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Review 3

Chronic Congestive Heart Failure in Infancy and


Childhood: New Aspects of Diagnosis and Treatment
Herzversagen im Kindesalter: neue Aspekte der Diagnostik und Therapie

Author A. A. Schmaltz

Affiliation Former: Clinic for Pediatric Cardiology, University Childrens Hospital, Essen, Germany

Key words Abstract Zusammenfassung

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▶ congestive heart failure
▼ ▼

▶ infancy and childhood
Congestive heart failure (CHF) is the inability Von Herzversagen spricht man, wenn das Herz

▶ diagnosis
of the heart to meet the metabolic demands of nicht die metabolischen Bedürfnisse des Körpers

▶ treatment
the body. As a disease of the advanced age with decken kann. Als eine Erkrankung des höheren
a frequency of 1–2 % of the population it is rare Alters mit einer Häufigkeit von 1–2 % der Bev-
Schlüsselwörter

▶ Herzversagen in infancy and childhood. The incidence ranges ölkerung ist sie im Kindesalter selten. Die Inzi-

▶ Kindesalter from 2.95 (in all US children’s hospitals) to 23.2 denz reicht von 2,95 (bei US-Kinderkliniken)

▶ Diagnostik (University’s Childrens Hospital Essen) on 1 000 bis 23,2 (Universitäskinderklinik Essen) auf

▶ Therapie discharges. Among the diagnostic procedures 1 000 Entlassungen. Bei der Diagnostik ist die
echocardiography is the primary modality of Echokardiografie die wesentlichste Methode der
imaging. Tei-index and tissue-Doppler are more Bildgebung. Tei-Index und Gewebs-Doppler sind
sensitive parameters for LV-dysfunction. BNP/ ausgesprochen sensitive Parameter der LV-Dys-
NT-proBNP are age-dependent and can guide funktion. BNP/NT-proBNP sind altersabhängig
the long-term therapy. Treatment in childhood und können die Langzeittherapie steuern. Die
does not differ basically from that in adulthood, Behandlung im Kindesalter unterscheidet sich
recommended by several guidelines, but data nicht wesentlich von der des Erwachsenenalters,
regarding the various substances – outlined in wie sie in mehreren Leitlinien empfohlen wird.
detail – are very limited. Here a big work has to Dabei ist die Datenlage und damit die Evidenz-
be done in future! basis bei den verschiedenen Substanzen, die im
einzelnen ausgeführt werden, schlecht. Hier ist
noch viel zu tun!

In 1999, I published a review paper about con- frequent disease and has a considerable morbid-
gestive heart failure (CHF) in childhood in this ity and mortality. In Europe, its prevalence is
journal [57]. I described the pathophysiological about 1–2 % of the population [41], but more
mechanisms, symptoms and diagnosis, and the than 10 % in persons over 70 years of age. Risk
therapeutic approach. 15 years later it is interest- factors are hypertension, myocardial infarction,
Bibliography ing to look for changes and developments, which coronary heart disease, diabetes, left ventricular
DOI  http://dx.doi.org/ I recognize mainly in the field of diagnosis and hypertrophy in the ECG and heart valvular dis-
10.1055/s-0034-1389974
treatment of this disease. On the other side we eases [29].
Klin Padiatr 2015; 227: 3–9
© Georg Thieme Verlag KG
will see that many additional studies need to be Comparable epidemiological studies covering
Stuttgart · New York done to give our therapeutic approach a stronger the pediatric age group are very rare. In a popula-
ISSN 0300-8630 scientific basis. tion-based study Rodeheffer et al. [51] found an
incidence of 4 infants  < 1 year of age in 1 000 per-
Correspondence son years and a prevalence in children  < 10 years
Prof. Achim A. Schmaltz Prevalence and Etiology of age of 1.3 in 1 000.
Weg zur Platte 98
45133 Essen
▼ An epidemiological study from Germany investi-
In its simplest and most succinct definition, CHF gated the patient population of the University
Germany
Tel.:   +  49/201/411 335
can be defined as an inability of the heart to meet Children’s Hospital Essen as a tertiary center for a
Fax:   +  49/201/4553 825 the metabolic demands of the body. With an esti- time range of 10 years [61] – with a certain bias
achim.schmaltz@web.de mated 15 million patients worldwide, CHF is a for worse cases. Among 1 755 patients with any

