pediatric heart failure a practical guide to diagnosis and management

+ MODEL Pediatrics and Neonatology (2017) xx, 1e10 Available online at www.sciencedirect.com ScienceDirect journal homepage: http://www.pediatr-neonatol.com REVIEW ARTICLE Pediatric Heart Failure: A Practical Guide to Diagnosis and Management Daniele Masarone*, Fabio Valente, Marta Rubino, Rossella Vastarella, Rita Gravino, Alessandra Rea, Maria Giovanna Russo, Giuseppe Pacileo, Giuseppe Limongelli Cardiologia SUN e Heart Failure Unit, Department of Cardiothoracic Sciences, Second University of Naples, Naples, Italy Received Jun 24, 2016; received in revised form Jan 4, 2017; accepted Jan 9, 2017 Available online - - - Key Words cardiomyopathies; congenital heart diseases; pediatric cardiac transplantation; pediatric heart failure Pediatric heart failure represents an important cause of morbidity and mortality in childhood Currently, there are well-established guidelines for the management of heart failure in the adult population, but an equivalent consensus in children is lacking In the clinical setting, ensuring an accurate diagnosis and defining etiology is essential to optimal treatment Diuretics and angiotensin-converting enzyme inhibition are the first-line therapies, whereas beta-blockers and devices for electric therapy are less used in children than in adults In the end-stage disease, heart transplantation is the best choice of treatment, while a left ventricular assist device can be used as a bridge to transplantation (due to the difficulties in finding organ donors), recovery (in the case of myocarditis), or destination therapy (for patients with systemic disease) Copyright ª 2017, Taiwan Pediatric Association Published by Elsevier Taiwan LLC This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/) Introduction Pediatric heart failure (PHF) represents an important cause of morbidity and mortality in childhood.1 Etiology and pathogenesis are different between adults and children: * Corresponding author Cardiologia SUN e Heart Failure Unit, Department of Cardiothoracic Sciences, Second University of Naples, Via Leonardo Bianchi n 1, Naples 80100, Italy E-mail address: danielemasarone@libero.it (D Masarone) the first mainly relates to ischemia (60e70% of cases), the latter as a consequence of congenital heart diseases (CHDs) or cardiomyopathies in most of the cases.2 Hence, managing PHF requires specific knowledge and skills.3 Presently, there are well-established guidelines for the management of heart failure (HF) in the adult population,4 but the equivalent consensus for PHF is lacking This article offers an overview on the etiology, diagnosis, and therapy of PHF, with a specific focus on practical issues required for management http://dx.doi.org/10.1016/j.pedneo.2017.01.001 1875-9572/Copyright ª 2017, Taiwan Pediatric Association Published by Elsevier Taiwan LLC This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) Please cite this article in press as: Masarone D, et al., Pediatric Heart Failure: A Practical Guide to Diagnosis and Management, Pediatrics and Neonatology (2017), http://dx.doi.org/10.1016/j.pedneo.2017.01.001 + MODEL D Masarone et al Definition Etiology In the 1950s, HF was described as a clinical syndrome caused by low cardiac output.5 In recent years, knowledge of the pathophysiology has been expanded and neurohormonal and molecular pathways that modulate cardiac performance in failing hearts have been discovered.6 The contemporary vision describes HF as a clinical syndrome characterized by typical symptoms and signs associated with specific circulatory, neurohormonal, and molecular abnormalities.7 In children, cardiac failure is most often due to CHDs and cardiomyopathies The cardiac and noncardiac causes of PHF are summarized in Table At birth, HF is caused by fetal cardiomyopathies or extracardiac conditions (such as sepsis, hypoglycaemia, and hypocalcaemia) In the 1st week after birth, CHDs with ductus-dependent systemic circulation (such as severe aortic stenosis/aortic coarctation and hypoplastic left heart syndrome), in which the closure of the ductus arteriosus causes severe reduction of end-organ perfusion,8 Table Etiology of pediatric heart failure Type of diseases Pathophisiology Examples Congenital heart diseases Left to right shunt (volume overload) Ventricular septal defects Complete atrioventricular canal defects Patent ductus arteriosus Aortoepulmonary windows Mitral regurgitation Aortic regurgitation Aortic stenosis Valvular regurgitation (volume overload) Outflow tract obstruction (pressure overload) Cardiomyopathies (inherited or acquired) Coronary insufficiency (decreased O2 supply to cardiomyocyte) Systolic dysfunction (low cardiac output) Diastolic dysfunction (elevated pulmonary capillary pressure) Tunnel type subaortic stenosis Supravalvular aortic stenosis Pulmonary stenosis Pulmonary vein stenosis Coronary artery anomalies Dilated cardiomyopathy - Myocarditis Barth syndrome Carnitine deficency Familial dilated cardiomyopathy Neuromuscular disorder (i.e., Becker dystrophy/ Duchenne dystrophy) Hypertrophic cardiomyopathy - Pompe diseases Noonan syndrome Maternal diabetes Mitochondrial diseases Familial hypertrophic cardiomyopathy Idiopathic restrictive cardiomyopathy Arrhythmias Systolic dysfunction (low cardiac output) Tachycardia induced cardiomyopathy - Atrioeventricular node reentry tachycardia - Atrioeventricular reentry tachycardia - Ectopic atrial tachycardia Congenital third degree atrioeventricular block Infection Systolic dysfunction Sepsis induced myocardial dysfunction High output state Volume overload Thyrotoxicosis Systemic arteriovenous fistula Severe anemia Please cite this article in press as: Masarone D, et al., Pediatric Heart Failure: A Practical Guide to Diagnosis and Management, Pediatrics and Neonatology (2017), http://dx.doi.org/10.1016/j.pedneo.2017.01.001 + MODEL Pediatric Heart Failure are the main cause In the 1st month of life, frequent causes of PHF are CHDs with left to right shunt (such as ventricular septal defects, patent ductus arteriosus, and aortopulmonary windows), in which pulmonary blood flow progressively increases with the fall of pulmonary resistance.9 Finally, HF in adolescence is rarely secondary to CHDs, but is more often related to cardiomyopathies or myocarditis.10 Pathophysiology of PHF An “index event,” regardless of the cause, produces an initial reduction of cardiomyocyte contractility in HF The initial injury results in a reduction in cardiac output that is, in turn, countered by two major “compensatory mechanisms” (Figure 1) The first of these mechanisms is the activation of the sympathetic nervous system, resulting in increased release and decreased uptake of norepinephrine, with peripheral vasoconstriction to maintain (by increasing systemic vascular resistance) mean arterial pressure and organ perfusion Enhanced catecholamine levels, however, lead to further cardiomyocyte injury, dysfunctional intracellular signaling, and ultimately cardiomyocyte death.11 The second important “compensatory” mechanism is the stimulation of the rennineangiotensin aldosterone system, consisting of increased circulating levels of renin, angiotensin II, and aldosterone Renin is responsible of cleaving angiotensinogen in angiotensin I, which is converted into angiotensin II by the angiotensin-converting enzyme (ACE) Angiotensin II is a potent vasoconstrictor that preserves end-organ perfusion Aldosterone causes salt and water retention, resulting in increased preload and then cardiac output according to the FrankeStarling mechanism However, the elevation of both aldosterone and angiotensin II promotes cardiac fibrosis and apoptosis.12 These mechanisms may temporarily contribute to circulatory stability, but over time become maladaptive and promote the progression of HF.13 Clinical presentation Infant and young children: The typical presentation is characterized by difficulty in feeding (from prolonged feeding time intake to frank intolerance) Cyanosis, tachypnea, sinus tachycardia, and diaphoresis can be present Older children and adolescence: Fatigue, shortness of breath, tachypnea, and exercise intolerance are the main symptoms Abdominal pain, oliguria, and leg pitting edema may also be present The severity of HF in children must be staged according to the Ross modified classification15 that recognizes four functional classes with increasing severity of clinical features from I to IV (Table 2) Diagnostic approach The first step in diagnostic approach in patients with PHF is based on noninvasive clinical investigations 6.1 Electrocardiogram Sinus tachycardia is common in acute HF In chronic HF, an abnormal electrocardiogram increases the likelihood of decompensated HF.16 Table failure Class I Class II Class III Class IV Modified Ross classification for pediatric heart Asymptomatic Mild tachypnea or diaphoresis with feeding in infants Dyspnea on exertion in older children Marked tachypnea or diaphoresis with feeding in infants Prolonged feeding times with growth failure Marked dyspnea on exertion in older children Symptoms such as tachypnea, retractions, grunting, or diaphoresis at rest The clinical picture of PHF is strictly related to age.14 Figure Pathophysiology of heart failure RAAS Z renin-angiotensin-aldosterone