Chronic Heart Failure

The objectives of this review are to discuss the para digms used to stage heart failure in children, the classification and physiologic profile of cardiomyopathies, and the acute and chronic pharmacologic management of heart failure.

Chronic Heart Failure Timothy M Hoffman, MD, FACC, FAHA Objectives: The objectives of this review are to discuss the paradigms used to stage heart failure in children, the classification and physiologic profile of cardiomyopathies, and the acute and chronic pharmacologic management of heart failure Data Source: MEDLINE, PubMed Conclusion: The etiology of chronic heart failure in pediatrics is vast The paradigm of extrapolating adult clinical trials and technological advancements to treat heart failure in children has become a nonsustainable model The field of pediatric heart failure continues to advance with more robust guideline-directed care and the imminent creation of a dynamic, contemporary international database As the field involves a markedly heterogeneous patient population, it is imperative to use pediatric specific descriptors of disease impact The fields of pediatric heart failure and critical care medicine will continue to evolve together as childhood specific registries, quality improvement guidelines, and research will lead to practice models eliciting optimal therapy for patients with heart failure in the intensive care setting (Pediatr Crit Care Med 2016; 17:S119–S123) Key Words: cardiomyopathy; diastolic function; heart failure; inotropic support; pediatrics; systolic function T he field of pediatric heart failure has been an ever-evolving art The practice originally was predicated on the extrapolation of adult multicenter trials and an overflow of technology from the adult cardiovascular world Although this certainly created the framework for care delivery, it has become increasingly clear that this does not translate completely to the pediatric population In pediatrics, many factors exist that discredit the paradigm of translating medical and technologic advances in adult heart failure to children A few examples of such include a vastly different underlying pathophysiology and etiology of heart failure, age-related functional maturation of organs including hepatic and renal systems, and limits of size and Division of Cardiology, Department of Pediatrics, University of North Carolina School of Medicine, University of North Carolina Children’s Hospital, Chapel Hill, NC., Dr Hoffman disclosed off-label product use (inotropic medications in pediatrics) For information regarding this article, E-mail: tmhoff@email.unc.edu Copyright © 2016 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000755 Pediatric Critical Care Medicine anatomic variations that preclude adaptability of adult devices to children Over the last several years, the field has made tremendous strides with more robust guidelines for optimal management as well as advancements and trialing of pediatric specific ventricular assist devices (1–3) Simultaneously, plans are forging ahead for dynamic and contemporary registries, quality improvement metrics, and the development of practice models DEFINITION AND STAGING In general, a commonly accepted definition of heart failure has been challenging, yet in pediatrics, it is further confounded by the overlapping use of the term with structural heart disease with excessive pulmonary blood flow (left to right shunting) This physiology, namely pulmonary over-circulation, should not be confused with the true crux of the term heart failure For the purposes of this article, heart failure will involve a complex interplay of neurohumoral alterations and mechanical factors that lead to a deterioration in cardiac performance This decline may encompass decreased cardiac output, systolic and/or diastolic dysfunction, metabolic derangements, and myocardial cell death In pediatrics, the etiology of heart failure is vast but the staging of heart failure is conglomerated into four categories This staging system allows for identification of those at risk for heart failure yet is asymptomatic to those on the other end of the spectrum, who manifest symptoms and thus would require therapeutic intervention (Table 1) (4) If a patient presents with symptoms, further classification into perfusion (warm vs cold) and congestion (filling pressure) status (dry vs wet) provides a current clinical context with the ultimate goal of being warm and dry (well perfused with normal filling pressures) (Table 2) (5) In