Pediatric Cardiac Intensive Care Society 2014
Consensus Statement: Pharmacotherapies in
Cardiac Critical Care Chronic Heart Failure
Joseph W. Rossano, MD1; Antonio G. Cabrera, MD2; John L. Jefferies, MD3;
M.P.H. Maryam Y. Naim, MD1; Timothy Humlicek, PharmD2
Objective: Heart failure is a serious complication that can occur in
patients with a variety of congenital and acquired disorders including
congenital heart disease, cardiomyopathy, and myocarditis. Further-
more, heart failure patients comprise an increasing number of ICU
admissions. Thus, it is important for those caring for patients with
critical cardiovascular disease to have a thorough understanding of
the medications used for the treatment of heart failure. The aim of this
review is to provide an overview, rationale, indications, and adverse
effects of medications used in the treatment of chronic heart failure.
Data Sources: PubMed, Medline, Cochrane Database of Systemic
Reviews.
Study Selection: Studies were selected on their relevance for
pediatric heart failure. When limited data on pediatric heart failure
were available, studies in adult patients were selected.
Data Extraction: Relevant findings from studies were selected by
the authors.
Data Synthesis: The rationale for the efficacy of most heart failure
medications used in pediatric patients is extrapolated from studies
in adult heart failure. Commonly used medications for chronic heart
failure include β-receptor antagonists (e.g., carvedilol and meto-
prolol), and medications aimed at blocking the renin-angiotensin-
aldosterone system (e.g., angiotensin-converting enzyme inhibitors,
angiotensin receptor blockers, aldosterone receptor antagonists).
In addition, diuretics are useful for symptoms of fluid overload. For
1
Cardiac Center, Perelman School of Medicine at the University of
­Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, PA.
2
Division of Cardiology, Department of Pediatric Medicine, Baylor College
of Medicine, Texas Children’s Hospital; Houston, TX.
3
Division of Cardiology, Department of Pediatrics, University of Cincin-
nati College of Medicine, Cincinnati Children’s Hospital Medical Center,
­Cincinnati, OH.
Dr. Cabrera disclosed off-label product use: angiotensin-converting
enzyme inhibitors β-blockers inotropes including levosimendan. Dr.
­Humlicek disclosed off-label product use: the pharmacotherapy dis-
cussed in the article includes medications not specifically labeled for the
patient population discussed. The remaining authors have disclosed that
they do not have any potential conflicts of interest.
For information regarding this article, E-mail: rossanoj@email.chop.edu
Copyright © 2016 by the Society of Critical Care Medicine and the World
Federation of Pediatric Intensive and Critical Care Societies
DOI: 10.1097/PCC.0000000000000624
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patients with impaired perfusion, inotropic agents are useful acutely,
but may be associated with worse outcomes when used chronically.
Newer medications that have been recently approved in adults (e.g.,
serelaxin, ivabradine, and neprilysin inhibitor [angiotensin receptor
blocker]) may prove to be important in pediatric heart failure.
Conclusions: Heart failure patients are in an important popula-
tion of critically ill children. The pharmacologic approach to these
patients is aimed at treating symptoms of congestion and/or poor
perfusion and improving long-term outcomes. (Pediatr Crit Care
Med 2016; 17:S20–S34)
Key Words: angiotensin-converting enzyme inhibitor; digoxin;
diuretic; heart failure; inotropes; natriuretic peptides
H
eart failure is serious complication that can occur in
patients with a variety of congenital and acquired disor-
ders including congenital heart disease, cardiomyopathy,
and myocarditis. In the United States, there were approximately
14,000 heart failure–related hospitalizations in 2006, many of
whom require intensive care management (1, 2). It is important
for those caring for patients with critical cardiovascular disease to
have a thorough understanding of the medications used for the
treatment of heart failure. The authors of this consensus state-
ment performed an extensive review of the current literature and
present those findings along side expert opinion from heart fail-
ure physicians and pharmacologists. Table 1 represents the sum-
mary of the pharmacologic therapies outlined in the article.
ANGIOTENSIN-CONVERTING ENZYME
INHIBITORS, ANGIOTENSIN RECEPTOR
BLOCKERS, ALDOSTERONE RECEPTOR
ANTAGONISTS
Angiotensin-converting enzyme (ACE) inhibitors decrease
the formation of angiotensin II, block the activation of the
renin-angiotensin-aldosterone system, and decrease adrenergic
­activity (3). Multiple, prospective randomized controlled trails
of various agents within this class have demonstrated improve-
ment in symptoms with reduced progression of heart failure,