system; SNS Z sympathetic nervous system Please cite this article in press as: Masarone D, et al., Pediatric Heart Failure: A Practical Guide to Diagnosis and Management, Pediatrics and Neonatology (2017), http://dx.doi.org/10.1016/j.pedneo.2017.01.001 + MODEL D Masarone et al 6.2 Chest radiography 6.5 Cardiac magnetic resonance Chest radiography is indicated in all children with suspected HF to assess heart size and to check for other signs of HF such as pulmonary edema, septal lines (or Kerley B lines), and pleural effusions.17 Cardiac magnetic resonance is indicated to study complex CHDs or for tissue characterization and therefore for diagnosis, risk-stratification, and ongoing management of patients with specific forms of cardiomyopathies.19 6.6 Cardiac catheterization 6.3 Echocardiography The echocardiogram is the most useful, widely available, and low-cost test for patients with PHF Echocardiography provides immediate data on cardiac morphology and structure, chamber volumes/diameters, wall thickness, ventricular systolic/diastolic function, and pulmonary pressure These data are crucial to make the correct diagnosis and to guide appropriate treatment.18 Despite advances in noninvasive diagnostic techniques, cardiac catheterization is presently indicated for20: - accurate evaluation of pressure gradients in patients with complex valve diseases - evaluation of hemodynamic parameters (pulmonary and systemic vascular resistance, cardiac output, and cardiac index) in Fontan patients or during pre-transplant screening 6.4 Laboratory investigations 6.7 Endomyocardial biopsy The role of laboratory tests in HF management is summarized in Table Endomyocardial biopsy is an invasive procedure with significant risk and should be performed only to confirm the Table Laboratory test in heart failure Test Rationale Complete blood count Useful to assess anemia, which may cause or aggravate heart failure Leukocytosis may result from stress or signal an underlying infection Hyponatremia reflects an expansion of extracellular fluid volume in the setting of a normal total body sodium Hypokalemia and hypochloremia can be the result of prolonged administration of diuretics Hyperkalemia can be the result of impaired renal perfusion and marked reductions in glomerular filtration rate or from intracellular potassium release due to impaired tissue perfusion Elevated BUN and BUN/creatinine ratio are seen in decompensated heart failure Congestive hepatomegaly is often associated with impaired hepatic function, which is characterized by elevation of AST, ALT, LDH, and other liver enzymes Hyperbilirubinemia (both direct and indirect) is related to acute hepatic venous congestion and is common with severe right heart failure Elevated ALP, and prolongation of the PTT time can be seen In children with long-standing heart failure and poor nutritional status, hypoalbuminemia results from hepatic synthesis impairment Natriuretic peptides levels correlate closely with the NYHA/Ross classification of heart failure and with ventricular filling pressures Useful if the clinical scenario is suggestive of an ischemic process or myocarditis Elevated lactate is seen in patients with decompensated heart failure as a result of decreased tissue perfusion and/or decreased metabolism due to secondary liver dysfunction and can be a useful serologic marker for monitoring response to therapeutic interventions Both severe hyper or hypothyroidism can cause heart failure Usually reveal mild hypoxemia in patients who have mild-to-moderate heart failure Severe heart failure often leads to severe hypoxemia, or even hypoxia Hypocapnia occurs in the early stages of pulmonary edema because of V/Q mismatch, progressing to hypercapnia and respiratory acidosis, related to decreased vital capacity and poor ventilation Electrolytes Renal function tests Liver function tests Natriuretic peptides (NT-proBNP/BNP) CPK-MB, troponin I and T Lactate Thyroid function tests Arterial blood gas ALT Z alanine aminotransferase; AST Z aspartate aminotransferase; BNP Z B-type natriuretic peptide; BUN Z blood urea nitrogen; CPK-MB Z creatine phosphokinase; LDH Z lactic dehydrogenase; NT-proBNP Z N-terminal proBNP; PTT Z prothrombin time; V/Q Z ventilation/perfusion Please cite this article in press as: Masarone D, et al., Pediatric Heart Failure: A Practical Guide to Diagnosis and Management, Pediatrics and Neonatology (2017), http://dx.doi.org/10.1016/j.pedneo.2017.01.001 + MODEL Pediatric Heart Failure clinical diagnosis of myocarditis and to choose the appropriate therapeutic management21 (such as giant cell myocarditis) Therapeutic approach Treatment of PHF