turn, functional status may be further described using the New York Heart Association (NYHA) classification in older patients and the Ross classification in infants The Ross classification similarly indicates the degree of symptoms a patient has but is applicable to infants and children In other words, in parallel with the NYHA classification detailing functional limitations with activities of daily living and at rest, the Ross classification similarly discusses symptoms but with activities pertinent to infants such as feeding (4) Finally, recent pediatric guidelines advocate for documentation of heart failure severity using the aforementioned classification schemes and staging, where appropriate, therefore facilitating patient management and the ability to follow disease progression (1, 2) This paradigm of routinely www.pccmjournal.org S119 Copyright © 2016 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Unauthorized reproduction of this article is prohibited Hoffman Pediatric Disease Staging for Heart Failure (2) Table Stage (Class) Description A At an increased risk of developing heart failure but with normal cardiac function and chamber size B Abnormal cardiac morphology or function with no past or current symptoms of heart failure C Past or current heart failure symptoms and structural or functional heart disease D Marked symptoms at rest despite maximal medical management classifying and staging should facilitate care as well as dynamically assessing the degree of heart failure burden Predicting the outcome for chronic heart failure is challenging in the pediatric population In adult medicine, the Seattle Heart Failure Model uses readily available patient data that predicts through 3-year survival (6) When validated within several multicenter trial cohorts of varying ages (youngest patient was 14 yr old) and countries of origin, the score indicated that NYHA class, ischemic etiology, diuretic dose, ejection fraction, systolic blood pressure, serum sodium, hemoglobin, percent lymphocytes, uric acid, and cholesterol each had independent predictive power on survival (6) Obviously, some of these parameters are also used within the pediatric population but others would be of little to no benefit Interestingly, the most dynamic aspect of this model is that there is the ability to examine the estimated effect of medications and devices on the outcome (6) Additionally, the Acute Decompensated Heart Failure National Registry (ADHERE) was used to assess risk factors for in-hospital mortality for this adult patient population, which is in contrast to the Seattle Heart Failure Model that predicts overall mortality not just in those hospitalized (7) ADHERE risk stratification noted that the initial systolic blood pressure and blood urea nitrogen/creatinine values were associated with a worse outcome In other words, a decreasing systolic blood pressure and increasing blood urea nitrogen were significantly associated with worse 30-day and 1-year mortality (7) Biomarkers in adult cardiovascular medicine have aided in the identification of patients at risk for heart failure and have been proven to be useful in the diagnosis and risk stratification of heart failure (8) Additionally, biomarkers may be useful in monitoring the impact of therapeutic interventions (8) In pediatrics, the utility of such is an evolving science Natriuretic peptides have shown usefulness as a marker Table of change in left ventricular wall stress, function, and filling pressure (9) Using the patient as their own control, a drop in natriuretic peptide levels correlates with an overall better expected outcome However, in pediatrics, biomarkers may be more useful in some disease states when compared with others For example, the use of biomarkers in single ventricle physiology including those palliated is an area in evolution and thus firm speculation based on levels should be avoided In time, with the application of newer biomarkers and further study in all patient populations, predictive models may be formulated in pediatrics for those with heart failure associated with cardiomyopathy versus those with associated congenital heart disease CARDIOMYOPATHY: DEFINITION AND CLASSIFICATION Although the etiology of childhood chronic heart failure is vast, a firm understanding of the definition of cardiomyopathy and the classification system is important to the intensive care practitioner who cares for pediatric patients Cardiomyopathy is defined as a “heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually (but not invariably) exhibit inappropriate ventricular hypertrophy or dilatation and are due to a variety of causes that frequently are genetic” (10) Cardiomyopathies are either considered primary or secondary Secondary cardiomyopathies are a subset representing those associated with a systemic disorder, such as infiltrative, storage, or neuromuscular disorders Primary cardiomyopathies include those with a genetic, mixed (genetic and non-genetic), or acquired etiology (Table 3) This classification scheme is more inclusive than the previously accepted designated descriptors of dilated, hypertrophic, restrictive, arrhythmogenic right ventricle dysplasia, and noncompaction cardiomyopathy Regardless of the reason for critical care admission, it is imperative to understand the hemodynamic and physiologic profile of the patient in the context of the underlying cardiomyopathy or cause of chronic heart failure Therapeutic strategies should aim to achieve the previous baseline hemodynamic profile in regards to preload, afterload, chronotropy, and contractility (11) Dilated cardiomyopathy is hallmarked generally by dilatation of the left ventricle but may be biventricular in nature Additionally, those with dilated cardiomyopathy may have not only systolic but also diastolic dysfunction with elevated filling pressures Atrioventricular valve regurgitation is common and the altered myocardium may be arrhythmogenic Hypertrophic cardiomyopathy encompasses a wide spectrum of physiologic alterations, based on the degree and pattern Perfusion and Congestion Classification (5) Perfusion Exam No Congestion (Dry) Congestion (Wet) Adequate perfusion (warm) Warm and dry (goal physiology) Warm and wet Inadequate perfusion (cold) Cold and dry Cold and wet S120 www.pccmjournal.org August 2016 • Volume 17 • Number (Suppl.) Copyright © 2016 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Unauthorized reproduction of this article is prohibited Supplement Table Primary Cardiomyopathy Classification by Etiology (10) Genetic Mixed Acquired Hypertrophic CM Dilated cardiomyopathy Myocarditis Arrhythmogenic right ventricular dysplasia Restrictive cardiomyopathy Arrhythmia induced Non-compaction Infants of diabetic mothers Glycogen storage Mitochondrial Conduction defects (ion channel) of hypertrophy For example, the classic description involves asymmetric septal hypertrophy that may cause dynamic left ventricular outflow tract obstruction Hypertrophic cardiomyopathy may be associated with myocardial bridging and thus coronary perfusion may be impaired during times of tachycardia Finally, it is well established that patients with hypertrophic cardiomyopathy are prone to arrhythmias Restrictive cardiomyopathy is associated with impaired biventricular filling, in other words, bilateral diastolic dysfunction with oftentimes preserved systolic function However, this diastolic change leads to elevated pulmonary vascular resistance in many and the prognosis for this disease is poor Arrhythmogenic right ventricular dysplasia is a disease of fibro-fatty infiltration especially of the right ventricular outflow tract; however, biventricular disease has been known to occur A progression of disease may occur from arrhythmogenesis (torsade de pointes) to right ventricular failure to ultimately biventricular dysfunction Finally, noncompaction cardiomyopathy is a spectrum of disease that must be evaluated on a continuum of preserved function to severe heart failure This type of cardiomyopathy can be associated with other systemic diseases and may be noted in those with congenital heart disease The deep myocardial trabeculations in some patients may beget intraventricular thrombus formation As stated, the underlying pathology of chronic heart failure is vast in pediatrics and countless genetic, metabolic, and primary disease processes contribute to the phenotype A comprehensive outline of these etiologies is beyond the scope of this article; however, it is reasonable to understand the potential physiologic impact of basic preexisting cardiomyopathies The hemodynamic considerations for optimizing intensive care are outlined in Table for each of the subtype of cardiomyopathy (11) INOTROPIC SUPPORT Inotropic support in children has mainly centered upon agents that ultimately act via alterations in myocardial intracellular cyclic adenosine monophosphate (cAMP), although in some countries, the use of calcium sensitizing agents (levosimendan) has beget new guideline-based therapy practice