Schmaltz AA. Chronic Congestive Heart Failure …  Klin Padiatr 2015; 227: 3–9
4 Review

form of heart diseases the incidence of CHF was 23.2 in 1 000. in adults (61 % vs. 0.3 %). The proportion of cardiac procedures
Among children with congenital heart defects 39.1 % suffered was also significantly higher (61.4 % vs 0.28 %). There was no dif-
from CHF at one point of time, in 70.6 % of cases during the first ference in the mortality rate between children and adults (7.5 %
year of life. Mortality was 11.4 % in the patients with CHF and vs. 7.9 %) [54, 67].
 ▶  Fig. 1 shows the age
occurs mainly during the first year of life. ●
at the beginning of the first episode of congestive heart failure in Causes of heart failure in childhood:  Hsu and Pearson [26]
patients with congenital heart defects. ●  ▶  Fig. 2 shows the fre- gave a very good overview of the various causes of pediatric
quency of deaths for CHF during the first 20 years of life with an  ▶  Table 1 we completed this survey by the fig-
heart failure. In ●
absolute peak in the first and second year of life. In contrast to ures of frequencies we have found in our own study [61]: among
adult age, where CHF is an end-stage disease and has no chance all patients suffering from CHF, 81 % had congenital heart dis-
of complete recovery, CHF in childhood ends in 78 % with the eases, 7 % had cardiomyopathies and 2 % had rhythm distur-
end of the postoperative period; i. e., it is a transitory disease bances. However, it has to be pointed out that in most cases CHF
ended mostly by surgery, although with a high mortality. in congenital heart diseases is an indication for intervention or
In an analysis of 50 % of U.S. pediatric hospital discharges the operation to attempt to treat and to end the heart failure. In con-
incidence of CHF was 2.95 in 1 000 children in comparison to trast, in patients with cardiomyopathies or acquired heart dis-
102 in 1 000 adults. In contrast to the adults, children had differ- eases heart failure is often a longer lasting problem which has to
ent comorbidities: the percentage of congenital heart diseases be treated over a longer period.
or other congenital anomalies was much higher in children than

450 Current methods of diagnosis


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400 387
The guideline of the European Society of Cardiology (ESC) [41]
350 gives clear recommendations for diagnosis and treatment of CHF
300 in adults. They are based on a huge body of literature about this
topic. They have been prepared by a task force of respected
250
experts in this field, circulated and approved by several review
n

200 boards. The task force has classified and ranked the usefulness
150 and/or efficacy of the recommended procedures and/or treat-
ments and the levels of evidence. Further guidelines were
100
defined by the American Heart Association [69] and the German
37 31
50 18 10 Society of Cardiology (DGK) [23].
6 10 6 2 4 2 2 3 3 1 1 2 2
0
As discussed above CHF is rare in infancy and childhood and lit-
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 erature is scarce [2, 10, 26, 57]. Until recently, the only guidelines
Age
published worldwide were the 2007 guidelines by the German
Society of Pediatric Cardiology (DGPK) about diagnosis and
Fig. 1  Number of patients in dependency of age at beginning of first
treatment in pediatric cardiology [58]. Written by several
CHF: Data from a tertiary center for a 10 years range [61].
experts, discussed and consented in a formalized group process
by the guideline task force and agreed by the board of the society
60 57
these guidelines fulfill the S2-criteria of the AWMF [3].
In December 2013 the Canadian Cardiovascular Society pub-
lished a guideline about “Presentation, Diagnosis, and Medical
50 Management of Heart Failure in Children”. “This statement was
developed following a thorough consideration of medical litera-
ture and the best available evidence and clinical experience….”
40
(30 – introduction).
The clinical symptoms of heart failure – ●  ▶  Table 2 – are similar to
30
the adult age. Infancy is an exception as there is a predominance
n

of uncharacteristic symptoms like failure to feed and to thrive,


diaphoresis, respiratory rate and pattern, hepatomegaly and car-
20 diomegaly on x-ray. These various symptoms were first com-
piled into a grading system by Ross et al. (1987) [52] describing
12
the severity of heart failure. The system was modified in 2002 by
10 ▶  Table 3), who evaluated 5 different signs and
Läer et al. [35] ( ●
3 4 2 11 12 symptoms to define different degrees which are added up to
11 2 1 1 1 1 1
0
derive a score. A score of 3–6 describes mild heart failure, a score
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 of 7–9 moderate and a score of 10–12 severe heart failure. A
Age at death
much more complicated grading system is the New York Univer-
Acquired heart Congenital heart defect sity Pediatric Heart Failure Index [11], which assigns up to 30
disease/cardiomyopathy
points for severe HF. Recently Ross proposed a further revision,
in which he evaluates 10 different criteria depending on various
Fig. 2  Number of deaths in dependency from the age and etiology
age groups [53]. The Läer-system [34], as depicted here, is the
(acquired or congenital heart defect). Same patient cohort as ●
 ▶  Fig. 1 [61].
most frequently used score in literature. It describes the clinical