aims to: - eliminate the causes of PHF - control the symptoms and disease progression Eliminate the causes of HF When possible, the causes of HF must be corrected through different approaches: - corrective treatment should be performed in CHDs22 - systemic diseases (such as sepsis) or electrolytic imbalance (such as hypocalcemia) must be carefully researched and treated Control of symptoms and disease progression 9.2 Medical therapy Medical therapy for HF (Table 4) focuses on three main goals25: - decrease of pulmonary wedge pressure - increase of cardiac output and the improvement of endorgan perfusion - delay of disease progression 9.3 Diuretics Diuretics therapy plays a crucial role in the treatment of pediatric patients with HF The benefits of diuretic therapy include reduction of systemic, pulmonary, and venous congestion.26 Spironolactone may exert additional beneficial effects by attenuating the development of aldosterone-induced myocardial fibrosis27 and catecholamine release Potential complications of diuretic therapy include electrolyte abnormalities (hyponatremia, hypo- or hyperkaliemia, and hypochloremia) and metabolic alkalosis Electrolyte balance should be carefully monitored, especially during aggressive Table Drugs used in pediatric heart failure 9.1 General measures Drugs In infants, nutritional support must ensure a caloric intake about of 150 kcal/kg/d This is achieved using dietary supplements, preferring small and frequent meals that are better tolerated.23 In children and adolescents, current recommendations suggest that 25e30 kcal/kg/d is a reasonable target for most patients Carbohydrates should not exceed g/kg/d and lipids should not exceed 2.5 g/kg/d The provision of essential amino acids is necessary in the critically ill Evidence suggests that 1.2e1.5 g/kg/d of protein is needed Nutritional supplementation is required in HF secondary to metabolic and mitochondrial diseases (such as carnitine and ubiquinone) In acyanotic CHD patients or in patients with cardiomyopathies, ventilatory support with oxygen must be initiated when SaO2 < 90% On the contrary, in patients with cyanotic CHD, oxygen has little effect in raising SaO2 and is not indicated However, in some cases with chronic left to right shunting, irreversible pulmonary vascular disease can develop and cause right to left shunting (Eisenmenger syndrome) In the early stages, the resulting pulmonary hypertension may be responsive to oxygen; hence, this is indicated while the child is waiting for cardiac transplantation or for palliation surgery.24 Reduction of salt intake is recommended in all patients with edemas and fluid retention Restriction of fluids is indicated in patients with edemas unresponsive to diuretic therapy or hyponatremia Furosemide Furosemide Routes of Doses administration Oral Intermittent bolus Furosemide Continuous infusion Captopril Oral Enalapril Oral Losartan Oral Carvedilol Oral Metoprolol Oral Spironolactone Oral Nitroglycerin Continuous infusion Nitroprusside Continuous infusion Hydralazine Intermittent bolus Hydralazine Oral Digoxin Oral Dobutamine Continuous Infusion Epinephrine Continuous Infusion Epinephrine Intermittent bolus Milrinone Continuous Infusion Levosimendan Continuous Infusion 1e2 mg/kg q6e12h 0.5e2 mg/kg q6e12h 0.1e0.4 mg/kg/h 0.3e2 mg/kg q8h 0.05e0.25 mg/kg q12h 0.5e1.5 mg/kg/d 0.05 mg/kg/d q12h 0.25 mg/kg/d q12h 0.5e1.5 mg/kg q12h 0.5e10 mg/kg/min 0.5e4 mg/kg/min 0.1e0.2 mg/kg every 4e6 h 0.3e1 mg/kg/d in q8e12h 5e10 mg/kg/d 2.5e10 mg/kg/min 0.01e0.1 mg/kg/min 0.01 mg/kg 0.5e1 mg/kg/min 0.05e0.2 mg/kg/min Please cite this article in press as: Masarone D, et al., Pediatric Heart Failure: A Practical Guide to Diagnosis and Management, Pediatrics and Neonatology (2017), http://dx.doi.org/10.1016/j.pedneo.2017.01.001 + MODEL diuretic therapy, as the failing myocardium is more sensitive to arrhythmias induced by electrolyte imbalance 9.4 ACE inhibitors ACE inhibitors prevent, attenuate, or possibly reverse the pathophysiological myocardial remodeling In addition, they decrease afterload by antagonizing the rennineangiotensin aldosterone system.28 According to recent guidelines of The International Society of Heart and Lung Transplantation on the management of pediatric HF, ACE inhibitors are recommended in all patients with HF and left ventricular systolic dysfunction.29 Therapy with ACE inhibitors should be started at low doses with a subsequent up-titration to the target dose with careful monitoring of blood pressure, renal function, and serum potassium 9.5 b blockers b blockers are now an accepted therapy in the pediatric population b blockers antagonize the