with reduced progression of heart failure, decreased hospitalization, and improved survival in adults with chronic heart failure (11,12,13,14,15,16). The mortality benefit is primarily due to decreased deaths from pump failure. Angiotensin receptor blockers (ARBs), primarily used in adults unable to tolerate ACE inhibitors, have also demonstrated reduction in mortality that is comparable, and possibly superior to the ACE inhibitors (17). The combination of ACE inhibitor and ARB treatment may provide additional benefits to improve left ventricular geometry, ejection fraction, and exercise capacity (18,19).

Although ACE inhibitors have been shown to reduce the Qp:Qs ratio in children with large left-to-right shunt lesions (20), long-term treatment has not been shown to be efficacious. Since heart failure symptoms and ventricular dysfunction are common in infants with single-ventricle hearts, the Pediatric Heart Network conducted a randomized controlled trial of ACE inhibition in this population (21). Administration of enalapril to infants with single-ventricle physiology in the first year of life did not improve somatic growth, ventricular function, or heart failure severity (21). In addition, a trial of ACE inhibition in Fontan patients also failed to demonstrate improvement in resting cardiac index, diastolic function, systemic vascular resistance (SVR), or exercise capacity (22).

Although there have been no large randomized controlled trials of ACE inhibitors in the treatment of children with dilated cardiomyopathy (DCM), there are multiple small studies to suggest efficacy in these patients. In children with DCM, Bengur et al. (23) demonstrated that a single dose of 0.5 mg/kg of captopril increased cardiac index and stroke volume by 22% and decreased SVR without a significant decrease in mean aortic pressure. Stern et al. (24) prospectively studied 12 children with DCM. A 3-month course of captopril (mean dose 1.8 mg/kg/d) was associated with an improvement in left ventricular end-diastolic and end-systolic volumes and reduced aldosterone and plasma atrial natriuretic peptide. Mori et al. (25) reported similar echocardiographic results in a prospective study of patients with aortic and mitral regurgitation treated with ACE inhibitors. A retrospective study of children with DCM reported improved survival with ACE inhibition, although the survival benefit was not statistically significant beyond 1 year of therapy (26). On the basis of the supportive pediatric evidence and abundant adult data, the International Society for Heart and Lung Transplantation (ISHLT) guidelines recommend ACE inhibition for moderate or severe degrees of LV dysfunction in infants and children, and ARB therapy if ACE inhibition is not tolerated.

As with ACE inhibitors, there is abundant evidence from large randomized controlled trials that β-blockers in adult patients with chronic heart failure demonstrate improvement in symptoms, heart function, frequency of hospitalization, and survival (27,28,29,30). Despite negative inotropic properties, the presumed benefit of β-blockade is inhibition of the effects of the sympathetic nervous system (31). Data on β-blocker use in pediatric heart failure are limited and contradictory. Shaddy et al. (32) reviewed the experience of metoprolol in 15 children with DCM at three centers in the United States. Metoprolol was associated with a significant increase in fractional shortening and ejection fraction. Carvedilol use was reviewed in 46 patients with DCM (80%) or palliated congenital heart disease (20%) and was found to be associated with improvement in New York Heart Association (NYHA) functional class and fractional shortening at 3 months (33). A small randomized, placebo-controlled study in 22 children with severe left ventricular dysfunction found that patients given carvedilol had an improvement in ejection fraction and NYHA class over a 3-month period (34). Additionally, 64% of the patients in the carvedilol group improved enough to be taken off the cardiac transplantation list. A large multicenter prospective pediatric study of carvedilol randomized 161 children to placebo, low-dose, or high-dose carvedilol (35). Heart failure outcomes were not different among the treatment groups, but the incidence of heart failure progression was lower than predicted, so the study was thought to be underpowered (35). A prespecified analysis of the interaction effect between ventricular morphology and carvedilol response showed a trend toward improvement in children with DCM and morphologic left ventricles. Although ISHLT guidelines do not recommend β-blockers in infants and children with heart failure (4), β-blockers are often empirically used in children with DCM on the basis of the abundant adult data and the supportive data in children with DCM.

Digoxin, the oldest medication used for treatment of heart failure symptoms, is a cardiac glycoside that improves contractility by inhibiting the Na-K-ATPase pump in the cardiac myocyte membrane. The increase in intracellular sodium is exchanged across the cell membrane by a Na-Ca transporter, which results in increased intracellular calcium and contractility (36).
Although digoxin is effective in alleviating symptoms of heart failure (37

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