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PRACTICE GUIDELINES

nternational Society for Heart and Lung Transplantation: Practiceuidelines for Management of Heart Failure in Children

avid Rosenthal, MD, Chair, Maryanne R.K. Chrisant, MD, Erik Edens, MD, PhD, Lynn Mahony, MD,harles Canter, MD, Steven Colan, MD, Anne Dubin, MD, Jacque Lamour, MD, Robert Ross, MD,obert Shaddy, MD, Linda Addonizio, MD, Lee Beerman, MD, Stuart Berger, MD, Daniel Bernstein, MD,lizabeth Blume, MD, Mark Boucek, MD, Paul Checchia, MD, Anne Dipchand, MD,onathan Drummond-Webb, MD, Jay Fricker, MD, Richard Friedman, MD, Sara Hallowell, RN,obert Jaquiss, MD, Seema Mital, MD, Elfriede Pahl, MD, Bennett Pearce, MD, Larry Rhodes, MD,
athy Rotondo, MD, Paolo Rusconi, MD, Janet Scheel, MD, Tajinder Pal Singh, MD, and Jeffrey Towbin, MD
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NTRODUCTIONhe Need for Pediatric Guidelines

eart failure (HF) in the United States is well recognizeds a major public health problem, with over 900,000ospital admissions annually in the United States, andreater than 250,000 deaths per year. The great major-ty of heart failure occurs in adults. In children, thecope of the problem is less well defined, but recentata from the Pediatric Cardiomyopathy Registry sug-est an annual incidence of 1.13 cases of cardiomyop-thy per 100,000 children.1 While some of this repre-ents asymptomatic disease, the burden of diseaseverall is nonetheless quite high. In the Pediatric Car-iomyopathy Registry, the majority of children withardiomyopathy also had HF, with mortality rates of3.6% at 2 years in dilated forms of cardiomyopathy.The etiology of heart failure differs greatly between

hildren and adults. Children in the Pediatric Cardio-yopathy Registry had a recognizable syndrome or

enetic diagnosis in 27% of cases, with an additional% of cases due to myocarditis. Furthermore, a largeercentage of children with end-stage HF (between5% and 75%, depending upon the age group) haven underlying diagnosis of congenital heart disease.2

n contrast to adult patients, ischemic heart disease isare in children.

There is a large, and rapidly growing literature ad-ressing HF treatment for adult patients, with a muchmaller literature concerning HF therapy in children.xcellent guidelines for adult patients have recentlyeen published, but given the significant differencesetween adult and pediatric patients with HF, there is

rom the International Society for Heart and Lung Transplantation,ddison, Texas.Reprint requests: David Rosenthal, MD, (W) 725 Welch Road, room

751, Stanford, California 94304, Telephone: 650 497-8676, Fax: 65097-8422. E-mail: [email protected] Lung Transplant 2004;23:1313-33.opyright © 2004 by the International Society for Heart and Lungransplantation. 1053-2498/04/$–see front matter. doi:10.1016/

.healun.2004.03.018

ittle reason to believe that these guidelines are directlypplicable to children.3 Accordingly, in this documente have attempted to summarize the relevant literature

nd synthesize management guidelines for childrenith HF. The document that follows has been prepared

n a consensus fashion, with input from pediatricardiologists at multiple sites throughout the Unitedtates and Canada.

evels of Evidence and Strength of Recommendations

ach recommendation in this document is ranked withegard to the level of supporting evidence:

Level A recommendations are based upon multiplerandomized clinical trials.Level B are based upon a single randomized trial ormultiple non-randomized trials.Level C are based primarily upon expert consensusopinion.

The level of evidence upon which a recommendations based, differs from the strength of the recommenda-ion. A given recommendation may be based uponandomized trials yet still be controversial. Other formsf therapy, which are based solely upon expert consen-us, may be strongly recommended.

Recommendations in this document adhere to theormat of guidelines previously published by the Amer-can College of Cardiology (ACC) and American Heartssociation (AHA).

Class I: Conditions for which there is general agree-ment that a given therapy is useful and effective.Class II: Conditions for which there is conflictingevidence or a divergence of opinion concerning theusefulness and effectiveness of a therapy.● Class IIa: Weight of evidence/opinion favors use-

fulness/effectiveness.● Class IIb: Weight of evidence/opinion is less in

favor of usefulness/effectiveness.

Class III: Conditions for which there is general agree-ment that a therapy is not useful and (in some cases)
may be harmful.
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1314 Rosenthal et al. The Journal of Heart and Lung TransplantationDecember 2004

EFINITIONS AND CLASSIFICATIONefinition of Heart Failure

eart failure is a complex clinical syndrome, withultiple etiologies and diverse clinical manifestations.any definitions have been offered, but we prefer that

et forth by Arnold Katz, which not only describes thelinical aspects of HF, but also reflects a growingnderstanding of the cellular processes which accom-any this condition:4

“�heart failure is a clinical syndrome in which heartdisease reduces cardiac output, increases venous pres-sures, and is accompanied by molecular abnormalitiesthat cause progressive deterioration of the failing heartand premature myocardial cell death.”

It is important to note that at present, this definitions not clinically applicable as a diagnostic roadmap. Inact, there is no gold standard diagnostic approach toF. Rather, the recognition of HF depends on a thor-ugh characterization of the patient from a clinical,emodynamic, and – increasingly – neurohumoral per-pective. In specific cases, the weight of the diagnosisay stem from elements of the medical history, while in

ther cases, echocardiography or cardiac catheteriza-ion may provide essential data. Perturbations in circu-ating hormones such as the natriuretic peptides areoming to play a substantial role in the diagnosis of HFn the adult population, but are less widely used for thisurpose in children.Additionally, there is often ambiguity concerning the

se of the term HF for children with uncorrectedtructural lesions resulting in left to right shunting withreserved systolic function. In this manuscript, we doot address the clinical issues posed by such patients,hich are very different from HF associated withyocyte dysfunction.

YHA Classification

he New York Heart Association (NYHA) classifications widely used for grading HF in adult patients becausef its simplicity in providing a practical assessment ofunctional limitation. It is an ordinal scale defined by theegree to which symptoms of HF limit a patient’shysical activity. However, the applicability to youngerhildren and infants is limited.

oss Classification

he Ross Classification was developed for grading HF innfants and younger children (Table 1).5 In 1994 theoss Classification was adopted by the Canadian Car-iovascular Society as their official system for gradingF in children,6 and the system is currently used in theational Cardiomyopathy Registry and in a multicenter
tudy of carvedilol. A direct correlation between the m
oss class and plasma norepinephrine concentrations5

nd an inverse relationship between the Ross class and-receptor density support the validity of the Rosslassification system.7

ther Scoring Systems

everal other scoring systems have been proposed forrading HF in children. One such system developed fornfants has a 12-point scale based on variables assignedy 4 pediatric cardiologists blinded to the patient’siagnosis.8 These variables were: quantity and durationf feeding, respiratory rate and pattern, heart rate,eripheral perfusion, presence of a diastolic fillingound, and degree of hepatomegaly. Another recentlyroposed system is the New York University Pediatriceart Failure Index.9 In this system, a total score from 0

o 30 is obtained by adding together points based onhysiologic indicators and the patient’s specific medicalegimen. Items scored are signs and symptoms, HFedications, and ventricular pathophysiology. None of

hese systems have been validated in large numbers ofhildren nor tested against biological markers of HF orxercise capabilities.10 Ohuchi and colleagues haveecently published a detailed analysis of the relationshipetween changes in neurohumoral indices and clinicaltatus of children and young adults with congenitaleart disease.11

taging System

oth the NYHA and Ross HF scales concentrate onurrent symptomatology. Neither of these scales dis-riminates well among patients with early stages ofisease, nor between stable and decompensated stagesf illness. Overt HF symptoms occur late in the diseaserocess, indicating a failure of compensatory mecha-isms. The ACC/AHA 2002 HF guidelines thereforedvocate a HF classification schema that addresses theseeficiencies and complements the NYHA scale.12 TheCC/AHA staging identifies patients at risk for HF whoequire early intervention to prolong the symptom-freetate; it also delineates patients who require aggressive

able 1. Ross Classification

Class Interpretation

I AsymptomaticII Mild tachypnea or diaphoresis with feeding in infants.