models Catecholamines and phosphodiesterase III inhibitors ultimately lead to an increase in intracellular cAMP, although via different mechanisms of action Catecholamines (dobutamine Pediatric Critical Care Medicine and epinephrine) act via interaction with adrenergic receptors leading to the stimulation of increased cAMP production However, phosphodiesterase III inhibitors (milrinone) bind to the esteratic site of the enzyme in a competitive fashion with cAMP thus leading to an accumulation of cAMP in the myocyte (12) Catecholamines are limited by several acute and chronic factors including: 1) down-regulation of adrenergic receptors in those with heart failure; 2) increased myocardial oxygen consumption; and 3) excessive chronotropy at escalating dosing strategies Phosphodiesterase inhibitors exhibit positive inotropy, enhanced lusitropy, and reduced systemic and pulmonary vascular resistance while having the advantage of not increasing myocardial oxygen consumption (12) Calcium sensitizing agents (levosimendan) bind to cardiac troponin C in a calcium-dependent process that alters the configuration of tropomyosin This process leads to an exposure of actin and myosin that begets a more efficient cardiac contraction Calcium sensitizing agents not elicit an increase in myocardial intracellular calcium thus preserving diastolic relaxation Additionally, these medications open adenosine triphosphate vascular potassium channels that lead to a decrease in systemic vascular resistance (13) It is well known that in the adult literature and experience, inotropic support is associated with increased all-cause mortality regardless of the etiology of heart failure (14) In contrast, the use of vasodilators is not associated with a worse outcome unless used in combination with inotropic agents (14) With this knowledge, it has been a long-standing controversy whether this phenomenon translates well to the pediatric population Debate over the use of inotropic support in pediatrics has often centered upon the fact that there are likely underlying differences in the etiology of heart failure in children that allow for a better outcome on inotropic support, for example the markedly infrequent incident of ischemic disease in children Concurrently, since there are less options for optimal mechanical circulatory support for children, inotropic medications continue to be employed regularly in pediatric patients The collective guidelines suggest that inotropic support should only be used when there is significant hemodynamic impact from heart failure (1–3) In other words, simply having a diagnosis of heart failure or cardiomyopathy would not be an indication for inotropic support On the contrary, the only disease process that may elicit an early indication for www.pccmjournal.org S121 Copyright © 2016 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Unauthorized reproduction of this article is prohibited Hoffman Table Cardiomyopathy Hemodynamic Considerations Classification Hemodynamic Considerations Intensive Care Optimization Dilated cardiomyopathy Decreased contractility Chamber dilatation Atrioventricular valve regurgitation Avoid increased systemic vascular resistance Hypertrophic cardiomyopathy Left ventricular outflow tract obstruction Ventricular cavity obliteration Subset with restrictive component Myocardial bridging Avoid intravascular volume depletion Assure normal to increased systemic vascular resistance Avoid excessive chronotropy Restrictive cardiomyopathy Diastolic dysfunction Preserved systolic function Elevated pulmonary vascular resistance Assure preload Avoid agents and interventions that exacerbate pulmonary vascular resistance Arrhythmogenic right Subset with systolic dysfunction ventricular dysplasia Arrhythmia Noncompaction Avoid or minimize exogenous catecholamines Avoid increased systemic vascular resistance Assure normal volume status Systolic and diastolic dysfunction varies (normal Avoid increased systemic vascular resistance to severe dysfunction) Assure normal volume status Prone to intracardiac thrombus formation device therapy and is supported by the guidelines is fulminant myocarditis With the ultimate hope of recovery, early consideration for device therapy as a bridge to decision in this disease may be justified (3) However, in all other disease processes, it is still considered reasonable to initiate inotropic support in those with cardiogenic shock to maintain systemic perfusion and end organ function Overuse and misapplication of inotropic