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 impaired perfusion, inotropic agents are useful acutely,
patients with a variety of congenital and acquired disorders including but may be associated with worse outcomes when used chronically.
congenital heart disease, cardiomyopathy, and myocarditis. Further- Newer medications that have been recently approved in adults (e.g.,
more, heart failure patients comprise an increasing number of ICU serelaxin, ivabradine, and neprilysin inhibitor [angiotensin receptor
admissions. Thus, it is important for those caring for patients with blocker]) may prove to be important in pediatric heart failure.
critical cardiovascular disease to have a thorough understanding of Conclusions: Heart failure patients are in an important popula-
the medications used for the treatment of heart failure. The aim of this tion of critically ill children. The pharmacologic approach to these
review is to provide an overview, rationale, indications, and adverse patients is aimed at treating symptoms of congestion and/or poor
effects of medications used in the treatment of chronic heart failure. perfusion and improving long-term outcomes. (Pediatr Crit Care
Data Sources: PubMed, Medline, Cochrane Database of Systemic Med 2016; 17:S20–S34)
Reviews. Key Words: angiotensin-converting enzyme inhibitor; digoxin;
Study Selection: Studies were selected on their relevance for diuretic; heart failure; inotropes; natriuretic peptides
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

H
the authors. eart failure is serious complication that can occur in
Data Synthesis: The rationale for the efficacy of most heart failure patients with a variety of congenital and acquired disor-
medications used in pediatric patients is extrapolated from studies ders including congenital heart disease, cardiomyopathy,
in adult heart failure. Commonly used medications for chronic heart and myocarditis. In the United States, there were approximately
failure include β-receptor antagonists (e.g., carvedilol and meto- 14,000 heart failure–related hospitalizations in 2006, many of
prolol), and medications aimed at blocking the renin-angiotensin- whom require intensive care management (1, 2). It is important
aldosterone system (e.g., angiotensin-converting enzyme inhibitors, for those caring for patients with critical cardiovascular disease to
angiotensin receptor blockers, aldosterone receptor antagonists). have a thorough understanding of the medications used for the
In addition, diuretics are useful for symptoms of fluid overload. For treatment of heart failure. The authors of this consensus state-
ment performed an extensive review of the current literature and
1
Cardiac Center, Perelman School of Medicine at the University of present those findings along side expert opinion from heart fail-
­Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, PA. ure physicians and pharmacologists. Table 1 represents the sum-
2
Division of Cardiology, Department of Pediatric Medicine, Baylor College mary of the pharmacologic therapies outlined in the article.
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, ANGIOTENSIN-CONVERTING ENZYME
­Cincinnati, OH.
INHIBITORS, ANGIOTENSIN RECEPTOR
Dr. Cabrera disclosed off-label product use: angiotensin-converting
enzyme inhibitors β-blockers inotropes including levosimendan. Dr. BLOCKERS, ALDOSTERONE RECEPTOR
­Humlicek disclosed off-label product use: the pharmacotherapy dis- ANTAGONISTS
cussed in the article includes medications not specifically labeled for the Angiotensin-converting enzyme (ACE) inhibitors decrease
patient population discussed. The remaining authors have disclosed that
they do not have any potential conflicts of interest. the formation of angiotensin II, block the activation of the
For information regarding this article, E-mail: [email protected] renin-angiotensin-aldosterone system, and decrease adrenergic
Copyright © 2016 by the Society of Critical Care Medicine and the World ­activity (3). Multiple, prospective randomized controlled trails
Federation of Pediatric Intensive and Critical Care Societies of various agents within this class have demonstrated improve-
DOI: 10.1097/PCC.0000000000000624 ment in symptoms with reduced progression of heart failure,