Dyspnea on exertion in older children.III Marked tachypnea or diaphoresis with feeding in infants.

Prolonged feeding times with growth failure due toheart failure. In older children, marked dyspnea onexertion.

IV Symptoms such as tachypnea, retractions, grunting, ordiaphoresis at rest.

anagement of symptoms once they become manifest.

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The Journal of Heart and Lung Transplantation Rosenthal et al. 1315Volume 23, Number 12

The system advocated by the ACC/AHA for HF stag-ng in adults can be readily applied to infants andhildren as well, with minor modifications as shown inable 2.12 The writing committee of this document hasdopted this nomenclature due to the advantages enu-erated above.

HRONIC HEART FAILURE IN THE BIVENTRICULARIRCULATION

ntroduction

he spectrum of etiologies for HF in children is consid-rable, and a discussion of the diagnostic approach tohildren with HF is beyond the scope of this manu-cript. This topic has been addressed thoroughly in aumber of excellent publications, to which the reader

s referred for further detail.13–15

HF in children may develop from myocyte dysfunc-ion (such as is seen in idiopathic cardiomyopathy, orost-operative forms of cardiac dysfunction), or on theasis of congenital disorders resulting in volume orressure overload. In the current era, both volume

oading and pressure loading are typically – but notnvariably – addressed surgically or in the catheteriza-ion laboratory.

Chronic volume overload associated with mitral orortic insufficiency may be well tolerated for a pro-onged period of time. In contrast to adult patients,

itral valve replacement for infants and children isften delayed because of technical difficulties inherento the patient size and anticoagulation requirements.imited data suggest that although early ventricularysfunction after surgery is common after correction ofhronic mitral insufficiency in children, left ventricular

able 2. Proposed Heart Failure Staging for Infants and Children*

Stage Interpretation

Patients with increased risk of developing HF, but who havenormal cardiac function and no evidence of cardiacchamber volume overload. Examples: previous exposure tocardiotoxic agents, family history of heritablecardiomyopathy, univentricular heart, congenitally correctedtransposition of the great arteries.

Patients with abnormal cardiac morphology or cardiacfunction, with no symptoms of HF, past or present.Examples: aortic insufficiency with LV enlargement, historyof anthracycline with decreased LV systolic function.

Patients with underlying structural or functional heart disease,and past or current symptoms of HF.

Patients with end-stage HF requiring continous infusion ofintropic agents, mechanical circulatory support, cardiactransplantation or hospice care.

HF, heart failure; LV, left ventricular.

unction frequently normalizes over time.16,17 c

eft Ventricular Systolic Dysfunction

harmacotherapy.

igitalis.

linical Data in Adult Patients with HF. Digoxinmproves symptoms in adults with HF.18 However,espite large study cohorts, digoxin has not beenhown to improve survival in HF. Adams and colleaguesave recently shown that low doses of digoxin are asffective as higher doses in preventing further HF, anday reduce the incidence of side effects and toxicity,

specially when other medications are instituted whichan increase digoxin levels.19 In one recent post-hocnalysis of the DIG trial, higher serum digoxin levelsere associated with increased mortality in men withF, independent of glomerular filtration rate.20

linical Data in Pediatric Patients. Although onlycant pediatric data are available, digoxin is widely usedo treat HF in infants and children. Recommendationsan only be extrapolated from those for adult patientsith left ventricular systolic dysfunction and HF.

iuretics.

linical Data in Adult Patients. Few data are availableoncerning the appropriate use of diuretics, but theirse is widespread. Current guidelines in adult patientsecommend the use of diuretics in all patients with HFnd fluid retention in order to achieve a euvolemictate.

Spironolactone, specifically, has been shown to im-rove survival in adults with advanced HF.21 This doesot appear to represent a diuretic effect, but rather ispecifically due to blockade of aldosterone; the benefitas also been demonstrated with another aldosteronentagonist, eplerenone.22 The activation of the renin-ldosterone-angiotensin system (RAAS) is thought to beritical in the pathogenesis of HF, and interruption ofhe RAAS is a foundation of modern HF therapy.23

lthough this is primarily accomplished in currentanagement by administration of ACE inhibitors, spi-

onolactone has an additive effect in adults with severeF.

linical Data in Pediatric Patients. No publishedlinical studies are available concerning the effective-ess of diuretics in reducing mortality or improvingymptoms in pediatric patients.

ngiotensin Converting Enzyme Inhibitors andngiotensin Receptor Blockers.

linical Data in Adult Patients. HF is associated with
hronic activation of the RAAS and increased sympa-

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hetic drive.24 These alterations, which may be benefi-ial acutely, contribute to the progression of HF overime. Increased adrenergic tone increases afterload andyocardial oxygen demand. Angiotensin II is a vasocon-

trictor which causes myocyte hypertrophy and fibrosiss well as aldosterone secretion. Increased concentra-ions of both aldosterone and angiotensin II are associ-ted with a poor outcome in HF patients.25 The efficacyf ACE inhibitor therapy in HF is related to disruption ofhe activation of the renin-angiotensin axis and toecreased cardiac adrenergic drive.23,24,26

Multiple large clinical trials have shown that therapyith ACE inhibitors improves symptoms and survival in

dult patients (primarily middle-aged men) with HF, andeduces the rate of disease progression in asymptomaticatients.27–30 In the majority of trials, ACE inhibitorsere well tolerated. Symptomatic hypotension canccur; careful uptitration of these agents and adjust-ent of diuretic dosages is necessary. Cough, which is

ften associated with pulmonary edema, is presentore frequently in patients treated with ACE

nhibitors.28

A frequent observation in the literature evaluatingreatment of patients with HF concerns the underutili-ation of ACE inhibitors. On the one hand, only ainority of eligible adults receives an ACE inhibitor.31

f equal importance, those patients who are treatedith ACE inhibitors are often treated with doses con-

iderably lower than the doses for which efficacy haseen established in clinical trials.31 Although there isome controversy regarding appropriate dosing of ACEnhibitors for HF, most studies suggest a more robustesponse to higher doses of ACE inhibitors when hemo-ynamics, symptoms or neurohumoral profiles are con-idered.32–35 The ATLAS trial compared the effects ofow and high dose lisinopril on the morbidity and

ortality of 3164 subjects with NYHA class II-IV.35 Nourvival benefit was seen from high dose therapy asompared to low dose, but high dose therapy reducedhe composite outcome of death or hospitalization by2%, and reduced hospitalization by 13%. Althoughizziness, hyperkalemia and hypotension were all moreommon in the high dose group, these side effects didot require withdrawal from therapy more commonlyhan in the lower dose group. The ATLAS trial con-rmed that certain benefits of ACE inhibition are greatert higher doses, and that these agents are clinicallyolerated at higher doses. It is also noteworthy that theffect on symptoms was not associated with dose level,uggesting that titration of ACE inhibitors according tolinical endpoints is not a viable strategy.Data concerning administration of ACE inhibitors to

atients with structural heart disease is understandablyimited. However, the beneficial effects of ACE inhibi-
ion on LV volume, dimensions, mass index, wall stress c
nd reduction in the volume-loaded ventricle have beenemonstrated for adult patients with aorticegurgitation.36

There are important differences between the ACEnhibitors and the angiotensin receptor blockersARB’s). The ARB’s are competitive antagonists for thengiotensin II receptor that is responsible for mediatingll the known actions of angiotensin II. ARB’s block theell surface receptor37 for angiotensin, rather thancting through blockade of angiotensin converting en-yme. Unlike ACE inhibitors, ARB’s do not inhibitradykinin breakdown, which has been implicated inausing the troublesome cough that is a prominent sideffect of ACE inhibitors. ARB’s are not nephrotoxic,ffording these drugs a theoretical advantage over ACEnhibitors.