Schmaltz AA. Chronic Congestive Heart Failure …  Klin Padiatr 2015; 227: 3–9
Review 5

Table 1  Cardiovascular causes of heart failure in children according to Hsu DT and Pearson GD [26] and their percentage distribution among all cases with CHF
according to Sommers C et al. [61].

Congenital cardiac malformation 81 %


volume overload left-to-right-shunt (VSD, PDA, AVSD…) 31 %
valve incompetence aortic, pulmonary regurgitation 13 %
pressure overload left and right-sided obstruction 13 %
complex congenital heart disease SV, HLHS, TGA, ccTGA, systemic RV 21 %
structurally normal heart cardiomyopathies, myocarditis 7 %
rhythm disturbances 2 %

Table 2  Symptoms characteristic of heart failure in children [30].

Commonly encountered Less commonly encountered


infants and young children tachypnea cyanosis
feeding difficulty (reflux, vomiting, feeding refusal) palpitations
diaphoresis syncope
pallor facial edema
dependent edema
ascites
older children and adolescents fatigue palpitations

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effort intolerance chest pain
dyspnea dependent edema
orthopnea
abdominal pain
nausea
vomiting

tion [36]. By determining the systolic time intervals in the inflow


Table 3  The scoring system of CHF in infancy and childhood, modified by
Läer et al. [35]. and outflow tract the Tei-index (TX) can be calculated [9]. In
childhood, a TX  > 0.5 and a ratio of systolic duration to diastolic
Clinical score duration (S/D)  > 1.0 are abnormal [47]. Tissue Doppler measure-
0 1 2 ments for the velocity of the tricuspid (TASPE) and mitral ring
history and the velocity of mitral inflow with the E/A ratio are well ac-
diaphoresis head head and body head and cepted and widely used today. Both are sensitive parameters for
only during exercise body at rest LV – especially diastolic – dysfunction. They have been used to
physical examination predict adverse clinical outcome even in children [40]. At least
breathing normal retractions dyspnea the spherical index has been proven to be a useful measure of
respiratory rate/min
the spherical remodeling of the left ventricle. It can be easily cal-
0–1 years  < 50 50–60  > 60
culated as LV minor axis divided by LV major axis [49].
2–6 years  < 35 35–45  > 45
Cardiac MRI has the advantage of avoiding x-rays. It enables
7–10 years  < 25 25–35  > 35
11–14 years  < 18 18–28  > 28
measuring heart function and assists in the diagnosis of myocar-
heart rate (beats/min) ditis by enhancing contrast media. Its disadvantages are the
0–1 years  < 160 160–170  > 170 costs and the need for sedation/anesthesia in smaller children.
2–6 years  < 105 105–115  > 115
7–10 years  < 90 90–100  > 100 Laboratory:  in the last 10 years the measurement of blood
11–14 years  < 80 80–90  > 90 concentration of natriuretic peptides has been established as
hepatomegaly (liver edge from  < 2 2–3  > 3 obligatory – see below. But also perturbations of electrolytes,
right costal margin)(cm) fluid-balance, acid-base status, renal, liver and thyroid function
have to be cleared and concomitant comorbidities should be
status best, but like the other scoring systems it has no prognos- identified. Lymphocytopenia or hyponatriemia might predict a
tic value. worsened outcome [48].
Diagnostic procedures are directed on the severity of AHF, try to
clear the causes of CHF and do not differ markedly from adult Health status measurement:  in some cases it may be recom-
age [30]. I will restrict the review to newer developments. mended to also measure the subjective health status in order to
Echocardiography is the primary method of imaging. It shows describe the quality of life. The most popular tool is the SF-36. In
structural abnormalities and allows the functional assessment childhood the KINDL-R-Fragebogen of the Robert-Koch-Institute
of the heart. Fractional shortening (FS) from the M-mode and has been proven to be the most meaningful in Germany. In the
ejection fraction (EF) in 2-dimensional planar cuts from 2-D USA, the neurodevelopmental status is usually assessed by the
echo (Simpson-method) in combination with the endsystolic Bayley Scales of infant development and Functional Status II-
and enddiastolic diameters are the most frequently used and Revised Tables [6, 64].
most reproducible parameters. An SF  < 25 % and/or an EF  < 55 %
are currently considered the borderlines for LV systolic dysfunc-