decreased hospitalization, and improved survival in adults
(4–9). Angiotensin receptor blockers (ARBs), primarily used in
adults who are not tolerant of ACE inhibitors, have also dem-
onstrated an improvement in mortality that is comparable, and
possibly superior to ACE inhibitors (10). The use of aldosterone
receptor antagonists, such as spironolactone and eplerenone, is
also associated with improved mortality as add-on therapy to
patients treated with β-blockers and ACE inhibitors (11, 12).
There have been no large randomized controlled trials of
these medications in pediatric heart failure (13–15). A small,
randomized trial on boys with Duchenne muscular dystrophy
demonstrated a similar improvement in ejection fraction with
lisinopirl compared with losartan (16). Several other studies
in patients with Duchenne muscular dystrophy have dem-
onstrated that ACE inhibitors and ACE inhibitors along with
β-blockers result in improved echocardiographic parameters
and possibly survival (17–19). Although strong data for the
benefit of these medications in pediatric heart failure are lack-
ing (20), they are commonly used and recommended by con-
sensus guidelines (21, 22).
β-RECEPTOR ANTAGONISTS
The safety and efficacy of β-blockers in adults with heart fail-
ure have been established through large randomized trials with
generally beneficial findings of reduced symptoms, morbidity,
and mortality. Trials investigating β-antagonists such as biso-
prolol (23, 24), carvedilol (25–27), metoprolol (27, 28), and
nebivolol (29) have led to these members of this class of medi-
cation to be recommended as a part of the treatment of heart
failure in adults (30–32).
However, conditions that can commonly lead to heart fail-
ure in adults such as coronary artery disease, uncontrolled
hypertension, valvular defects, arrhythmias, or myocardial
infarction are different from the common etiologies of heart
failure in children, which include congenital heart defects and
cardiomyopathy (33, 34). Partially due to differences in the eti-
ology of heart failure in adults from children, the efficacy of
β-antagonists remains to be fully elucidated (35). There is evi-
dence that suggests that similar mechanisms can be influenced
through adrenergic antagonism in both adults and children
with heart failure.
β-antagonists are thought to exert their action by reduc-
ing the impact of prolonged neurohormonal activation (36).
Neurohormonal overstimulation is pathophysiological pro-
cess induced by decreased cardiac output and baroreceptor
signaling, which results in adrenal medullary catecholamine
release and activation of the renin-angiotension aldoste-
rone system (37). The release of these chemical messengers,
referred to as “neurohormones,” contributes to myocardial
apoptosis, fibrosis, and progressive worsening of cardiac
output. The concentration of various neurohormones, such
as epinephrine (38), norepinephrine (38, 39), renin (40),
vasopressin (41), atrial natriuretic peptide (42), brain natri-
uretic peptide (43), and endothelin-1 (44), has been shown
to be increased in children with heart failure and potentially
associated with functional status. β-antagonists can impact
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the neurohormonal pathway directly by reducing systemic
catecholamines in patients with heart failure (36). Further
benefits based on the numerous pharmacodynamic prop-
erties of β-blockers can result in improved left ventricu-
lar systolic and diastolic function through afterload and
preload reductions, heart rate control, and prevention of
arrhythmias.
In children with heart failure, carvedilol and metoprolol
have been the most widely studied β-blockers. The largest
trial to date with β-antagonists in pediatric heart failure was
conducted by Shaddy et al (45) and included 161 children and
adolescents with heart failure due to cardiomyopathy or con-
genital heart disease. Although not powered to show a survival
difference versus placebo, there were several trends in ventricu-
lar remodeling and neurohormonal parameters that may favor
the intervention group, especially in patients with a systemic
left ventricle. Although functional status did not improve over
placebo in all patients, several previous analyses have suggested
improvements in symptoms (46–48) and ejection fraction (49,
50). β-antagonists may also attenuate the risk of sudden death
in heart failure by reducing arrhythmias and have demon-
strated that they have favorable effects in improving electro-
physiological risk factors (51, 52).
There are several possibilities for the discrepant findings for
β-antagonists when compared between children and adults.
As stated above, the etiology of heart failure is characteristi-
cally different. Another difference may be the influence of
different pharmacokinetic and pharmacodynamic properties
of β-antagonists between children and adults. Studies that
have measured systemic exposure to carvedilol have indi-
cated that pediatric patients have increased clearance and
may require higher doses relative to body weight or more
frequent administration to achieve comparable exposure to
adults (48, 53). Finally, β-adrenergic receptor expression and
adaptation may also be distinct when compared with adults.
Children may have higher absolute expression of maladap-
tive β1 receptors and reduced preservation of β2-adrenergic
receptors, which may play a cardioprotective role in heart fail-
ure (54–57). These differences tender more consideration to
whether β-antagonists should be titrated to a target dose or
with another measure. With the findings of published trials
and ongoing research attempting understanding the effects of
these agents, β-antagonists will continue to play a significant
role in the treatment of pediatric heart failure.
DIGOXIN
Digoxin has a variety of physiologic actions that are medi-
ated through inhibition of Na-K ATPase. Although not cur-
rently used as a first-line therapy in the management of heart
failure, digoxin has a class IIa recommendation to potentially
decrease heart failure–related admissions in adult patients
with reduced left ventricular ejection fraction unless other-
wise contraindicated (58). The current recommendations
are based on results from the Digitalis Investigation Group
study that showed no mortality benefit over placebo, but
 Rossano et al