Despite these mechanistic differences, trials in adultatients with HF have not shown any important differ-nces in hemodynamic effects, efficacy and safety be-ween ARB’s and ACE inhibitors.38,39 Currently ARB’sre recommended in adults intolerant to ACE inhibitors.he addition of ARB’s to ACE inhibitor therapy may

ncrease efficacy40 and is often recommended in adultF patients intolerant to �-blockade.

linical Data in Pediatric Patients. Although ACEnhibitors have been used in the pediatric populationor two decades, relatively few studies concerning thedministration of ACE inhibitors to children with HF arevailable. Numerous small observational studies havehown that ACE inhibitors benefit children with HFaused by systemic ventricular systolic dysfunc-ion.41–46 Effects on mortality have not been described,ith the exception of one retrospective report, inhich survival was improved by administration of ACE

nhibitors during the first year of treatment but notubsequently.46

The use of ACE inhibitors in patients with structuraleart disease is less well understood. However, a singleontrolled study in children with preserved ventricularunction and volume-overloaded ventricles from valvarnsufficiency showed a reduction in both LV volumeverload as well as hypertrophy in the ACE inhibitorreated group over an average of 3 years of follow-up.47

No safety or efficacy data regarding the use of ARB inhildren with HF are available. There is very limitedxperience with ARB therapy for pediatric patientsith hypertension.48

adrenergic Blockers.

eneral Remarks. Initial compensatory mechanisms inhe failing heart include activation of the sympatheticervous system and increased levels of circulating
atecholamines. In the long term the increased levels of

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atecholamines, particularly norepinephrine, contrib-te to the progression of HF through multiple mecha-isms, including myocardial fibrosis and apoptosis,eripheral vasoconstriction, and salt/water retention byhe kidneys.49–51 The rationale for the use of adrenergicntagonists in HF is to antagonize the deleterious effectsf sympathetic activation on the myocardium.The risks associated with the use of beta-blockers

nclude hypotension and worsening HF.52–55 Usuallyhese symptoms occur in the first 48 hours after initia-ion of treatment or at the time of up-titration of therug. Fluid retention may cause an increase in symp-oms56–58 and adjustment in diuretic dosage may beeeded. Bradycardia is seen with the use of �-blockers,

s usually asymptomatic, but may require dose reduc-ion if there is associated hypotension.52 �-blockers areontraindicated in patients with severe bradycardia,ick sinus syndrome and second or third degree heartlock, unless a pacemaker is in place. �-blockers arelso contraindicated in patients with bronchial asthmand in patients with cardiogenic shock.

linical Data in Adult Patients. Metoprolol was therst �-blocker studied in placebo-controlled trials inatients with HF. Early studies failed to show a statisti-ally significant decrease in the risk of death or listingor transplantation.59,60 Eventually, in a trial involving991 patients with ischemic and non-ischemic cardio-yopathy and mild to moderate CHF, administration ofetoprolol reduced mortality by 34%, which was sta-

istically significant.61 In addition to metoprolol, carve-ilol has been studied extensively in adult patients withF resulting from left ventricular dysfunction. Severallacebo-controlled trials have shown that carvedilolherapy decreases the risk of clinical progression of HFnd decreases all-cause mortality.62–64 Of particularnterest, the COPERNICUS study (Carvedilol Prospec-ive Randomized Cumulative Survival Trial)65 evaluatedhe effects of carvedilol in 2289 patients with severe HFrom either ischemic or non-ischemic cardiomyopathy.atients treated with carvedilol had a 24% reduction inombined risk of death and hospitalization for anyeason and a 35% reduction in mortality, showing thatven these severely compromised patients benefitedrom carvedilol therapy.

linical Data in Pediatric Patients. The reported usef �-blockers in children with HF is very limited, and no

arge placebo-controlled trials are available.In a multi-institutional experience Shaddy, et al.

eviewed the results with metoprolol in 15 childrenith cardiomyopathy of different etiologies.66 Metopro-

ol was started at 0.2-0.4 mg/kg/day and slowly in-reased to a maximum dose of 1.1 mg/kg/day. There
as no significant difference in ejection fraction on
onventional therapy from the time of diagnosis to theime when metoprolol was started, but after a mean of3 months on metoprolol there was a statisticallyignificant and clinically important increase in ejectionraction from 27% to 41%.

The experience with carvedilol in pediatric patientsith HF is similarly limited. Bruns, et al.53 reviewed these of carvedilol in 46 infants and children with cardio-yopathy (80%) or congenital heart disease (20%) at 6

enters. Patients were on standard treatment withigoxin, diuretics, and ACE inhibitors for at least threeonths before the start of �-blocker therapy. Carvedilolas initiated at an average dose of 0.08 mg/Kg/day and

itrated to a mean maximum dose of 0.92 mg/kg/day.fter 3 months of therapy, modified NYHA class im-roved in 67% of patients and worsened in 11%.hortening fraction improved slightly, from 16.2% to9.0%. Side effects, mainly dizziness, hypotension, andeadache, occurred in 54% of patients and were wellolerated overall.

In a single center study Rusconi, et al.54 reviewed theesults in 24 pediatric patients with dilated cardiomy-pathy. Carvedilol was added to standard treatment at aean of 14 months after the diagnosis of cardiomyop-

thy was made, with an average maximum dose of 1.0g/kg/day. Adverse effects occurred in 5 patients. Theedication was tolerated in 22 patients. The mean left

entricular ejection fraction improved from 25% to 42%p�0.001). The NYHA class improved in 15 patients, 1atient died and 3 were transplanted. Lower doses ofarvedilol may also be effective, as suggested by Azekand colleagues.67 In this study of 22 children with DCM,mprovement of both ejection fraction and clinicaltatus was seen at 6 months with treatment dose of 0.2g/kg day of carvedilol, which was tolerated in allatients.

herapeutic Recommendations: No structuralisease.Recommendation 1: The underlying cause of new-

nset ventricular dysfunction (HF Stages B, C or D)hould be evaluated thoroughly in all patients. Thevaluation may include metabolic and genetic evalua-ion in selected cases, as indicated by the availableistory and physical findings. Invasive assessment, in-luding myocardial biopsy, may be considered in se-ected cases. In infants, particular care should be paid tohe exclusion of coronary artery anomalies and othernatomic causes. (Level of Evidence C; Strength ofecommendation I)Recommendation 2: Screening of first-degree rela-

ives should be considered in patients with new-onsetentricular dysfunction due to DCM (HF Stages B, C or D).Level of Evidence C; Strength of Recommendation I)

Recommendation 3: Patients with fluid retention

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ssociated with ventricular dysfunction (HF stage C)hould be treated with diuretics to achieve a euvolemictate using clinical criteria of fluid status and cardiacutput. (Level of Evidence C; Strength of Recommen-ation I)Recommendation 4: Digoxin is not currently rec-

mmended for patients with asymptomatic forms of leftentricular dysfunction (HF Stage B) because this agentid not alter survival in large trials of adult patients withF. (Level of Evidence C; Strength of Recommendation

Ib)Recommendation 5: Digoxin should be employed

or patients with ventricular dysfunction, and symp-oms of HF (HF Stage C), for the purpose of relievingymptoms. Lower doses of digoxin are preferred forhis purpose. (Level of Evidence B; Strength of Recom-endation I)Recommendation 6: For the treatment of moderate

r severe degrees of left ventricular dysfunction with orithout symptoms (HF Stage B and C), ACE inhibitors

hould be routinely employed unless there is a specificontraindication. These medications should be startedt low doses, and should be up-titrated to a maximumolerated safe dose. Uptitration may require a reductionn the dose of diuretics. (Level of Evidence B; Strengthf Recommendation I)Recommendation 7: For the treatment of decom-

ensated left ventricular dysfunction (HF Stage D), these of ACE inhibitors as initial therapy is not recom-ended. (Level of Evidence C; Strength of Recommen-

ation IIb)Recommendation 8: Patients who have an indica-

ion for ACE inhibitors therapy, but are intolerant ofCE inhibitors should be considered for ARB therapy.Level of Evidence C; Strength of Recommendation IIa)