Schmaltz AA. Chronic Congestive Heart Failure …  Klin Padiatr 2015; 227: 3–9
6 Review

Biomarker BNP/NT-proBNP:  The natriuretic peptides are a The immediate goals of treatment are to improve symptoms like
family of structurally similar peptides which induce natriuresis, dyspnoea and/or fatigue and to stabilize the hemodynamic con-
diuresis and vasodilation. They are synthesized as pre-prohor- ditions. The short term benefits must also be accompanied by
mones, and finally cleaved to the N-terminal pro-hormone NT- favorable effects on long term outcomes.
proBNP and the C-terminal biologically active peptide BNP [43]. For medical treatment of adults the big textbooks like Braun-
Both are markers for hemodynamic overload, especially volume wald’s Heart Disease or the ESC guideline [41] give clear recom-
overload [13, 34, 39]. In the course of dilated cardiomyopathy mendations for the various medicinal product groups and cover
they reflect the severity of failure with a significantly positive vasodilators, nesiritide, various inotropic agents, cardiac glyco-
correlation [32, 38]. sides, ACE-inhibitors, β-blocker, aldosterone receptor antago-
NT-proBNP has the advantage that it is more stable in vitro. It nists and diuretics. They are often based on controlled,
has a longer half-life (70 vs. 15 min) and can be collected in randomized studies with several thousands of patients – figures
standard tubes [30]. Ultimately, the choice of assay depends on which we will never reach in pediatrics.
the co-working laboratory. Every kit establishes its own limits of Our therapeutic recommendations for childhood follow patho-
normal [33, 43]. In 2009 four studies using the same methodol- physiological and pharmacological considerations which have
ogy were combined and ●  ▶  Table 4 was calculated [44]. It became been transferred from adulthood to the pediatric age group.
evident that there is a strong age-dependency with high values They also take small studies on individual substances into
in the neonatal age up to 6 000 pg/ml. These were dropping to account [66]. Pharmacological trials in the pediatric age group
100 pg/ml after the age of one year with no statistically signifi- often fail to include enough patients, so they are underpowered
cant difference between male and female. A mean value plus 2 to detect significant differences in survival rates. Additionally,
standard deviations should be used as a discriminator between there are different responses to medications depending on the
healthy and pathological. age of patients, pharmacokinetic/-dynamic characteristics,

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In the adults, there are several studies about natriuretic peptide- underlying causes of CHF and their molecular characteristics.
guided therapy in chronic heart failure. A meta-analysis of 2 686 These may e. g. provoke a different response to β-blockers. This is
patients in 12 randomized trials [56] concludes that the use of pointed out very clearly by Rossano and Shaddy [55]: “Extrapo-
these biomarkers “reduces mortality and HF related hospitaliza- lating evidence from adult patients to children with heart failure
tion in patients with chronic HF”. However it is not the initial may have limited utility. This presents a challenging dilemma
value of BNP/NT-proBNP that has good predictive value for the for the practitioner for deciding to use or not to use...without the
outcome, but the control value after 6 months [45]. In childhood guidance of evidence-based recommendations”.
there are some reports on serial measurements in children with The 3 neurohumoral antagonists – ACE-inhibitor (or angiotensin
dilated cardiomyopathy showing a substantial improvement receptor blockers), the β-blockers and the mineralocorticoid
( = decrease) of NT-proBNP in patients. A serum NT-proBNP level receptor antagonists break the vicious circle described above at
at 3 months above 681 pg/ml (for the Elecsys 2010, Roche Diag- different levels. They are fundamentally important in modifying
nostics) was associated with a more adverse outcome, such as the course of systolic heart failure. Until today there have been
LVFS < 10 % or cardiac death [32]. very few controlled randomized trials evaluating the treatment
of chronic CHF in childhood: Only one trial with enalapril [25]
and 5 prospective trials about β-blockers in chronic congestive
Current treatment heart failure – with different results! [4, 7, 28, 46, 59]. The evalu-
▼ ation of the various drugs below is based on the Canadian guide-
Generally speaking, the aim of therapy is to interrupt the patho- line [30].
physiological responses to the causes of congestive heart failure
(CHF): increased pump demand, decreased O2 supply or 1) Angiotensin-converting enzyme inhibitor and angiotensin
impaired myocardial contractility. These induce neurohormonal II receptor blocker therapy:  2 key randomized controlled tri-
activation with increased neurohormones (noradrenaline, angi- als, CONSENSUS- and SOLVD-trial [12, 62] assigned 2 800 adult
otensin II, vasopressin and aldosterone). These lead to vasocon- patients with mild to severely symptomatic CHF and various
striction, sodium and water retention in the kidney as well as conventional treatments to placebo or enalapril. They showed a
myocyte hypertrophy, dilatation and fibrosis, summarized as 27 % and 16 % reduction of mortality. This reduction of mortality
remodeling of the heart. The result is a circulus vitiosus which and risk of hospitalization combined with improvement of
aggravates heart failure [17, 57]. symptoms, exercise tolerance and performance as well as qual-