Table 1. Medications Used for the Management of Heart Failure

Medication Typical Dosing Absorption Metabolism

Angiotensin-converting enzyme inhibitors

 Captopril Children: 60–75% 50% Hepatic via
CYP2D6
Oral: 0.3–2.5 mg/kg/d divided every 8–12 hr
in infants and 0.3–6 mg/kg/d divided every
8–12 hr in children and adolescents
Adults:
Oral: 6.25 mg three times daily up to 50 mg
three times daily
 Enalapril Children: 55–75% Hepatic to active enalaprilat
Oral: 0.1–0.5 mg/kg/d divided every 12 hr
IV (as enalaprilat): 5–10 μg/kg/dose every 8–24 hr
Adults:
Oral: 2.5 mg twice daily ≤ 10–20 mg twice daily
IV (as enalaprilat): 0.625–1.25 mg/dose every 6 hr

 Lisinopril Children: Pediatrics: None

20–36%
Oral: initial: 0.07–0.1 mg/kg/dose once
daily ≤ 0.5–0.6 mg/kg/d Adults: 25%
(6–60%)
Adults:
Oral: initial: 2.5–5 mg once daily ≤ 20–40 mg
once daily
 Perindopril Adults: 75% Hepatic to active
metabolite, perindoprilat
Oral: initial 2 mg once daily ≤ 8–16 mg (17–20%) and inactive
once daily
 Ramipril Children: 50–60% Hepatic to active metabolite
Oral: 2–6 mg/m2 daily ≤ 10 mg daily
Adults:
Oral: 1.25–2.5 mg once daily ≤ 10 mg
once daily
Angiotensin-II receptor antagonists
 Losartan Children: 25–35% Hepatic via CYP2C9
and CYP3A4 to active
Oral: initial: 0.5 mg/kg once daily not to exceed metabolite
12.5–25 mg once daily. Up to 1.4 mg/kg once
daily not to exceed 150 mg/d
Adults:
Oral: 12.5–50 mg once daily ≤ 150 mg
 Valsartan Children (hypertension): 25 (10–35)% Minimally hepatic to inactive
metabolite
Oral: 1–5 yr: 0.4–3.4 mg/kg once daily; 6–16 yr:
initial: 1.3 mg/kg/dose once daily
≤ 2.7 mg/kg/dose once daily
Adults:
Oral: initial: 40 mg twice daily ≤ 80–160 mg
twice daily

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 Supplement

Half-Life Elimination Adverse Effects

Infants: 3.3 hr Urine (> 95%) Hypotension, dizziness, headache, rash,

hyperkalemia, cough, angioedema
Children: 1–2.3 hr
Increase in serum blood urea nitrogen, serum
Adults: 1.9–2.1 hr creatinine

Enalapril: Urine (60–80%)

Neonates: 10.3 hr Fecal
Infants and children: 2.7 (1.3–6.3) hr
Adults: 3.4–5.8 hr
Enalaprilat:
Neonates: 11.9 (5.9–15.6) hr
Infants and children: 11.1 (5.1–20.8) hr
Adults: 35–38 hr
11–13 hr Urine (unchanged)

Perindopril: 1.5–3 hr Urine (75%)

Perindoprilat: 3–10 hr

Ramiprilat: 13–17 hr Urine (60%)

Fecal (40%)

1.5–2 hr; active metabolite: 6–9 hr Feces Hypotension, dizziness, headache, hyperkalemia,

hypoglycemia, diarrhea
Urine (4% unchanged, 6%
metabolites) Increase in serum blood urea nitrogen, serum
creatinine