Recommendation 9: Given the limited informationvailable concerning the efficacy and safety of � agonisteceptor blockade in infants and children with HF, noecommendation is made concerning the use of thisherapy for patients with left ventricular dysfunctionHF Stage B or C). If a decision is made to initiate-blocker therapy, consultation or co-management withheart failure or heart transplantation referral centeray be desirable. (Level of Evidence B; Strength ofecommendation IIa)Recommendation 10: Use of �-blocker therapy is

ot indicated for patients in HF Stage D. (Level ofvidence C; Strength of Recommendation IIb)

herapeutic Recommendations: Volume or Pres-ure Overload Conditions. Recommendation 11: Inll cases of HF associated with structural heart diseaseHF Stage B, C or D), consideration should be given tourgical repair of significant lesions, as the long-term
utlook may be more favorable than with medical a
anagement alone. (Level of Evidence C; Strength ofecommendation I)Recommendation 12: In pressure-induced left ven-

ricular hypertrophy, with normal myocardial function,CE inhibitors are not recommended in the absence ofnon-cardiac indication such as hypertension. (Level ofvidence C; Strength of Recommendation III)

eft Ventricular Diastolic Dysfunction

verview. Diastolic dysfunction is a syndrome charac-erized by impaired filling of one or both ventricles.68,69

iastolic heart failure refers to a clinical syndrome of HFith preserved systolic function.70–72 Diastolic dysfunc-

ion is the sole or primary cause of HF in as many as 1/3f adult patients with HF.12,70–74 No published esti-ates of the prevalence of diastolic dysfunction in theediatric population are available.There are 2 fundamental types of diastolic abnormal-

ty: impaired ventricular relaxation (affecting early dias-ole), and increased myocardial stiffness (affecting lateiastolic filling).70 The hemodynamic consequences ofiastolic dysfunction include increased ventricular fill-

ng pressures leading to elevation in atrial and venousressures, and in the case of left ventricular dysfunc-ion, leading also to an increase in pulmonary arterialressure.Conditions that cause diastolic dysfunction are varied

nd include pericardial as well as myocardial etiolo-ies.75–78 Of note, patients with chronic diastolic dys-unction are at risk for sudden death, as well as foreveloping pulmonary hypertension, which furtheromplicates treatment and limits survival.75–78

harmacotherapy. There are no large-scale, random-zed controlled trials of diastolic HF therapy in the adultr pediatric population.70,71

iuretics.

linical Data. Diuretics are the first line of therapy foriastolic dysfunction. Diuretics reduce pulmonary con-estion and relieve symptoms such as orthopnea, coughnd dyspnea. Injudicious or excessive use will reducereload and result in diminished cardiac output.73–75

CE Inhibitors and Angiotensin Receptor Block-rs.

linical Data in Adult Patients. Therapy with ACEnhibitors may benefit some forms of diastolic dysfunc-ion as tissue ACE levels are increased in models ofypertrophy,70,79,80 and angiotensin II is known to

nduce myocyte hypertrophy as well as fibrosis. ACEnhibitors may be employed to obtain regression of leftentricular hypertrophy, reverse vascular hypertrophy
nd fibrosis, and improve endothelial function. Theo-

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etically, ACE inhibitors and perhaps angiotensin recep-or blockers may be a reasonable treatment option.70

In the PRESERVE study, enalapril had moderatelyeneficial and statistically indistinguishable effects onegression of left ventricular hypertrophy comparedith nifedipine.81 There are currently no mortality data

o support the use of ACE inhibitors for patients withhronic HF and preserved ejection fraction in thebsence of another indication for ACE inhibitors ther-py (such as hypertension).

Limited experience in the adult population demon-trates improved exercise tolerance with ARB therapyn patients with diastolic dysfunction.82

linical Data in Pediatric Patients. Captopril waseleterious in 1 small study with 4 pediatric patientsith restrictive cardiomyopathy who demonstrated sys-

emic hypotension without an improvement in cardiacutput.41

alcium Channel Blockers.

linical Data in Adult Patients. Much of the literatureegarding calcium channel blockers is in the elderlyopulation and in patients with hypertrophic cardiomy-pathy. There are no prospective randomized trials.enefit may be achieved by cardiac slowing, prolonginglling time, and improving myocardial relaxation.73,79

rolonged administration of calcium channel blockersay lead to regression of left ventricular hypertrophy.81

alcium channel blockers may also directly improveentricular relaxation or compliance, but there are fewata to indicate that this is a clinically importantffect.74

When compared to enalapril, nifedipine had moder-tely beneficial and statistically indistinguishable effectsn regression of left ventricular hypertrophy comparedith enalapril.81 Some patients may deteriorate after

dministration of calcium channel blockers; this is likelyhe result of a decrease in afterload.73

linical Data in Pediatric Patients. There are no datan the use of calcium channel blockers for the treat-ent of diastolic dysfunction in children.

Blockers.

linical Data. Use of �-blockers has been reported foriastolic dysfunction in elderly patients with hypertro-hic cardiomyopathy but no prospective randomizedtudy has been performed. The rationale for use in-ludes reduced heart rate leading to a prolonged fillingime and relief of cardiac ischemia.73,74 It is recognizedhat some patients deteriorate with institution of �lockade.73 �-blockers are proposed to directly im-
rove diastolic dysfunction by augmenting ventricular w
elaxation or improving compliance, but there are fewata to indicate that these agents exert a clinically

mportant effect by this mechanism.

itrates.

linical Data. Nitric oxide or drugs that enhance NOelease (sodium nitroprusside, nitroglycerin) improveiastolic dysfunction when administered locally to theoronary arteries.69,83 Systemic use of nitrates mayesult in decreased systemic venous preload, increasedulmonary venous filling, reduced systemic afterload,ypotension and clinical deterioration.73 Patients withhronic restrictive disease may have typical or atypicalnginal pain, which may respond to nitrate therapy.

herapeutic Recommendations. Recommenda-ion 13: Clinical management of diastolic dysfunctionhould address symptoms and attempt to address thenderlying cause of the diastolic dysfunction, if known.his should include a careful evaluation for pericardialisease, and coronary insufficiency with attendant myo-ardial ischemia. Systemic hypertension, if present,hould be controlled aggressively. (Level of Evidence C;trength of Recommendation I)Recommendation 14: Fluid management to control

ymptoms remains a cornerstone in the management ofymptomatic diastolic dysfunction (HF Stage C). Diuret-cs can be very useful to control symptoms but must besed cautiously as cardiac output depends on thelevated filling pressures. Renal function should beollowed closely with care taken not to over-diurese aatient. Finally, sodium and fluid restriction may beelpful in controlling symptoms. (Level of Evidence C;trength of Recommendation I)Recommendation 15: Patients with marked atrial

ilatation due to diastolic dysfunction (HF stage B or C)ave a propensity for the formation of thrombi androphylactic anticoagulation may be considered in thisetting. (Level of Evidence C; Strength of Recommen-ation IIa)Recommendation 16: Atrial arrhythmias are not

nfrequent in patients with diastolic dysfunction due totrial enlargement. However, atrial contribution to ven-ricular filling is particularly important for this group ofatients (HF Stage B and C). Therefore, efforts shoulde made to maintain sinus rhythm by use of antiarrhyth-ic therapy and pacemaker therapy. (Level of Evidence; Strength of Recommendation I)Recommendation 17: Asymptomatic diastolic dys-

unction (HF Stage B) should be followed closely, butoes not require pharmacotherapy. (Level of Evidence; Strength of Recommendation IIa)Recommendation 18: Treatment with agents
hich reduce afterload, such as ACE inhibitors, �

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lockers, calcium channel blockers and nitrates, shoulde cautiously undertaken with close monitoring.brupt decreases in afterload in patients with restric-

ive or constrictive disease may be deleterious. (Level ofvidence C; Strength of Recommendation IIb)Recommendation 19: Patients with diastolic dys-

unction that is refractory to optimal medical/surgicalanagement should be evaluated for heart transplanta-

ion as they are at high risk of developing secondaryulmonary hypertension, and of sudden death (HFtage C). (Level of Evidence B; Strength of Recommen-ation I)

he Systemic Right Ventricle

verview. The morphologic right ventricle (RV) isonnected to the aorta and is thus the systemic ventri-le in 2 main groups of patients with biventricularirculation: patients born with d-transposition of thereat arteries who were treated with atrial baffle sur-ery (Mustard or Senning repair) and patients born withongenitally-corrected transposition of the great arter-es. RV dysfunction has been described in both theseroups of patients and may lead to HF. Although RVerformance at rest is often normal,84 exercise ability isften limited in patients who have undergone atrialaffle surgery because of both chronotropic incompe-ence and limited stroke volume reserve.85–92