Table 4  NT-proBNP levels (pg/ml) of normal infants, children and adolescence from birth to 18 years of age [44].

Age interval n Median (pg/ml) Range (pg/ml) 5 %tile 95 %tile 97.5 %tile


0–2 days 43 3 183 260–13 224 321 11 987 13 222
3–11 daysa 84 2 210 8–7 250 263 5 918 6 502
 > 1mo to  < 1years 50 141 5–1 121 37 646 1 000
 > 1 to  < 2years b 38 129 31–675 39 413 675
 > 2 to  < 6years 81 70 5–391 23 289 327
 > 6 to  < 14 years 278 52 5–391 10 157 242
 > 14 to  < 18 years 116 34 5–363 6 158 207
a No data for patients 12 to 30 days of age
b A significant decrease with age in this interval

Schmaltz AA. Chronic Congestive Heart Failure …  Klin Padiatr 2015; 227: 3–9
Review 7

ity of life is supported by several randomized controlled trials addition to conventional therapy led to a relative reduction of
with more than several 10 000 participants [20, 41]. the risk of death by 30 % (aRR 11.4 %), and of CHF hospitalization
In contrast to that, evidence on pediatric patients is extremely by 35 % in adults. Similar success could be demonstrated with
limited. There are only 3 studies on 8–12 children about the eplerenone in patients with mild heart failure, although associ-
acute hemodynamic effects of ACE-inhibitors on left-to-right- ated with a certain risk of hyperkaliemia and worsening of renal
shunts [36, 38, 63] and 6 observational studies with 12–63 function [70].
patients that found a beneficial effect of ACE-inhibitors used in
addition to conventional therapy on weight gain, respiratory In pediatric patients spironolactone is a common component of
rate, and survival rate after 1 and 2 years. On the other hand, in diuretic regimens due to its potassium-sparing property [8].
the only recent randomized controlled study [27] involving 230 However empirical evidence is very scarce. One study showed
infants with single-ventricle physiology, administration of enal- hyperaldosteronism in 4 infants with CHF [5]. In 2 additional
april did not improve somatic growth, ventricular function, or studies 11 children with CHF and 62 children with a great vari-
severity of heart failure. Apart from this study, there are no other ety of heart diseases were treated with clinical success [22, 31].
randomized controlled clinical trials of ACE inhibitors in infants However, there is absolutely no major trial with clearly defined
and children with heart failure. In summary this is a widely used, end points for judging efficacy and safety. The Canadian guide-
but non-evidence based therapy. Caution is advised for the first 4 line states that “data regarding the role of spironolactone or
months of life, because renal failure is more common. Adequate related agents in the treatment of children with CHF are very
pregnancy avoidance measures are required in adolescent limited” [30].
female patients for teratogenic effects.
4) Diuretics  play a key role in the treatment of patients with
2) β-Blockers:  β-blockade is an established therapy in adults congestion and related symptoms. For a long time the use of