Children: 4–5 hr Feces (83%) and urine (13%)

primarily unchanged
Adults: 6 hr

(Continued )

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 Rossano et al

Table 1. (Continued ). Medications Used for the Management of Heart Failure

Medication Typical Dosing Absorption Metabolism

Mineralocorticoid (aldosterone) receptor antagonists

 Spironolactone Children: 73% Hepatic to active and
inactive metabolites
Oral: initial 1 mg/kg/d in divided doses every
6–24 hr ≤ 12.5 to 25 mg/d
Maximum: 3.3–6 mg/kg/d divided every 6–24 hr
not to exceed 100 mg/d
Adults:
Oral: initial 12.5–25 mg/d ≤ 50 mg. For edema,
≤ 200 mg/d in 1–2 divided doses have been used
 Eplerenone Adults: 69% Hepatic via CYP3A4 to
inactive metabolites
Oral: initial: 25 mg once daily or every other day
depending on estimated GFR and potassium
Maximum: 25–50 mg once daily depending on
estimated GFR and presence of mild to moderate
CYP3A4 inhibitors
β-adrenergic blocking agents
 Bisoprolol Adults: 80% Hepatic via CYP3A4 and
CYP2D6
Oral: > 50 kg: 1.25 mg once daily
Maximum: 10 mg once daily
 Metoprolol Children: Immediate Hepatic via CYP2D6
release: 40–50%
Oral: initial: 0.1–0.25 mg/kg/dose twice daily; not
to exceed 12.5–25 mg up to a maximum daily dose Extended
of 1–2 mg/kg/dose twice daily; not to exceed release: 77% of
100 mg twice daily corresponding
immediate
Adults: release dose
Extended release (initial): 12.5–25 mg once daily ≤
200 mg daily
 Carvedilol Children: Immediate Hepatic via CYP2C9, 2D6,
release: 25–35% 3A4, 2C19, 1A2, and
Oral: initial: 0.1 mg/kg/d divided twice daily not to 2E1 to three active
exceed 3.125 mg up to a maximum daily dose of Extended metabolites
0.8–1 mg/kg/d divided twice daily; not to exceed release: 85%
25 mg twice daily of immediate
release dose
Adults:
Oral: initial: 3.125 mg twice daily up to 25 mg twice daily
(in patients < 85 kg); maximum 50 mg twice daily
(patients > 85 kg)
Loop diuretics
 Bumetanide Children 80% Partially hepatic
(59–89%)
IV, intramuscular, or oral: 0.015–0.1 mg/kg/dose every
6–24 hr
Adults
Oral: 0.5 – 2 mg/dose every 12 – 24 hr
IV, intramuscular: 0.5–1 mg/dose
Continuous IV infusion: 0.5–2 mg/hr

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 Supplement

Half-Life Elimination Adverse Effects

1.4 hr; active metabolites: 12–20 hr Urine and feces Diarrhea, nausea, vomiting, dizziness, hyperkalemia,
gynecomastia

4–6 hr Urine (67%) and feces (32%) Diarrhea, dizziness, hyperkalemia

9–12 hr; 27–36 hr in renal impairment Urine (50% unchanged) Bradyarrhythmias, hypotension, headache,
dizziness, fatigue
8–22 hr in cirrhosis Feces (< 2%)

3–4 hr (7–9 hr in poor CYP2D6 metabolizers) Urine (10% unchanged)

7–10 hr Feces

Neonates: 6 hr Urine (81%, 45% unchanged) Hyperuricemia, hypomagnesemia, hyponatremia,

hypokalemia, metabolic alkalosis
Infants: 2.4 hr Feces (< 2%)
Adults: 1–1.5 hr

(Continued )