support should be circumvented via adherence to the guideline-directed paradigm of only treating when there are signs of hemodynamic impact from the disease process OUTPATIENT MEDICAL THERAPY AND IMPACT ON CRITICAL CARE DECISIONS β-blocking agents have been studied extensively in large multicenter adult trials In those with heart failure, it has been noted that β-blocking agents may prevent further decline in myocardial function, reverse remodeling, and may alleviate the adverse effects of the neurohumoral cascade (15) Additionally, a systematic review of the adult literature concluded that patients randomized to receive β-blocker therapy experienced a 35% relative risk reduction in mortality when compared with the control population In turn, the absolute difference in mortality was 5.1% and similarly, the decrease in hospital admissions was 5.7% (15) In pediatrics, the largest trial of a β-blocker, specifically carvedilol, showed that regardless of dosing strategy the drug did not significantly improve outcomes in those with symptomatic systolic heart failure (16) There is a suggestion, however, that the study was likely underpowered noting the event rates were lower than predicted (16) Therefore, with the acknowledgment of this probable limitation, recent pediatric heart failure guidelines mirror those in adult heart failure and recommend that it is reasonable to consider β-blocker therapy in symptomatic or asymptomatic patients with left S122 Assure normal volume status www.pccmjournal.org ventricular systolic dysfunction (1) Additionally, many other disease states aforementioned such as those with hypertrophic cardiomyopathy or arrhythmia associated pathologic conditions may beget chronic β-blocker utilization Regardless of the reason a patient is on β-blockade, this is paramount to the critical care physician especially if treating a concomitant process that necessitates inotropic support Data exist in the adult literature that dobutamine elicits a blunted increase in cardiac output in the setting of β-blocker treatment and may increase systemic vascular resistance via α-adrenergic stimulation, which would be detrimental to those with decreased systemic ventricular function (17, 18) However, the use of phosphodiesterase III inhibitors, namely milrinone, yielded the expected hemodynamic effects in the setting of complete β-blockade because the site of action is independent of the β-adrenergic receptor (17, 18) Decisions regarding inotropic therapy are complex and multifaceted, yet the clinical situation of a patient with chronic β-blockade must be taken into account when considering the type of agent Angiotensin-converting enzyme (ACE) inhibitors are the mainstay of outpatient treatment for heart failure especially in those disease entities hallmarked with systemic ventricular dysfunction If a patient is on ACE inhibition and is in need of apheresis, regardless of technique, it has been recommended to discontinue the ACE inhibitor at least 24 hours prior to the planned procedure The reason for such is that anaphylactic type reactions have been reported in patients on ACE inhibition at the time of apheresis (19) In one publication, all patients on ACE inhibition had an atypical reaction characterized by flushing, hypotension, dyspnea, and bradycardia when compared with only 7% in those not on therapy (19) The physiologic mechanism for this anaphylactic type reaction during apheresis is postulated to be associated with bradykinin (20) It is felt that exposure of plasma to components of August 2016 • Volume 17 • Number (Suppl.) Copyright © 2016 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Unauthorized reproduction of this article is prohibited Supplement the extracorporeal circuit releases bradykinin and concomitant ACE inhibition inhibits inactivation of bradykinin SUMMARY Knowing that the etiology of heart failure and spectrum of the disease severity in pediatrics is vast, staging systems and guideline-directed therapy should yield quality care Distilling the degree of heart failure, the underlying pathophysiology, and the current snapshot of hemodynamic impact may facilitate therapeutic decisions The field of pediatric heart failure is an evolving art that with dynamic guidelines, research, and quality improvement initiatives, practice evolution will accelerate dramatically In the ICU, one variable begets another variable In other words, not one therapeutic decision is in isolation and in turn, each has a multifaceted impact In the setting of