The mechanism of systemic right ventricular dysfunc-ion is poorly understood. Various theories include: (a)

sub-optimal myocardial fiber arrangement and me-hanics in the right ventricle, (b) adverse pattern andeduced heterogeneity of ventricular strain, (c) tricus-id insufficiency and, (d) myocardial fibrosis secondaryo prolonged hypoxemia during infancy while awaitingtrial baffle surgery.93 Perfusion defects with associatedall motion abnormalities have been described using

ingle photon emission computed tomography,94–96

uggesting a role for chronic subendocardial ischemia.The clinical course in patients with congenitally-

orrected transposition of the great arteries is oftenetermined by associated structural (ventricular septalefect, pulmonary stenosis) or electrophysiologic ab-ormalities (AV block). Although there are reports ofatients without such abnormalities whose right ventri-les have continued to function normally well intodulthood, systemic RV dysfunction and HF occur withncreasing prevalence with advancing age. By 45 yearsf age, 25% of patients without and 67% of patients withssociated lesions have HF.97

There is a limited surgical experience with conver-ion of the atrial baffle to a systemic left ventricle“double-switch”), with baffle takedown accompaniedy arterial switch procedure. Early results indicate thaturgery is feasible, but surgical risk may be substantial
or this approach, and the long-term results are not E
nown.98 A similar procedure has been performed inmall numbers of patients with corrected transposition,lthough again, long-term outcomes are not yet defined.

harmacotherapy.

linical Data. Data specifically addressing the medicalherapy of systemic right ventricular dysfunction arexceptionally scanty. Administration of ACE inhibitorso 14 survivors of the Mustard operation did not affectxercise tolerance or right ventricular ejection frac-ion.99 However, selected patients did show benefit. Inhe absence of more specific data, the managementuidelines below are based on clinical experience andhe effectiveness of these regimens in adult patientsith systemic LV failure.

pecial Considerations. Although �-blockers are nowonsidered an important part of HF therapy in adultatients with cardiomyopathy, specific problems maye encountered in administration of these agents toatients with a systemic RV. These difficulties relate tohe high prevalence of sinus node dysfunction in survi-ors of atrial baffle repair and AV node dysfunction inatients with congenitally corrected transposition ofhe great arteries. The administration of �-blockers inhese patients may be particularly problematic, and mayesult in symptomatic bradycardia and exacerbation ofF.

herapeutic Recommendations. Recommenda-ion 20: Patients with a right ventricle in the systemicosition are at risk of developing systemic ventricularysfunction (HF Stage A) and should undergo periodicvaluation of ventricular function. (Level of Evidence B;trength of Recommendation I)Recommendation 21: Patients with fluid retention

ssociated with systemic right ventricular dysfunctionHF stage C) should be treated with diuretics to achieveeuvolemic state. In patients receiving chronic diuretic

herapy, electrolyte balance and renal function shoulde evaluated periodically. (Level of Evidence C;trength of Recommendation I)Recommendation 22: Digoxin should be employed

or patients with symptomatic systemic RV dysfunctionHF Stage C), for the purpose of relieving symptoms.igoxin is not currently recommended for patientsith asymptomatic systemic right ventricular dysfunc-

ion (HF Stage B). (Level of Evidence C; Strength ofecommendation IIa)Recommendation 23: For the treatment of asymp-

omatic systemic right ventricular dysfunction (HFtage B), ACE inhibitors should be routinely employednless there is a specific contraindication. These medi-ations should be employed at standard doses. (Level of
vidence C; Strength of Recommendation IIa)

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Recommendation 24: For the treatment of symp-omatic systemic right ventricular dysfunction (HFtage C), ACE inhibitors should be routinely employed,s above. (Level of Evidence C; Strength of Recommen-ation I)Recommendation 25: Patients who have an indica-

ion for ACE inhibitors therapy, but are intolerant ofCE inhibitors should be considered for ARB therapy.Level of Evidence C; Strength of Recommendation IIa)

Recommendation 26: Consideration of surgical re-ision of the tricuspid valve should be given where bothystemic right ventricular dysfunction and severe tricus-id valve regurgitation are present, particularly whenhe regurgitation is due to an intrinsic abnormality ofhe tricuspid valve (HF Stage B and C). (Level ofvidence C; Strength of Recommendation IIa)Recommendation 27: Anatomic revision (“double-

witch”) or cardiac transplantation should be consid-red for patients with advanced systemic right ventric-lar failure (HF Stage C) that is refractory to medicalherapy. (Level of Evidence C; Strength of Recommen-ation IIa)

HRONIC HEART FAILURE IN THE UNIVENTRICULARIRCULATION

verviewor most patients with single ventricle anatomy, surgi-al management is the primary treatment path, and maynclude a variety of early palliative procedures followedy bi-directional Glenn (superior cavopulmonary con-ection, SCPC), and ultimately the Fontan proceduretotal cavopulmonary connection, TCPC). Early pallia-ion with complete mixing of systemic and pulmonaryenous flow requires that ventricular output must beaintained at a level that is 2 to 3 times normal.100,101

his chronic volume overload places the myocardiumt considerable risk.100 Ventricular anatomic type andhe specifics of early management are important deter-inants of ventricular outcome after the SCPC or TCPC.

n particular, patients with a prior aortopulmonaryhunt typically have larger postoperative ventricularize than those with a prior pulmonary artery band.102

n some series,102 systemic left ventricles are moreilated than systemic right ventricles at the time ofolume-unloading surgery, although other reports haveound no difference in size or function between mor-hologically single right or left ventricles.103 The dura-ility of the systemic right ventricle is in question, witheports suggesting this may104–106 or may not107 be aroblem. In one series, early postoperative survival wasetter in patients with a morphologic left ventricle buty 6 months after completion of the Fontan procedure,entricular morphology did not influence survival.107

In patients who have completed the bi-directional
lenn or Fontan palliation, the manifestations of HF do o
ot include the typical symptoms that occur in patientsith 2 ventricles. After SCPC, TCPC, or Fontan pallia-

ion, systemic venous pressure is by necessity higherhan pulmonary. These patients experience peripheraldema, pleural and pericardial effusions, cyanosis, andymptoms related to reduced cardiac output such ashronic fatigue, loss of appetite, and extreme exercisentolerance. These symptoms can clearly be related toactors other than myocardial dysfunction, many ofhich are common in this patient population. Theasic physiology of the post-Fontan circulation is not

ntrinsically distinguishable from HF: activation of theenin-angiotensin system is usual if not universal, neu-ohumoral activation does not correlate with hemody-amic variables, and increased levels of catecholamineso not track well with severity of symptoms.108,109

Reduction in exercise capacity may be helpful inaking this distinction; however exercise performance

n children with successful or optimal Fontan palliationay be quantitatively identical to that in children withild HF.110 Reduced exercise capacity may in part be

xplained by diminished resting stroke volume andtroke volume reserve111 compared with normal hearts.he impact of reduced stroke volume in patients whoave had the Fontan operation is compounded byhronotropic incompetence, with most series reportingaximum achieved heart rate to be about 75% of the

ge-predicted normal value,112–114 and in some se-ies,115,116 though not all,117 peak heart rate correlatesith the percent of predicted VO2max that is achieved.

xercise-induced hypoxia may also be a limiting factor.rterial saturation typically falls during exercise inontan patients113,118 and correlates with exercise ca-acity.116 The cause of the exercise-related hypoxia isot clear. Vital capacity and functional residual capacityre reduced,119 consistent with a restrictive pattern ofulmonary abnormality.114 Adult patients after Fontanave been reported to have sufficient restriction so as toanifest severely diminished maximum ventilationith secondary reduction in aerobic capacity.114

The role of ventricular dysfunction and myocardialnsufficiency in limiting exercise capacity in these pa-ients remains unclear. This highlights the importancef identifying other potentially treatable sources ofxercise intolerance before classifying the patient asaving cardiogenic HF.

iagnostic Approach. In patients who have previ-usly undergone Fontan-type repair, thorough evalua-ion and management of circulatory insufficiency isssential. Significant systemic or pulmonary venousbstruction is unlikely to be tolerated. Valve regurgita-ion is common and may be progressive, causing per-istent volume overload, and is associated with a poorer
utcome.105

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Atrial arrhythmias increase in frequency with age120

nd may be associated with tachycardia-induced ven-ricular dysfunction. Chronotropic incompetence maye more poorly tolerated than in other forms of heartisease.121 Residual right-to-left shunts may augmenturing exercise, severely limiting exercise capacity. Ineneral, invasive hemodynamic investigation is neededoth to document that myocardial dysfunction is pri-arily responsible and that other potentially treatable

ontributing factors are not present.