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 Rossano et al

Table 1. (Continued ). Medications Used for the Management of Heart Failure

Medication Typical Dosing Absorption Metabolism

  Ethacrynic acid Children: Hepatic (35–40%) to

active cysteine conjugate
Oral: 0.5–1 mg/kg/dose every 6–12 hr
IV: 1–2 mg/kg/dose every 8–12 hr
Adults:
Oral: 25–400 mg/d divided 1–2 doses
IV: 0.5–1 mg/kg/dose every 8–12 hr
 Furosemide Children: 47–64% Minimally hepatic
Oral: 1–2 mg/kg/dose every 6–24 hr
IV, intramuscular: 0.5–2 mg/kg/dose every 6–24 hr
Continuous IV infusion: 0.1–0.4 mg/kg/hr as a
continuous infusion
Adults:
Oral: 20–80 mg/dose every 6–24 hr (maximum daily
dose: 600 mg)
IV, intramuscular: 20–40 mg/dose every 6–24 hr
(maximum dose: 200 mg)
Continuous IV infusion: 10–40 mg/hr
≤ 80–160 mg/hr
 Torsemide Adults: 80% Hepatic (80%) via
CYP2C9, CYP2C8
IV, oral: 10–20 mg once daily (maximum dose: 200 mg)
Continuous IV infusion:
5–20 mg/hr
Thiazide and thiazide-like diuretics
 Chlorothiazide Children: 9–56% None
Oral: 10–40 mg/kg/d in divided doses every 12 hr
IV: 4–10 mg/kg/d divided every 12–24 hr (maximum
20 mg/kg/d or 500 mg)
Adults:
Oral: 250–1,000 mg/d divided in 1–2 doses
IV: 500–1000 mg once or twice daily
 Hydrochlorothiazide Children 50–80% None
Oral: 1–4 mg/kg/d in divided doses every 12–24 hr
Adults:25–100 mg/d in divided doses every 12–24 hr
 Metolazone Children: 40–65% None
oral: 0.2–0.4 mg/kg/d divided every 12–24 hr
Adults:
2.5–20 mg/dose every 24 hr
Cardiotonic agents
 Digoxin Children: 60–85% Minimally hepatic and
via intestinal enzymes
Oral: 5–15 mcg/kg/d divided every 12 hr
to active and inactive
IV: 4–12 mcg/kg/d divided every 12 hr metabolites
Adults:
Oral: initial 0.125–0.25 mg once daily
≤ 0.375–0.5 mg daily

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 Supplement

Half-Life Elimination Adverse Effects

2–4 hr Feces
Urine (30–60% unchanged)

0.5–2 hr; 9 hr in end-stage renal disease Urine (oral: 50%, IV: 80%)
Feces

3.5 hr; Urine (20% unchanged)

7–8 hr in cirrhosis

45–120 min Urine (oral: 10–15% Hyperuricemia, hypomagnesemia, hyponatremia,

unchanged; IV: 96% hypokalemia
unchanged)

6–15 hr Urine (unchanged)

6–20 hr Urine (70–95% unchanged)

Infants: 18–25 hr Urine (50–70% Nausea and vomiting

Unchanged
Children: 35 hr Dizziness, headache, dysrhythmias
Adults: 36–48 hr
Anuric Adults: 3.5–5 d

(Continued )
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 Rossano et al

Table 1. (Continued ). Medications Used for the Management of Heart Failure

Medication Typical Dosing Absorption Metabolism

 Milrinone Children: Hepatic (12%)

Continuous IV infusion: 0.25–0.75 mcg/kg/min
Adults:
Continuous IV infusion: 0.125–0.75 mcg/kg/min
 Levosimendan Adults: 85% Hepatic (extent unknown)
Continuous IV infusion: n-acetyltransferase to
6–12 μg/kg loading dose +0.1–0.2 μg/kg/min active metabolite, OR-
1896
β-adrenergic agonists
 Dobutamine Continuous IV infusion: Plasma, hepatic to inactive
metabolites
2–20 μg/kg/min
 Dopamine Continuous IV infusion: Plasma, hepatic, and
renal to inactive
1–20 μg/kg/min
metabolites (75%) and
norepinephrine (25%)
 Epinephrine Cardiac arrest: Hepatic, tissues via COMT
and monoamine oxidase
Children:
IV bolus: 0.01 mg/kg every 3–5 min
Adolescents/adults:
IV 1 mg every 3–5 min
Low cardiac output:
Children:
Continuous IV infusion: 0.01–1 μg/kg/min
Adults:
Continuous IV infusion:
0.1–0.5 μg/kg/min
 Norepinephrine Children: Hepatic, tissues via COMT
and monoamine oxidase
Continuous IV infusion: 0.05–0.3 μg/kg/min
(maximum dose: 2 μg/kg/min)
Adults:
0.1–0.5 μg/kg/min
Vasodilating agents
 Nitroprusside 0.3–4 μg/kg/min; maximum: 6 μg/kg/min for neonates, Combines with hemoglobin
12 μg/kg/min for children and produces cyanide
and cyanmethemoglobin
Cyanide conversion to
thiocyanate by rhodanese
 Nitroglycerin Continuous IV infusion: 0.25–5 μg/kg/min Hepatic (12%)
 Nesiritide Continuous I.V. Infusion: 0.01 μg/kg/min; if necessary, Vascular endopeptidases
titrate by 0.005 μg/kg/min every 3 hr to maximum of and cellular
0.03 μg/kg/min internalization
GFR = glomerular filtration rate, COMT = catechol-o-methyltransferase.