deleterious effects of chronic sympathetic myocardial activation and can reverse left ventricular remodeling and improve systolic function Recent reports seem to show that the addition of b blockers to the standard therapy may be useful in patients with left ventricular systolic dysfunction.30 In addition, a recent Cochrane Database of Systematic Reviews on b blockers for children with congestive HF was published Seven studies with a total of 420 children were included in the review and the authors conclude that the current available data suggest that children with HF might benefit from b-blocker treatment.31 Low-dose therapy should be started in stable patients with a progressive up-titration to the target dose D Masarone et al 9.8 Phosphodiesterase type III inhibitors This class of drugs incorporates amrinone, enoximone, milrinone, and olprinone, of which milrinone, the strongest and shortest acting with the best control, is the most commonly used in pediatric intensive care Phosphodiesterase type III inhibitors have vasodilatory and inotropic actions and improve diastolic ventricular relaxation.34 Despite the pro-arrhythmic effects of milrinone, it represents the first choice of therapy in patients with moderate/severe ventricular dysfunction with hypoperfusion symptoms 9.9 Calcium sensitizer Levosimendan exerts strong inotropic and vasodilating effects, possibly stronger than dobutamine, with less potential for myocardial ischemia The absence of proarrhythmic effects35 and the ability to reverse the effects of b blockade make levosimendan a potential drug of choice in the context of postoperative low-cardiac output syndrome rather than in acute HF in children.36 9.10 Vasodilators Vasodilators administered intravenously (nitroglycerin and nitroprusside) or orally (hydralazine and nifedipine) are indicated only in cases of37: - hypertensive acute HF refractory to treatment (b blockers and ACE inhibitors) - severe valve regurgitations in patients intolerant to ACE inhibitors 9.6 Inotropes 9.11 Promising new therapies Digoxin is the main oral inotropic drug used in PHF and is indicated in symptomatic patients with left and/or right ventricular systolic dysfunction.32 The use of intravenous inotropes should be reserved for patients with a severe reduction of cardiac output resulting in compromised vital organ perfusion (hypotensive acute/decompensated HF) Although increased inotropy results in improved cardiac output and blood pressure, the final result is increased myocardial oxygen consumption and demand The failing myocardium has a limited contractile reserve and hemodynamic collapse can occur with high-dose inotropic support in this setting There are several promising medications for PHF An elevated baseline heart rate is a risk factor for mortality in adults with HF Ivabradine, an If current inhibitor in the sinoatrial node, has an indication in patients with chronic HF The use of ivabradine was associated with fewer HF hospitalizations and deaths from HF.38 More recently, the combination of a neprilysin inhibitor and valsartan was compared with enalapril in a large, prospective, randomized trial Neprilysin is a neutral endopeptidase involved with degradation of natriuretic peptides, bradykinin, and adrenomedullin Inhibition of neprilysin can result in decreased vasoconstriction, sodium retention, and remodeling The trial was stopped early because of significantly improved mortality, risk of hospitalization, and improved symptoms among patients receiving the neprilysin inhibitor valsartan combination.39 Further study with these drugs will be warranted in children with HF 9.7 Sympathomimetic amines Dopamine and dobutamine have been shown to be effective inotropes and vasopressors in neonates, infants, and children with circulatory failure These drugs increase cardiac output and decrease systemic and pulmonary vascular resistance; however, they can induce tachycardia/tachyarrhythmia with a mismatch between myocardial oxygen delivery and the requirement.33 Therefore, we reserve the use of these drugs only for patients with low cardiac output despite other therapies 10 Device therapy Medical therapy has improved the survival and quality of life of children with HF; however, there is still a significant proportion of patients with poor prognosis due to the progression of the disease or sudden cardiac death These Please cite this article in press as: Masarone D, et al., Pediatric Heart Failure: A Practical Guide to Diagnosis and Management, Pediatrics and Neonatology (2017), http://dx.doi.org/10.1016/j.pedneo.2017.01.001 + MODEL Pediatric Heart Failure patients are candidates for device therapy