harmacotherapy.

iuretics. Use of diuretics is common in the earlyost-operative period and in many instances becomes aermanent component of therapy, even in the absencef specific findings that clearly point to fluid overload.eripheral edema, pleural and pericardial effusions, andther evidence of elevated systemic venous pressureccur frequently and often respond favorably to diuret-

cs. However, the absence of a pulmonary pumpinghamber renders the Fontan circulation particularlyulnerable to an inability to maintain an adequateystemic ventricular preload. Reduction of systemicenous pressure through diuresis reduces systemicentricular preload in a more direct fashion than inatients with a biventricular circulation. Although theeneficial use of diuretics for HF invariably represents aalancing act with regard to maintenance of cardiacutput, the margin of safety is far narrower in theseatients and requires a greater degree of vigilance withegard to electrolyte disturbances, pre-renal azotemia,nd exacerbation of exercise intolerance.

igoxin. Digoxin is in common use for post-Fontanatients despite the absence of specific evidence ofafety or benefit in this setting. There are no theoreticaloncerns that would make this population more or lessikely to benefit from this agent than other groups withentricular dysfunction.

CE Inhibitors. In patients with single ventricles,ctivation of the RAAS contributes to the increasedascular resistance that typically occurs after the Fontanrocedure, and a favorable response to ACE inhibitorsr ARB might therefore be anticipated.108 However, instudy of Fontan patients who did not have HF,

dministration of enalapril for 6 weeks did not alterystemic resistance, resting cardiac index, or exerciseapacity.122,123 Although these agents were well toler-ted, and clinical experience confirms that ACE inhibi-ors can be safely administered to patients who havead the Fontan operation, the efficacy and risks of

ong-term ACE inhibitor therapy in this setting are not
nown. s
Blockers. The utility of �-blockers in patients afterontan-type operations is unknown. Specific clinicalata in this population are absent. There is a reasonablerobability that �-blocker therapy may impair exerciseolerance in these patients because of the pervasivending of chronotropic incompetence in post-Fontanatients and the generally adverse impact of �-blockerherapy on VO2max.

herapeutic Recommendations. Recommenda-ion 28: In patients with a univentricular circulationho undergo deterioration in clinical status (HF Stage B

nd C), consideration should be given to invasivessessment of hemodynamics, due to the heightenedensitivity of this group to elevations of filling pressure.Level of Evidence C; Strength of Recommendation I)

Recommendation 29: A clinical decision as to theeverity or presence of HF symptoms in patients with aniventricular circulation must include consideration ofhe patient’s prior status and underlying anatomic de-ects. Longitudinal evaluation is of great importance inhis regard. (Level of Evidence C; Strength of Recom-endation I)Recommendation 30: Maintenance of atrioventric-

lar synchrony should be a priority in the managementf patients with a univentricular circulation and HF (HFtages B and C). (Level of Evidence C; Strength ofecommendation I)Recommendation 31: Patients with fluid retention

ssociated with systemic ventricular dysfunction in aniventricular circulation (HF stage C) should bereated with diuretics to achieve a euvolemic state. Inatients receiving chronic diuretic therapy, electrolytealance and renal function should be periodically eval-ated. (Level of Evidence C; Strength of Recommenda-ion I)

Recommendation 32: Digoxin should be employedor patients with systemic ventricular dysfunction in aniventricular circulation (HF Stage C), for the purposef relieving symptoms. Digoxin is not currently recom-ended for patients with asymptomatic systemic ven-

ricular dysfunction in a univentricular circulation (HFtage B). (Level of Evidence C; Strength of Recommen-ation IIa)Recommendation 33: For patients with a univen-

ricular circulation after SCPC or TCPC, in whomystolic function is normal (HF Stage A), ACE inhibitorshould not be employed routinely. (Level of Evidence; Strength of Recommendation III).Recommendation 34: For the treatment of asymp-

omatic systemic ventricular dysfunction in a univen-ricular circulation after SCPC or TCPC (HF Stage B),CE inhibitors should be employed unless there is a
pecific contraindication. These medications should be

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mployed at standard doses (Level of Evidence C;trength of Recommendation IIa).Recommendation 35: For the treatment of symp-

omatic systemic ventricular dysfunction in a univen-ricular circulation after SCPC or TCPC (HF Stage C),CE inhibitors should be employed, as above. (Level ofvidence C; Strength of Recommendation IIa)Recommendation 36: Use of �-blocker therapy is

ot routinely recommended for patients with systemicentricular dysfunction in a univentricular circulationfter SCPC or TCPC (HF Stage B and C). (Level ofvidence C; Strength of Recommendation IIb)

CUTE HEART FAILUREharmacologic Support

n adult studies, it has been recognized that inotropesay be required in the management of refractory acuteF exacerbations that are accompanied by hypoperfu-

ion and hypotension.124 Currently available inotropicgents increase contractility through a common path-ay of increasing intracellular levels of cyclic adenylateonophosphate (cAMP). Increased cytoplasmic levels

f cAMP cause increased calcium release from thearcoplasmic reticulum and increased contractile forceeneration by the contractile apparatus. Increases inAMP occur by two different mechanisms: �-adrener-ic-mediated stimulation (increased production) orhosphodiesterase III (PDE III) inhibition (decreasedegradation).125

The catecholamines are the most potent positivenotropic agents available; however, effects are notimited to inotropy. They also possess chronotropicroperties and complex effects on vascular beds of thearious organs of the body. Consequently, the choice ofn agent may depend as much on the state of theirculation as it does on the myocardium.Amrinone and milrinone belong to a class of nongly-

oside, nonsympathomimetic inotropic agents (phos-hodiesterase III inhibitors). Intravenous administrationf amrinone or milrinone increases cardiac output andeduces cardiac filling pressures, pulmonary vascularesistance, and systemic vascular resistance with mini-al effect on the heart rate and systemic blood pressure

f adult patients.126 These drugs are particularly usefuln the treatment of cardiogenic shock because theyncrease contractility and reduce afterload by periph-ral vasodilatation without a consistent increase inyocardial oxygen consumption. Milrinone has beenell studied in the pediatric population.126–128 A re-

ently completed randomized, controlled trial demon-trated that milrinone infusion reduced the incidence ofow cardiac output following cardiac surgery.129

Both of these agents require careful bolus dosingrior to initiating an infusion – a rapid infusion of the
olus dose may cause hypotension. An alternative ap- b
roach, which may be preferred in unstable patients, iso begin infusion without an initial bolus.130 Since bothf these drugs have relatively long half-lives, theyhould be used cautiously in the presence of significantypotension. However, recent data indicate that thealf-life of milrinone may be shorter than originallyxtrapolated from adult data.129

Nesiritide, a recombinant B-type natriuretic peptide,s the first new drug approved by the U.S. Food andrug Administration in 14 years for the treatment ofcutely decompensated HF in adults. Endogenous B-ype natriuretic peptide is a cardiac hormone producedy the failing heart to counteract the maladaptiveemodynamic, neural, and hormonal compensationsssociated with the syndrome of CHF. Nesiritide isdentical to the naturally occurring peptide, and likehis peptide, Nesiritide reduces preload and afterload,eading to increases in cardiac index without reflexachycardia or direct inotropic effect, increased diuresisnd natriuresis, and suppression of the renin-angioten-in-aldosterone axis and sympathetic system. In a largeandomized controlled clinical trial of 489 patients,esiritide was found to be faster and more effectivehan IV nitroglycerin plus standard care at improvingemodynamic and symptomatology in patients withcutely decompensated CHF who have dyspnea atest.131–133 Because of its unique mechanism of actionnd greater safety compared to both standard inotropicherapy with dobutamine and vasodilator therapy withitroglycerin, the availability of nesiritide may alter theurrent algorithms for CHF management. However, noediatric data are currently available.Infants and children with low blood pressure and

dequate cardiac function after cardiac surgery refrac-ory to standard cardiopressors respond well to theressor action of exogenous vasopressin and permitithdrawal or significant lowering of epinephrine dose.