did document a reduction in overall hospitalizations and considered when using digoxin. Serum levels of 0.5–0.9 ng/
heart failure–related hospitalizations (59). Careful atten- mL are typically targeted for optimal benefit (60). Digoxin
tion to dosing and concomitant renal dysfunction must be should be used with caution in patients receiving drugs that

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 Supplement

Half-Life Elimination Adverse Effects

Infants: 3.15 ± 2 hr Urine (83% unchanged) Hypotension, ventricular arrhythmias, headache

Children: 1.86 ± 2 hr
Adults (congestive heart failure): 2.3–2.4 hr

1 hr Urine Hypotension, tachyarrhythmias, nausea, headache

OR-1896: 80 hr Feces

2 min Urine Tachyarrhythmias

2 min Urine Hypertension, tachyarrhythmias

< 2 min Urine (84–96%) Tachyarrhythmias

< 2 min Urine Hypertension

2 min Urine (as thiocyanate) Hypotension, tachyarrhythmias, bradyarrhythmias,

methemoglobinemia
Thiocyanate: 3 d

2.5 hr Urine (85%) Hypotension, flushing, dizziness, headache

60 min Urine (minimal) Hypotension, serum creatinine increased

can affect sinoatrial or atrioventricular nodal function or DIURETICS

therapies that may alter digoxin levels including amiodarone Diuretics should be considered as a first-line therapy for patients
and/or β-blockers. with evidence of volume overload, unless contraindicated, to

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 Rossano et al
improve symptoms. This is a current class I indication in adult
heart failure management (58). Loop diuretics such as furose-
mide, torsemide, and bumetanide act at the loop of Henle and
are the preferred diuretic for use in most patients with heart
failure. Alternatively, thiazide diuretics such as metolazone that
act in the distal portion of the tubule may be used. Furosemide
is the typical loop diuretic used in heart failure management
and has been shown to increase sodium excretion and decrease
symptoms of congestion. Although strategies for optimal dos-
ing and delivery of furosemide have been debated, Felker et al
(61) found no significant differences in patient symptoms or
changes in renal function when furosemide was administered
by bolus versus continuous infusion or at high dose versus low
dose.
Diuretics should be considered in all patients with evidence
of fluid overload and in many with a history of volume over-
load. Although furosemide is commonly used, alternative loop
diuretics such as torsemide may be considered in patients who
are not responding well given the increased oral bioavailability
of torsemide (62). Diuretic resistance may develop, especially
in patients who have underlying renal dysfunction or hypo-
perfusion. This can typically be overcome by the use of IV
diuretics or by combination diuretic therapy such as combin-
ing a loop and thiazide diuretic. The potential side effects of
diuretic therapy are well documented and include electrolyte
derangements, fluid depletion, hypotension, and azotemia.
Appropriate monitoring is recommended for patients receiv-
ing diuretic therapy in the both acute and chronic settings
with correction of electrolytes and/or reduction in dosing as
needed.
INOTROPIC AGENTS
Inotropic agents are commonly used in heart failure, in the
both acute and chronic settings. However, it should be noted
that these agents are recommended for patients with evidence
if impaired perfusion (32). For patients with preserved perfu-
sion but symptoms of congestion, inotropic agents are not nec-
essary and may be harmful (2, 63, 64).
DOPAMINE
Dopamine is a synthetic precursor to norepinephrine. There is
ample evidence that dopamine is effective in treating hypoten-
sion in premature infants with and without cardiac disease (65).