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with CHF. 5 major prospective randomized trials performed in furosemide has been regarded as effective and safe in the pedi-
the nineties with more than 10 000 patients enrolled proved atric age group [16]. But again literature on this special age
clear symptom and survival benefits under β-blockade. The group is very limited. A Cochrane systematic review of diuretic
European Guideline recommends the administration of therapy in adults confirms that they effectively relieve symp-
β-blockers (in combination with ACE-inhibitors) in all patients toms, improve exercise capacity and “appear to reduce the risk
with systolic heart failure [41]. of death and worsening heart failure compared to placebo.... This
For childhood, there is more empirical evidence than for ACE- must be sufficient to justify their routine use in children with
inhibitors: There are at least 7 observational studies, partly CHF” [18].
multi-, partly single center. Without exception they showed an
improvement of clinical scores and echo-parameters. In some 5) Digitalis  has an effect inside the myocyte: Among others it
cases there was also an improvement of humoral parameters. slows down the Na/K-ATPase, improves contractility and dimin-
They covered 6–53 patients (199 patients in total). 5 studies ishes sympathicotonus (for detail see 57). Although it has been
refer to CHF caused by DCM, one refers to Duchenne-patients in clinical use for more than 250 years, the big, double-blinded,
and one to patients with univentricular hearts. randomized, placebo controlled, NIH-sponsored digitalis study
Furthermore, there are 5 prospective randomized controlled in adult patients with ischemic or cardiomyopathic CHF could be
studies [4, 7, 28, 46, 59], partly blinded, partly placebo-control- performed only in the mid-1990s [14]. It has been shown that
led, all dating from this century. The characteristics of the digitalis had a positive effect on left ventricular EF, exercise
patients treated vary widely: cardiomyopathies (n = 40, multi- capacity, quality of life and number of hospitalizations. How-
center; carvedilol – 28), LV-dysfunction before transplantation ever, survival rate in the whole cohort was not significantly
n = 14–4), infants with left-to right-shunt defects (n = 10; pro- improved. In a comprehensive post hoc study from 2006 [1] an
pranolol – 7), older children with operated Fallot’s Tetralogy improvement of survival and hospitalization rate were demon-
(n = 13; bisoprolol – 46 and the biggest multicentre study from strated in a cohort of 1 687 patients with serum digoxin concen-
North-America:106 patients carvedilol, 54 placebo – 59). Sur- trations of 0.5–0.9 ng/ml. The resulting discussion created quite
prisingly, the last 2 studies don’t show any benefit of treatment. a big stir. According to the ESC guideline [41] digoxin “may be
Differences in the etiology, insufficient numbers in the various used” in symptomatic CHF and atrial fibrillation and in patients
groups of patients and subtherapeutic drug-levels were dis- in sinus rhythm with symptomatic HF and a LVEF < 40 %.
cussed as cause for non-efficiency [19, 20]. On the other hand In childhood there are several early clinical observations which
there is a different adaptation of β-adrenergic receptors and demonstrated a good effect on CHF, including an improved con-
adrenergic signaling pathways in children with CHF compared tractility and a slowing of neurohormonal stimulation (for detail
to adults. There are also significant differences in the molecular see 57). On the other side, a recently published study on 48
remodeling. These factors may explain the differences [42]. In infants with CHF secondary to left-to-right shunt lesions who
short, a relevant review of the Cochrane Collaboration about were randomized to treatment with enalapril and furosemid   +  /-
beta-blockers in children (!) summarizes: “There is not enough digoxin could not find any clinical improvement. It concluded
evidence to support the use of β-blockers in children or to pro- that “digoxin does not provide any extra benefit in the treatment
pose a pediatric dosing scheme. The sparse data existing, how- of such patients” [15].This means that the future of digitalis use
ever, indicate that children with CHF might benefit from in children remains uncertain [24]. “No recommendation can be
β-blocker treatment” [19]. made for digitalis use in children with CHF” [30].

3) Aldosterone-antagonists:  Use of aldosterone-antagonists 6) Cardiac resynchronization therapy (CRT):  For patients


is the third possibility to reduce the neurohormonal stimulation with severe symptoms of CHF despite optimized pharmacologi-
in CHF. In the RALES trial [50] treatment with spironolactone in cal therapy multisite pacing offers the possibility to improve

Schmaltz AA. Chronic Congestive Heart Failure …  Klin Padiatr 2015; 227: 3–9
8 Review

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18 Faris RF, Flather M, Purcell H et al. Diuretics for heart failure. Cochrane
Database of Systematic reviews 2012 CD003838
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