The two main devices used in patients with heart failure are the implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy (CRT) In HF patients, ICD has a key role in preventing sudden cardiac death due to ventricular arrhythmias Based on data from observational studies, accepted indications for ICD implantation in PHF are40,41: - secondary prevention of sudden cardiac death in patients with aborted cardiac arrest or in patients with a previous episode of ventricular tachycardia determining hemodynamic instability - unexplained syncope in patients with surgically repaired CHDs - patients with severe left systolic ventricular dysfunction (left ventricular ejection fraction < 35%) Approximately 30% of adults with HF exhibit a left bundle branch block (LBBB) with mechanical dyssynchrony In contrast to the adult HF population, only 9% of pediatric HF patients present with LBBB and a QRS duration > 120 milliseconds, which likely reflects the variable causes of HF in the pediatric population.42 The rationale behind left ventricular dyssynchrony is that in failing hearts, left ventricular function is affected not only by a depressed contractile status of the myocardium, abnormal loading conditions, or both, but also by a disturbed synchronicity of the myocardial walls.43 Late activation of some segments leads to a slower rise in systolic pressure and delayed left ventricular ejection and also to slower relaxation and delayed left ventricular filling.44 This pathophysiological condition is the assumption that CRT, through biventricular pacing, improves the pattern of contraction of the left ventricle.45 Despite the lack of randomized clinical trials, retrospective studies demonstrated the utility of CRT in pediatric patients with46: - dilated cardiomyopathy, complete LBBB, and severe reduction of left ventricular systolic function (left ventricular ejection fraction < 35%) - third-degree atrioventricular block requiring the implantation of a pacemaker in DDD modality in patients with mild/moderate systolic dysfunction (left ventricular ejection fraction < 55%) - CHDs with double-ventricle physiology with systemic left ventricle with severe reduction of systolic function In patients with single ventricle physiology, evidence supporting CRT is limited to a few studies.47,48 These series demonstrated improved cardiac index, systolic blood pressure, and indexes of asynchrony after CRT, but in the heterogeneous patient population, technical limitations imposed by patient body size and unique forms of ventricular dyssynchrony have made it difficult to draw strong conclusions or to rationalize widespread use There are controversial results about the efficacy of CRT in patients with isolated right ventricle dysfunction Some studies have shown that CRT can improve right ventricle ejection fraction and New York Heart Association/Ross class and reduce QRS duration However, this response was significantly less pronounced than the response seen in patients with left ventricle dysfunction.42 Mechanical circulatory support systems can be used in patients with PHF who cannot be stabilized with medical therapy to unload the failing ventricle and maintain endorgan perfusion.49,50 Patients with cardiogenic shock/acute HF with underperfusion not responsive to medical therapy must be initially treated with short-term assistance using extracorporeal nondurable life support systems including extracorporeal life support51 and extracorporeal membrane oxygenation.52 In patients with chronic refractory HF despite medical therapy, a permanent implantable left ventricular assist device53 must be used as a bridge to transplantation or as a bridge to recovery and rarely as destination therapy 11 Heart transplantation Heart transplantation is an accepted treatment for patients with refractory HF Although controlled trials have never been conducted, there is a consensus that cardiac transplantation significantly increases survival, functional capacity, and quality of life The indications and contraindications54 for pediatric heart transplantation are summarized in Table In recent years, the outcome of pediatric transplantation has continued to improve The most recent data from the The International Society of Heart and Lung Transplantation demonstrate that the median survival is 19.7 years for infants, 16.8 years for children ages 1e5 years, 14.5 years for children ages 6e10 years, and 12.4 years for children 11e17 years of age at the time of transplantation.55 The major post-transplantation complications are: Rejection: Rejection is one of the main post-transplant complications limiting long-term graft survival Data from the