In general, at doses less than 3 µg/kg/min, dopamine has been
shown to activate D1 receptors and produce vasodilatation
of the renal arteries. Controversy exists about this effect given
that there is evidence that this low dose does not improve glo-
merular filtration rate. In the Renal Optimization Strategies
Evaluation in Acute Heart Failure (ROSE AHF) trial neither
low-dose dopamine nor nesiritide was better than placebo
(66). Doses of 3–10 µg/kg/min have been found to activate
β1-adrenergic receptors in the myocardium-increasing inotropy
and heart rate with additional promotion of norepinephrine
release and inhibition of its reuptake. At higher doses (10–20
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µg/kg/min), there is a significant systemic vascular resistance
increase through activation of α-adrenergic receptors (67).
Dopamine can be started in the intensive care and
optimized for chronic inotropic use. Price et al (68) reported
on a series of seven children with advance heart failure, three
receiving dopamine at 2–3 μg/kg/min alone or in combina-
tion with milrinone, that the medication was well-tolerated,
increased ejection fraction, decreased heart failure symptoms,
and reduced readmissions after starting therapy.
DOBUTAMINE
Dobutamine is a synthetic catecholamine that acts primarily
on the β1 receptors in the myocardium and produces vaso-
dilatation by its actions on β2-receptors and a relatively small
α1-mediated vasoconstriction through the opposing effects
of its two enantiomers (69). It should be used with caution
in patients with significant hypotension. Similar to other β1-
agonists, patients can develop tolerance and tachyphylaxis that
makes continuous infusions problematic. In patients who are
receiving β-receptor antagonists and infusion of dobutamine
may result in peripheral vasoconstriction through the abroga-
tion of β2-receptor–mediated vasodilatation (70). When used
in neonates with myocardial dysfunction for a short period
(20 min), dobutamine increased flow in cerebral, mesenteric,
and renal arteries (71). Dobutamine is a commonly used ino-
trope in adults with advanced heart failure and adults with
severe heart failure and ventricular dysfunction to ascertain
contractile reserve when considering transplantation or inten-
sive medical treatment (72). Scarce data exist about the con-
tinuation of dobutamine-based inotropic home therapy. Berg
et al (73) supported three patients with low-dose dobutamine
alone or in combination with milrinone.
Inotropic agents have been associated with increased mor-
tality in adults with acutely decompensated heart failure.
The mechanisms implicated on this effect have been associ-
ated with increased oxygen consumption by the myocardium
and increased tachycardia. These medications should be used,
in general, for a trial period to improve hemodynamics and
further optimize patients for potential mechanical support
alternatives
MILRINONE
Milrinone is commonly used for inpatient therapy of patients
with chronic heart failure. Milrinone is a phosphodiesterase
inhibitor that inhibits myocardial and vascular phosphodies-
terase activity resulting in improved myocardial contractility,
increased lusitropy of the myocardium during diastole, and
afterload reduction from vasodilation.
In IV form, its onset of action is within 5–15 minutes, with
a volume of distribution of 0.32–0.45 L/kg. Seventy percent of
milrinone is bound to plasma protein and is metabolized in
the liver (12%) with a half-life with normal renal function of
approximately 2.5 hours, which is prolonged in patients with
renal failure and in patients on continuous venovenous hemo-
filtration (74). It is excreted in the urine (85% as unchanged