chronic heart failure, intensive care interventions have a strong influence on the hemodynamic status and on the outcome of the patient The fields of pediatric heart failure and critical care medicine are intertwined and both disciplines complement the other on this journey to forge the best outcomes REFERENCES Kirk R, Dipchand AI, Rosenthal D (Eds): ISHLT Monograph Series: ISHLT Guidelines for the Management of Pediatric Heart Failure Vol 8, New York, Elsevier, 2014 Kirk R, Dipchand AI, Rosenthal DN, et al: The International Society for Heart and Lung Transplantation Guidelines for the management of pediatric heart failure: Executive summary [Corrected] J Heart Lung Transplant 2014; 33:888–909 Kantor PF, Lougheed J, Dancea A, et al; Children’s Heart Failure Study Group: Presentation, diagnosis, and medical management of heart failure in children: Canadian Cardiovascular Society guidelines Can J Cardiol 2013; 29:1535–1552 Rosenthal D, Chrisant MR, Edens E, et al: International Society for Heart and Lung Transplantation: Practice guidelines for management of heart failure in children J Heart Lung Transplant 2004; 23:1313–1333 Nohria A, Lewis E, Stevenson LW: Medical management of advanced heart failure JAMA 2002; 287:628–640 Levy WC, Mozaffarian D, Linker DT, et al: The Seattle Heart Failure Model: Prediction of survival in heart failure Circulation 2006; 113:1424–1433 Pediatric Critical Care Medicine Fonarow GC, Adams KF Jr, Abraham WT, et al; ADHERE Scientific Advisory Committee, Study Group, and Investigators: Risk stratification for in-hospital mortality in acutely decompensated heart failure: Classification and regression tree analysis JAMA 2005; 293:572–580 Braunwald E: Biomarkers in heart failure N Engl J Med 2008; 358:2148–2159 Rusconi PG, Ludwig DA, Ratnasamy C, et al: Serial measurements of serum NT-proBNP as markers of left ventricular systolic function and remodeling in children with heart failure Am Heart J 2010; 160:776–783 10 Maron BJ, Towbin JA, Thiene G, et al; American Heart Association; Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; Council on Epidemiology and Prevention: Contemporary definitions and classification of the cardiomyopathies: An American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention Circulation 2006; 113:1807–1816 11 Ing RJ, Ames WA, Chambers NA: Paediatric cardiomyopathy and anaesthesia Br J Anaesth 2012; 108:4–12 12 Overgaard CB, Dzavík V: Inotropes and vasopressors: Review of physiology and clinical use in cardiovascular disease Circulation 2008; 118:1047–1056 13 De Luca L, Colucci WS, Nieminen MS, et al: Evidence-based use of levosimendan in different clinical settings Eur Heart J 2006; 27:1908–1920 14 Elkayam U, Tasissa G, Binanay C, et al: Use and impact of inotropes and vasodilator therapy in hospitalized patients with severe heart failure Am Heart J 2007; 153:98–104 15 Shibata MC, Flather MD, Wang D: Systematic review of the impact of beta blockers on mortality and hospital admissions in heart failure Eur J Heart Fail 2001; 3:351–357 16 Shaddy RE, Boucek MM, Hsu DT, et al; Pediatric Carvedilol Study Group: Carvedilol for children and adolescents with heart failure: A randomized controlled trial JAMA 2007; 298:1171–1179 17 Bristow MR, Shakar SF, Linseman JV, et al: Inotropes and beta-blockers: Is there a need for new guidelines? J Card Fail 2001; 7(2 Suppl 1):8–12 18 Lowes BD, Simon MA, Tsvetkova TO, et al: Inotropes in the betablocker era Clin Cardiol 2000; 23:III11–III16 19 Owen HG, Brecher ME: Atypical reactions associated with use of angiotensin-converting enzyme inhibitors and apheresis Transfusion 1994; 34:891–894 20 Perseghin P, Capra M, Baldini V, et al: Bradykinin production during donor plasmapheresis procedures Vox Sang 2001; 81:24–28 www.pccmjournal.org S123 Copyright © 2016 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Unauthorized reproduction of this article is prohibited ... assessing the degree of heart failure burden Predicting the outcome for chronic heart failure is challenging in the pediatric population In adult medicine, the Seattle Heart Failure Model uses readily... remodeling in children with heart failure Am Heart J 2010; 160:776–783 10 Maron BJ, Towbin JA, Thiene G, et al; American Heart Association; Council on Clinical Cardiology, Heart Failure and Transplantation... with heart failure associated with cardiomyopathy versus those with associated congenital heart disease CARDIOMYOPATHY: DEFINITION AND CLASSIFICATION Although the etiology of childhood chronic heart