n a study of 11 children with vasodilatory shock afterardiac surgery, all 9 children with adequate cardiacunction improved with vasopressin and survived; the 2atients that received vasopressin in the setting of poorardiac function died, despite transient improvement inlood pressure.134 Plasma vasopressin levels were de-reased before treatment in 3 patients in whom bloodevels were tested indicating that deficiency of theormone may contribute to this hypotensive condition.

echanical Support

verview. Mechanical circulatory support has becomen important addition to the treatment armamentariumor the infant or child with acutely decompensated HFnd low cardiac output unresponsive to pharmacologicaneuvers. Options for mechanical circulatory support

nclude total heart-lung bypass (Extracorporeal Mem-
rane Oxygenation [ECMO]), or more limited cardiac

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upport with a left ventricular assist device (LVAD),ight ventricular assist device (RVAD), or intra-aorticalloon pump (IABP). In pediatric patients, most expe-ience has been with ECMO, primarily because sizeimitations have generally precluded extensive use ofther modalities. However, with the development ofmaller ventricular assist devices (primarily in Europe)nd the adaptation of existing devices, mechanicalentricular assistance has been applied to infants asoung as 5 days of age.135–145 The choice of modality ingiven patient will depend on the specific pathophys-

ology of HF in that patient, on the availability ofupport devices and on the expertise of the child’shysicians.

isks and Benefits. Mechanical assist in children cane life saving in low cardiac output situations wherehere is a reversible underlying abnormality that wouldenefit from short-term cardiac support.146 Mechanicalupport maintains end-organ function and reduces myo-ardial oxygen requirements during a critical period ofecovery from a cardiac insult. Preliminary evidencendicates that cardiac remodeling, on both a structuralnd molecular level, occurs during mechanical support.tudies with small number of patients have demon-trated rates of survival to hospital discharge rangingrom 25 to 65%.147–150 Ibrahim and colleagues reviewed

10-year experience in 96 cardiac patients requiringCMO (67 patients) or ventricular assist devices (29atients).147 Of these patients, 40% and 41%, respec-ively, survived to hospital discharge. The use of me-hanical support in patients with single ventricle phys-ology has been associated in some studies with aoorer outcome, although recent data from Jaggers etl. and others support the use of ECMO after Norwoodalliation.151 Overall hospital survival in the 35 patients

n that series was 61%.151

Mechanical assist can also be used a bridge to trans-lant when cardiac recovery is not expected.152 In thisase, mechanical support extends the period overhich a patient can wait for a donor organ. End-organ

unction may be preserved, or perturbations in functionay reverse with improved perfusion, thus improving

ransplant suitability and outcome.153

herapeutic Recommendations. Recommenda-ion 37: Institution of mechanical cardiac supporthould be considered in patients without structuralongenital heart disease, who manifest acute low car-iac output or who have intractable arrhythmias duringpresumably temporary condition that is refractory toedical therapy (HF Stage D) such as myocarditis,

eptic shock, or acute rejection following cardiac trans-lantation. (Level of Evidence C; Strength of Recom-
endation I) r
Recommendation 38: Institution of mechanical car-iac support should be considered in patients with orithout structural congenital heart disease, who have

cute decompensation of end-stage HF, primarily as aridge to cardiac transplantation (HF Stage D). (Level ofvidence B; Strength of Recommendation I)Recommendation 39: Institution of mechanical car-

iac support may be considered in patients who havexperienced cardiac arrest, hypoxia with pulmonaryypertension, or severe ventricular dysfunction with

ow cardiac output after surgery for congenital heartisease, including “rescue” of patients who fail to weanrom cardiopulmonary bypass or who have myocarditisHF Stage D). However, the outcomes in this group areess satisfactory than for other indications for mechan-cal support. (Level of Evidence B; Strength of Recom-

endation IIa)Recommendation 40: Mechanical cardiac support

s not indicated in those cases in which there isvidence of a severe and irreversible defect (e.g. cata-trophic intracranial hemorrhage, or advanced multisys-em organ failure). However, in practice, the determi-ation of the severity and/or irreversibility of thessociated condition may be difficult to determine, sohe decision concerning eligibility for mechanical sup-ort is a difficult clinical judgment. (Level of Evidence; Strength of Recommendation IIb)

LECTROPHYSIOLOGY CONSIDERATIONSverview

rrhythmia is a major cause of morbidity and mortalityn pediatric patients with end-stage HF.154–161 Myocar-ial scars and stretching associated with pressure orolume overload, previous heart surgery or intrinsicyocardial disease provide a ripe substrate for arrhyth-ogenesis.162,163 Multiple triggers for arrhythmia arerevalent in patients with HF and include electrolyte

mbalance, blood gas and pH abnormalities, ischemiand administration of potentially pro-arrhythmic drugsuch as digoxin, positive inotropes, phosphodiesterasenhibitors and anti-arrhythmic drugs themselves.164,165

lthough it is controversial whether ventricular arrhyth-ias are independent risk factors for sudden death in

his population, sustained tachycardia may cause hemo-ynamic collapse, and complex non-sustained ventric-lar ectopy reflects potential electrical instability of theyocardium.157 Atrial arrhythmias may also impair car-

iac output and aggravate HF by eliminating the atrialontribution to filling and/or causing a rapid ventricularesponse.

In patients with dilated cardiomyopathy, between 50nd 63% of those patients who die have ventricularrrhythmias at presentation.154,155 In pediatric patientswaiting transplantation, 62% had life-threatening ar-
hythmias, most commonly ventricular tachycardia.166

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rrhythmia management is an important component inhe overall care of the pediatric patient with HF.

Treatment can be broken down into the managementf acute arrhythmias causing hemodynamic collapsend chronic arrhythmias requiring long-term suppres-ion because they lead to impaired cardiac performancer may pose a significant risk factor for sudden death.

harmacotherapy

cute Arrhythmia Management. Arrhythmias likelyo require acute treatment in patients with HF includetrial tachyarrhythmias with a rapid ventricular rate,aroxysmal supraventricular tachycardia, junctional ec-opic tachycardia and sustained ventricular tachycardia.ynchronized DC cardioversion/defibrillation should beonsidered for treatment of either supraventricular orentricular arrhythmias if hemodynamic collapse ismminent.167,168

Atrial tachycardia, flutter or fibrillation can be initiallyanaged by controlling the ventricular rate with AV

odal blocking agents. For rate control, digoxin is notikely to be useful primarily because of its delayed onsetf action. Intravenous diltiazem is a reasonable firsthoice, but hypotension is a major concern in a settingf impaired ventricular function. An intravenous-blocker, such as esmolol can be useful in decreasing

he ventricular rate but hypotension is likely to pre-lude its use.The treatment of the atrial rhythm itself includes

ntravenous amiodarone, procainamide or ibutilide.owever, side effects such as hypotension and torsadee pointes occur frequently and elective cardioversion

s often preferable. There is very little experience usingV ibutilide for the acute conversion of atrial flutter orbrillation in pediatric patients with significant myocar-ial dysfunction. Paroxysmal supraventricular tachycar-ia is best treated with intravenous adenosine, but a

onger acting agent such as procainamide or amioda-one may be necessary for control of recurrentpisodes.Junctional ectopic tachycardia responds best to IV

miodarone and to minimizing the dose of any intrave-ous inotropes or phosphodiesterase inhibitors. Theharmacologic treatments for ventricular tachycardia,

nclude intravenous lidocaine, amiodarone and procain-mide.169,170 Lidocaine is the first line drug because ofts rapid onset of action and limited toxicity if drugevels are kept in the therapeutic range. If this isnsuccessful, either intravenous amiodarone or pro-ainamide can be utilized, but amiodarone is preferableecause of a lower incidence of hypotension andendency for arrhythmia aggravation.