drug) within 24 hours; active tubular secretion is a major elim-
ination pathway for milrinone.
Although milrinone is commonly used in children with acute
and chronic heart failure, to date there are no published random-
ized trials testing IV milrinone therapy in children with chronic
or acute heart failure. In the Prophylactic intravenous use of
milrinone after cardiac operation in pediatrics study of post-
operative low cardiac output in children, there was a significant
reduction in the prevalence of low cardiac output syndrome in
children who received high-dose milrinone (75-μg/kg bolus fol-
lowed by a 0.75 μg/kg/min infusion for 35 hr) (75). Milrinone has
been well studied in adults with heart failure. In the Short-term
intravenous milirnone for acute exacerbation of chronic heart
failure (64) study, adults with acute decompensated heart failure
were randomized at hospital admission to placebo versus milri-
none. There was no benefit of milrinone therapy, an increased
prevalence of hypotension and atrial arrhythmias, and a non-
significant increase in in-hospital death. In the ADHERE (76)
study of adults with acute decompensated heart failure patients
who received inotrope (milrinone or dobutamine) had a higher
in-hospital mortality than patients who received treatment with
a natriuretic peptide (nesiritide) or vasodilator (nitroglycerine).
Milrinone, similar to other inotropes such as catecholamines,
increases cytosolic calcium concentration, increases myocardial
oxygen consumption, and have no favorable remodeling effects,
making its physiologically not the ideal agent for patients with
heart failure and adequate perfusion (77).
NATRIURETIC PEPTIDES
Nesiritide, the recombinant form of the 32 amino acids of the
human B-type natriuretic peptide, has been shown to reduce
left ventricular filling pressures and has variable effects on
sodium and water excretion as well as cardiac output. The drug
is administered in a continuous IV form and is currently has
a class IIb indication in the adult heart failure guidelines as an
adjuvant to diuretic therapy for the treatment of dyspnea in
patients admitted for acute decompensated heart failure (58).
The safety profile of nesiritide was studied in the Acute study
of clinical effectiveness of nesiritde in decompensated heart
failure study that documented that the drug was not associated
with either an increase or a decrease in the rate of hospitaliza-
tion for heart failure or death (78). Although the drug did not
worsen renal function, the findings concluded that the drug
should not be routinely used for the treatment of decompen-
sated heart failure. Several reports of nesiritide use in pediatric
patients have documented relative safety and potential efficacy
of the drug, but no randomized data in children exist (79–81).
LEVOSIMENDAN
Levosimendan is a calcium-sensitizing agent that has a unique
dual activity. It improves myocardial contractility by increasing
cardiac troponin C calcium sensitivity, without increasing myo-
cardial oxygen consumption. In addition, it provides additional
peripheral and coronary vasodilatory effects by facilitation of
potassium channel opening leading to afterload reduction.
Pediatric Critical Care Medicine www.pccmjournal.org S31
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Levosimendan has a lusitropic effect by not eliciting an increase
in intracellular calcium-preserving diastolic relaxation.
On infusion of levosimendan it is extensively metabolized,
with a half-life of about 1 hour. Ninety-eight percent of levo-
simendan bound to plasma proteins, mainly albumin, but the
active metabolites have much lower protein binding of about
40%. Its active metabolites OR-1855 and OR-1896 are inter-
converted by acetylation and de-acetylation and have half-lives
of about 75 to 80 hours, producing a prolonged duration of
action. Metabolites and a small amount of unchanged drug
are excreted in urine and feces. More than 95% of a dose is
excreted within 1 week.
Like milrinone, the majority of data supporting the use of
levosimendan come from adult heart failure studies. In the
Levosimendan Infusion versus Dobutamine (LIDO) study of
adults with cardiogenic shock, levosimendan was superior to
dobutamine in reducing pulmonary artery occlusion pressure
and decreased mortality at 6 months (82). However, in the
Levosimendan vs Dobutamine for patients with acute decom-
pensated heart trial where these two agents were compared
with acute decompensated heart failure in adults, there was no
differences between groups in terms of symptomatic relief of
heart failure, death or days out of the hospital (83). In the more
recent REVIVE trial in adults with acute decompensated heart
failure, although levosimendan had rapid and durable symp-
tom relief, there was a greater risk of hypotension and cardiac
arrhythmias in the levosimendan group than in the placebo
group giving rise to concerns about safety of levosemendan
(84). In a preliminary small study of 15 children in Australia
with acute and chronic heart failure, levosimendan was safe,
decreased catecholamine requirements, and improved myo-
cardial performance (85). A subsequent study from the same
group in nine children with severe decompensated heart fail-
ure received a “rotating inotrope” regimen that included levo-
simendan, dobutamine, and in some cases milrinone, using
levosimendan was safe, and this regimen allowed some patients
to be weaned from positive pressure ventilation, get discharged
from ICU and hospital, and successfully bridged to transplan-
tation (86). However, levosimendan is currently not Food and
Drug Administration approved for use in the United States.
PROMISING NEW THERAPIES
There are no medications that are known to improve out-
comes for acute heart failure. Serelaxin, recombinant human
relaxin-2, is a naturally occurring peptide involved with mater-
nal adaptations to pregnancy. It can improve cardiac output as
well as increase renal blood flow and arterial compliance (87).
In a large, randomized trial of the serelaxin versus placebo in
adults with acute heart failure, the use of serelaxin was asso-
ciated with improved dyspnea score and decreased death at
180 days (87). The Food and Drug Administration, however,
did not approve serelaxin for use in the United States and rec-
ommended further studies of the drug’s efficacy.
There are several promising medications for chronic heart
failure. A chronically elevated baseline heart rate is a risk
factor for mortality among adults. Ivabradine, an If current
 Rossano et al
inhibitor in the sinoatrial node, was studied in adults with
chronic heart failure. The use of ivabradine was associated
with fewer heart failure hospitalizations and deaths from heart
failure (88). More recently, the combination mediation of a
neprilysin inhibitor and ARB (valsartan) was compared with
enalapril in a large, prospective, randomized trial. Neprilysin
is a neutral endopeptidase involved with degradation of natri-
uretic peptides, bradykinin, and adrenomedullin. Inhibition
of neprilysin can result in decreased vasoconstriction, sodium
retention, and remodeling. The trial was stopped early because
of significantly improved mortality, risk of hospitalization,
and improved symptoms among patients receiving the nepri-
lysin inhibitor—ARB combination (89). Further study will be
needed to determine the role, if any, these medications may
play in improving the outcomes of children with heart failure.
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