Paediatric Heart Transplant Study demonstrate that 64% of patients were free of rejection in the 1st year (36% of patients experiencing rejection) and 5-year freedom from rejection was 52%.56 Infection: Immunosuppression renders the host potentially susceptible to opportunistic infections that account for approximately 12% of deaths during the first year following transplantation.57 Cardiac allograft vasculopathy: Cardiac allograft vasculopathy remains one of the leading causes of mortality following pediatric transplantation affecting 34% of patients by 10 years’ post-transplantation.58 Malignancy: Tumors, particularly lymphoproliferative disease, remain a relatively uncommon post-transplant complication The incidence of malignancy in the ISHTL registry at years and 10 years following transplantation is 5% and 9.5%, respectively.59 12 Proposed approach to PHF A simplified approach to PHF is summarized in Figure In the emergency setting, at the first stage, acute HF should be considered as a unique syndrome independent from the underlying causes One exception is for patients with de Please cite this article in press as: Masarone D, et al., Pediatric Heart Failure: A Practical Guide to Diagnosis and Management, Pediatrics and Neonatology (2017), http://dx.doi.org/10.1016/j.pedneo.2017.01.001 + MODEL D Masarone et al Table Pediatric heart transplantation: indication and contraindication Patients to consider Contraindications End-stage HF associated with systemic ventricular dysfunction in patients with cardiomyopathies or previously repaired/palliated CHDs Advanced HF associated with severe limitation of exercise and activity If measurable, such patients would have a peak maximum oxygen consumption mm2) CHD Z congenital heart diseases; HF Z heart failure Figure Practical approach to acute and chronic heart failure CHDs Z congenital heart diseases; HF Z heart failure; PGE1 Z prostaglandin E1; Tx Z transplantation; VAD Z ventricular assist device novo acute HF due to CHD with ductus-dependent circulation or to extracardiac causes in which prostaglandin E1 or tailored treatment must be started as soon as possible In the remaining patients, management is balanced according to the presence of volume overload and hypoperfusion Volume overload is almost universally present, and therefore, the early use of intravenous loop diuretics is effective in virtually all patients with acute/decompensated HF However, considering the adverse effects of diuretic use, including sodium and potassium depletion, ototoxicity, and of course renal insufficiency, diuretic use should not be indiscriminate or excessive In cases of underperfusion, the use of low-moderate dose of inotropes is indicated After stabilization, accurate research of the etiology must be conducted In cases of cardiomyopathies and in patients with moderate/severe left ventricular systolic dysfunction, ACE inhibitors and b blockers represent the mainstay of medical therapy In patients with CHD, a corrective/palliative intervention must be planned and medical therapy is used only if left ventricular systolic dysfunction is present Finally, in end-stage patients, ventricular assist device implantation/ cardiac transplantation should be considered and discussed case by case for timing and indications 13 Conclusion HF in children is a complex syndrome with heterogeneous etiology and presentation Unlike adults, PHF is commonly due to structural heart disease and reversible conditions, thus lending it amenable to definitive therapy or short-term aggressive therapy While the general principles of management are similar to those in adults, there is a lack of randomized clinical trials and international guidelines for PHF A judicious balance between extrapolation from adult HF guidelines and the development of child-specific data on Please cite this article in press as: Masarone D, et al., Pediatric Heart Failure: A Practical Guide to Diagnosis and Management, Pediatrics and Neonatology (2017), http://dx.doi.org/10.1016/j.pedneo.2017.01.001 + MODEL Pediatric Heart Failure treatment represent a wise approach to optimize management in this challenging field Conflicts of interest The authors have no conflicts of interest relevant to this article References James N, Smith M Treatment of heart failure in children Current Paediatrics 2005;7:539e48 Rossano JW, Shaddy RE Heart failure in children: etiology and treatment J Pediatr 2014;165:228e33 Balfour I Management of chronic congestive heart failure in children Curr Treat Options Cardiovasc Med 2004;6:407e16 Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and 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