hronic Arrhythmia Management. Chronic drug
uppression of arrhythmias in patients with HF can be v
ery problematic. For atrial arrhythmias, many drugsave been shown to have a modest success rate includ-

ng those in the category of IA, IC and III. However,miodarone stands out as the most appropriate drugecause of its somewhat higher success rate and lesserendency for pro-arrhythmia.171,172 For ventricularachycardias, the superiority of amiodarone over thether drugs is even more evident. This medication issually well tolerated, even in patients with very poorontractility. The major limiting factor in the short-terms bradycardia and hypotension, while longer use re-uires monitoring for thyroid and liver dysfunction asell as pulmonary interstitial disease.As an alternative to pharmacotherapy in the setting of

hronic atrial arrhythmias, ablation therapy can beonsidered. The safety of radiofrequency or surgicalblation is well established, and there are significantata attesting to its efficacy.172–174 Triedman and col-

eagues report a 73% procedural success rate for radio-requency ablation, with approximately 50% success at

year, for a mixed population including Fontan andustard patients.172 In a population of Fontan patients,

hort-term control of atrial tachycardia was achieved in4/15 patients using a modified RA maze intraopera-ively, with no recurrences after 43 months ofollow-up.173

herapeutic Recommendations. Recommenda-ion 41: In patients with significant arrhythmias in theetting of HF associated with structural heart diseaseHF Stages B, C or D), consideration should be given tourgical repair of important uncorrected or residualefects, as this is likely to be essential to achievedequate rhythm control. (Level of Evidence C;trength of Recommendation I)Recommendation 42: In patients with significant

rrhythmias in the setting of HF associated with struc-ural heart disease (HF Stages B, C or D), considerationhould be given to improving or optimizing the medicalreatment for HF and correcting aggravating factorsuch as electrolyte abnormalities, as this is likely to be aey determinant of the successful control of arrhyth-ias. (Level of Evidence C; Strength of Recommenda-

ion I)Recommendation 43: In patients with significant

rrhythmias in the setting of HF associated with struc-ural heart disease (HF Stages B, C or D), maintenance oftrio-ventricular synchrony is of great importance inptimizing hemodynamics, and management of intra-trial arrhythmias should be oriented towards restora-ion of sinus rhythm rather than on ventricular rateontrol alone. (Level of Evidence C; Strength of Recom-endation I)Recommendation 44: In patients with impaired

entricular function (HF Stages B, C or D), many forms

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f tachycardia can precipitate acute hemodynamic col-apse, and many of the available pharmacotherapies canrecipitate hypotension. Therefore, considerationhould be given to early utilization of electrical cardio-ersion/defibrillation for treatment of both atrial andentricular tachycardias. (Level of Evidence C; Strengthf Recommendation IIa)Recommendation 45: For acute treatment of clini-

ally significant junctional ectopic tachycardia, the firstine of therapy should usually be amiodarone because ofts superior efficacy as compared to alternative medica-ions. (Level of Evidence C; Strength of Recommenda-ion IIa)

Recommendation 46: For chronic suppression oftrial arrhythmias in children with HF (HF Stages B, C or), the first line of therapy should usually be amioda-

one because of its superior efficacy as compared tolternative medications. (Level of Evidence C; Strengthf Recommendation IIa)Recommendation 47: Patients with potentially sig-

ificant atrioventricular tachycardias who are sched-led to undergo completion of the Fontan procedure,hould be considered for definitive ablation therapy,rior to the Fontan surgery, to reduce the risk of seriousrrhythmia during the postoperative period and be-ond. Ablation, in these circumstances, might be ac-omplished by transcatheter technique or by intra-perative Maze procedure. (Level of Evidence C;trength of Recommendation IIa)

evice Therapy.

ediatric ICD and Resynchronization Experience.he development of the ICD has improved survival in

he adult HF population.175 Recent multicenter trials indult HF patients have shown that ICD therapy is moreeneficial than antiarrhythmics in both ischemic and

diopathic cardiomyopathies.176,177 Data from Bockernd colleagues suggest that ICD therapy prolongs life inYHA classes I–III, with greatest initial benefit in class

I and III but longest benefit in class I.178 However noulticenter prospective trials of ICD therapy in chil-

ren with any heart disease have been performed.In a study of the use of defibrillator therapy in adult

atients awaiting cardiac transplant, 71% received ap-ropriate discharge with no inappropriate discharg-s.179 In a multicenter retrospective review of ICDherapy in pediatric patients awaiting heart transplanta-ion, 45% of the patients had appropriate dischargesith an inappropriate discharge rate of 27%. Freedom

rom appropriate discharge at 100 days was 63%.180

In pediatric practice it appears that ICD are com-only used in older HF patients with missed sudden

eath episodes, but not as commonly used in youngeratients, or those with syncope.181 This may be due to
he higher rate of complications and the technical v
ifficulties associated with placing ICD in the pediatricopulation. Berul and colleagues found a significantlyigher complication and infection rate when compar-

ng a pediatric group of ICD recipients to an adultroup.182 However, this issue may be diminishing withhe development of newer leadless ICD systems formaller children.183

In adult patients with HF associated with LV dysfunc-ion and left bundle branch block, LV resynchronizationas proven valuable in improving hemodynamics andlinical status, which is thought to be the result ofmproved mechanical efficiency within the left ventri-le.184–187 This therapy has not been validated in chil-ren, but Dubin and colleagues have shown that resyn-hronization of the right ventricle in patients with rightentricular dysfunction can produce favorable hemody-amic changes in an acute setting.188 In addition,anousek et al have shown improved blood pressure inatients with acute heart failure following repair ofongenital heart disease, by combining atrioventricularptimization with ventricular resynchronization of theight ventricle.189 While these results are intriguing,heir implications are not yet clear.

pecial Considerations in Structural Heart Disease.

atients with structural heart disease offer unique chal-enges in arrhythmia management that may not need toe considered when treating the patient with dilatedardiomyopathy alone. The negative inotropic proper-ies of anti-arrhythmic therapy may be accentuated inatients with congenital heart disease such as thoseith single ventricle physiology, multiple ventricular

cars, or significant dysfunction of either the atrioven-ricular or semilunar valves. A second area of concern ishat patients with significant ventricular dysfunctionay require an elevated heart rate to help maintain an

dequate cardiac output. Antiarrhythmic medicationsay lead to a relative bradycardia, and impair cardiac

utput. This is compounded in patients with congenitaleart disease who have underlying sinus or atrioventric-lar node dysfunction.There are also issues encountered with the use of

evice therapy in patients with congenital heart diseasehat are not seen in those with structurally normalearts. The use of transvenous pacing and defibrillator

eads is impossible in some forms of palliated congenitaleart disease. Patients who have undergone superiorena cava to pulmonary artery anastomosis have noccess to the heart from above. In patients who havendergone a Fontan procedure there is typically noirect venous access to the heart. Transvenous pacingnd defibrillator leads are contraindicated in patientsith residual right to left shunting such as seen in

isenmenger’s syndrome. The inability to use trans-
enous systems in these patients necessitates the place-

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ent of epicardial systems with their risks of morbiditynd mortality in a hemodynamically compromised pa-ient.

Although ventricular arrhythmias are the most worri-ome type of arrhythmias seen in patients with HF,upraventricular arrhythmias also can lead to significantemodynamic compromise. Patients with significantyocardial dysfunction will be compromised with rel-

tively modest increases in their heart rates and are atisk for the rhythm to degenerate into a life threateningrrhythmia. In a study by Rosenthal et al. of 96 patientsisted for cardiac transplantation, 2 of 5 patients withVT degenerated into ventricular fibrillation.166 Atrialachyarrhythmias are frequently seen in patients withongenital heart disease that have had atrial level sur-ery such as Fontan, Senning, or Mustard procedures.Ventricular arrhythmias are common in patients with

F. It is well known that patients who have undergoneurgery for congenital heart disease will often developentricular arrhythmias from scars and suture lines inhe heart. Although there would seem to be an in-reased preponderance of these arrhythmias in patientsith congenital heart disease and HF, Rosenthal and

olleagues found that of 8 pre-transplant patients withT only 1 had congenital heart disease.166 In the sametudy one patient with congenital heart disease devel-ped VF.

herapeutic Recommendations. Recommenda-ion 48: At this time, clinical criteria for ICD placementn children are in flux and are not well defined. ICDlacement may be considered as a bridge to cardiacransplantation in selected patients with advanced HFHF Stage C and D), on a case-by-case basis. (Level ofvidence C; Strength of Recommendation IIa)Recommendation 49: In patients with structural

eart disease, particularly including those with a uni-entricular circulation, pacemaker implantation shoulde considered as possible adjunctive therapy, to main-ain atrioventricular synchrony and chronotropic com-etence, and to permit administration of other pharma-otherapies that are needed for treatment of HF. (Levelf Evidence C; Strength of Recommendation IIa)

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