"Nihilism" of chronic heart failure therapy in children and why effective therapy is withheld

Abstract

Major advances in chronic heart failure (cHF) therapy have been achieved and documented in adult patients, while research regarding the mechanisms and therapy of cHF in children has lagged behind. Based on receptor physiological studies and pharmacological knowledge, treatment with specific ß1-adrenergic receptor blocker (ARB), tissue angiotensin-converting enzyme inhibitor (ACE-I), and mineralocorticoid antagonists have to be recommended in children despite lack of sufficient data derived from prospective randomized studies. At our institution, bisoprolol, lisinopril, and spironolactone have been firmly established to treat systolic cHF, hypoplastic left heart syndrome (HLHS) following hybrid approach and congenital left-right shunt diseases, latest in patients where surgery has to be delayed. Chronic therapy with long-acting diuretics and fluid restriction are not advocated because short-term effects are achieved at the expense of further neuro-humoral stimulation. It remains unclear why diuretics are recommended although evidence-based studies, documenting long-term benefit, are missing. However, that is true for all currently used drugs for pediatric cHF.

Conclusion: This review focuses on the prevailing "nihilism" of cHF therapy in children with the goal to encourage physicians to treat pediatric cHF with a rationally designed therapy, which combines available agents that have been shown to improve survival in adult patients with cHF. Because of the lack of clinical trials, which generate the needed evidence, surrogate variables like heart and respiratory rate, weight gain, image-derived data, and biomarkers should be monitored and used instead. The recommended pharmacological therapy for systolic heart failure is also provided as the basis for utilizing reversible pulmonary arterial banding (PAB) as a novel strategy in young children with dilative cardiomyopathy (DCM) with preserved right ventricular function.

What is known: • Heart failure (HF) in children is a serious public health concern. • HF has numerous etiologies, but unspecific symptoms. • HF interplays among neuro-humoral, and molecular abnormalities. • Pediatric cHF-therapy is currently based on loop-diuretics, fluid restriction and digoxin. What is New: • Cardiac function analysis has to include cardiac synchrony and VVI. • Considering enormous potential of cardiac regeneration, therapy has to extend with selective ß1-ARB, tissue ACE-I and mineralocorticoid blockers, loop-diuretics avoided as ever possible. • Inhibition of the endogenous neuro-humoral stimulation is monitored by surrogate parameters as heart and breath rate and systolic and diastolic blood pressure. • Advocated HF therapy serves for regenerative strategies as reversible Pulmonary Artery Banding in DCM.

Keywords: Bisoprolol; Chronic heart failure; Infants and children; Lisinopril; Pulmonary artery banding; Spironolactone.

Fig. 1

Parameters responsible for cardiac output. In addition to heart rate, contractility, preload, and afterload, cardiac synchrony as well as ventricular-ventricular interaction (VVI) defines cardiac function. CaO2 oxygen content, Ca-vDO2 arterial-venous oxygen content difference, CO cardiac output, DO2 oxygen delivery, HR heart rate, SaO2 arterial oxygen saturation, SvO2 venous oxygen saturation in superior and inferior caval vein, SV stroke volume, VO2 oxygen consumption

Fig. 2

Estimated survival and freedom of death in children with DCM [50]. Shown is the median follow-up 16 months (range 2–80 months) of 38 children in an age less than 3 years admitted at the Pediatric Heart Center Giessen. The Kaplan-Meier survival curve after the diagnosis of dilated cardiomyopathy revealed a 1-year survival of 97 % and a 5-year survival of 86 % [50]

Fig. 3

Shown is the mean brain natriuretic peptide (BNP) value of 20 infants and children younger than 3 years with left ventricular dilative cardiomyopathy (LV-DCM) and preserved right ventricular ejection fraction (pRV-EF), which were admitted for heart transplantation. The extremely high BNP values at admission decreased significantly [we believe as a consequence of the administered ‘triple therapy’] during the period prior to surgical pulmonary banding (PAB). At admission, all patients had been treated with in some high dosages of furosemide independent of continuously administered inotropic treatment. Furosemide was stopped and bisoprolol (B), lisionopril (L), and spironolactone (S) were started. The goal was to achieve a resting heart rate (HR) of less than 120/min with an adequate systemic blood pressure to sufficient diuresis. The inotropic treatment was continued, but if dobutamine had been part of the pre-admission regiment, it was changed to the inodilator milrinone

Fig. 4

Represents L/R shunt of hemodynamically relevant VSD; infants and young children not early surgically corrected, but mid-term treated by diuretics and fluid restriction develop as pictured severe cachexia because L/R shunt is favored by increased systemic vascular resistance and high oxygen consumption by compensating increased heart and breath rate and in particular of malnutrition

Fig. 5

Shows the schematic picture of Hybrid stage I consisting of duct stenting (DA stent), bilateral pulmonary banding (bPAB), and interatrial septum manipulation by stent placement. Left atrial (LAP) decompression to a pressure level of the right atrium (RAP) is an important part of a balanced parallel turned pulmonary to systemic circulation. The echocardiography shows an effective bPAB by its typical flow-pattern, but despite an effective bPAB, the systolic right-to-left flow through the duct is accompanied by a diastolic left-to-right reflow; one important indication to reduce the systemic vascular resistance without jeopardizing coronary blood flow. Additionally, bisoprolol reduces heart rate, which improves single ventricle filling; all factors together diminish pulmonary congestion, reduce total and myocardial oxygen consumption, and improve the baby’s functional class