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 Supplement

decreased hospitalization, and improved survival in adults the neurohormonal pathway directly by reducing systemic
(4–9). Angiotensin receptor blockers (ARBs), primarily used in catecholamines in patients with heart failure (36). Further
adults who are not tolerant of ACE inhibitors, have also dem- benefits based on the numerous pharmacodynamic prop-
onstrated an improvement in mortality that is comparable, and erties of β-blockers can result in improved left ventricu-
possibly superior to ACE inhibitors (10). The use of aldosterone lar systolic and diastolic function through afterload and
receptor antagonists, such as spironolactone and eplerenone, is preload reductions, heart rate control, and prevention of
also associated with improved mortality as add-on therapy to arrhythmias.
patients treated with β-blockers and ACE inhibitors (11, 12). In children with heart failure, carvedilol and metoprolol
There have been no large randomized controlled trials of have been the most widely studied β-blockers. The largest
these medications in pediatric heart failure (13–15). A small, trial to date with β-antagonists in pediatric heart failure was
randomized trial on boys with Duchenne muscular dystrophy conducted by Shaddy et al (45) and included 161 children and
demonstrated a similar improvement in ejection fraction with adolescents with heart failure due to cardiomyopathy or con-
lisinopirl compared with losartan (16). Several other studies genital heart disease. Although not powered to show a survival
in patients with Duchenne muscular dystrophy have dem- difference versus placebo, there were several trends in ventricu-
onstrated that ACE inhibitors and ACE inhibitors along with lar remodeling and neurohormonal parameters that may favor
β-blockers result in improved echocardiographic parameters the intervention group, especially in patients with a systemic
and possibly survival (17–19). Although strong data for the left ventricle. Although functional status did not improve over
benefit of these medications in pediatric heart failure are lack- placebo in all patients, several previous analyses have suggested
ing (20), they are commonly used and recommended by con- improvements in symptoms (46–48) and ejection fraction (49,
sensus guidelines (21, 22). 50). β-antagonists may also attenuate the risk of sudden death
in heart failure by reducing arrhythmias and have demon-
β-RECEPTOR ANTAGONISTS strated that they have favorable effects in improving electro-
The safety and efficacy of β-blockers in adults with heart fail- physiological risk factors (51, 52).
ure have been established through large randomized trials with There are several possibilities for the discrepant findings for
generally beneficial findings of reduced symptoms, morbidity, β-antagonists when compared between children and adults.
and mortality. Trials investigating β-antagonists such as biso- As stated above, the etiology of heart failure is characteristi-
prolol (23, 24), carvedilol (25–27), metoprolol (27, 28), and cally different. Another difference may be the influence of
nebivolol (29) have led to these members of this class of medi- different pharmacokinetic and pharmacodynamic properties
cation to be recommended as a part of the treatment of heart of β-antagonists between children and adults. Studies that
failure in adults (30–32). have measured systemic exposure to carvedilol have indi-
However, conditions that can commonly lead to heart fail- cated that pediatric patients have increased clearance and
ure in adults such as coronary artery disease, uncontrolled may require higher doses relative to body weight or more
hypertension, valvular defects, arrhythmias, or myocardial frequent administration to achieve comparable exposure to
infarction are different from the common etiologies of heart adults (48, 53). Finally, β-adrenergic receptor expression and
failure in children, which include congenital heart defects and adaptation may also be distinct when compared with adults.
cardiomyopathy (33, 34). Partially due to differences in the eti- Children may have higher absolute expression of maladap-
ology of heart failure in adults from children, the efficacy of tive β1 receptors and reduced preservation of β2-adrenergic
β-antagonists remains to be fully elucidated (35). There is evi- receptors, which may play a cardioprotective role in heart fail-
dence that suggests that similar mechanisms can be influenced ure (54–57). These differences tender more consideration to
through adrenergic antagonism in both adults and children whether β-antagonists should be titrated to a target dose or
with heart failure. with another measure. With the findings of published trials
β-antagonists are thought to exert their action by reduc- and ongoing research attempting understanding the effects of
ing the impact of prolonged neurohormonal activation (36). these agents, β-antagonists will continue to play a significant
Neurohormonal overstimulation is pathophysiological pro- role in the treatment of pediatric heart failure.
cess induced by decreased cardiac output and baroreceptor
signaling, which results in adrenal medullary catecholamine
release and activation of the renin-angiotension aldoste- DIGOXIN
rone system (37). The release of these chemical messengers, Digoxin has a variety of physiologic actions that are medi-
referred to as “neurohormones,” contributes to myocardial ated through inhibition of Na-K ATPase. Although not cur-
apoptosis, fibrosis, and progressive worsening of cardiac rently used as a first-line therapy in the management of heart
output. The concentration of various neurohormones, such failure, digoxin has a class IIa recommendation to potentially
as epinephrine (38), norepinephrine (38, 39), renin (40), decrease heart failure–related admissions in adult patients
vasopressin (41), atrial natriuretic peptide (42), brain natri- with reduced left ventricular ejection fraction unless other-
uretic peptide (43), and endothelin-1 (44), has been shown wise contraindicated (58). The current recommendations
to be increased in children with heart failure and potentially are based on results from the Digitalis Investigation Group
associated with functional status. β-antagonists can impact study that showed no mortality benefit over placebo, but

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 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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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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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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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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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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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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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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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 µg/kg/min), there is a significant systemic vascular resistance
heart failure management (58). Loop diuretics such as furose- increase through activation of α-adrenergic receptors (67).
mide, torsemide, and bumetanide act at the loop of Henle and Dopamine can be started in the intensive care and
are the preferred diuretic for use in most patients with heart optimized for chronic inotropic use. Price et al (68) reported
failure. Alternatively, thiazide diuretics such as metolazone that on a series of seven children with advance heart failure, three
act in the distal portion of the tubule may be used. Furosemide receiving dopamine at 2–3 μg/kg/min alone or in combina-
is the typical loop diuretic used in heart failure management tion with milrinone, that the medication was well-tolerated,
and has been shown to increase sodium excretion and decrease increased ejection fraction, decreased heart failure symptoms,
symptoms of congestion. Although strategies for optimal dos- and reduced readmissions after starting therapy.
ing and delivery of furosemide have been debated, Felker et al
(61) found no significant differences in patient symptoms or DOBUTAMINE
changes in renal function when furosemide was administered Dobutamine is a synthetic catecholamine that acts primarily
by bolus versus continuous infusion or at high dose versus low on the β1 receptors in the myocardium and produces vaso-
dose. dilatation by its actions on β2-receptors and a relatively small
Diuretics should be considered in all patients with evidence α1-mediated vasoconstriction through the opposing effects
of fluid overload and in many with a history of volume over- of its two enantiomers (69). It should be used with caution
load. Although furosemide is commonly used, alternative loop in patients with significant hypotension. Similar to other β1-
diuretics such as torsemide may be considered in patients who agonists, patients can develop tolerance and tachyphylaxis that
are not responding well given the increased oral bioavailability makes continuous infusions problematic. In patients who are
of torsemide (62). Diuretic resistance may develop, especially receiving β-receptor antagonists and infusion of dobutamine
in patients who have underlying renal dysfunction or hypo- may result in peripheral vasoconstriction through the abroga-
perfusion. This can typically be overcome by the use of IV tion of β2-receptor–mediated vasodilatation (70). When used
diuretics or by combination diuretic therapy such as combin- in neonates with myocardial dysfunction for a short period
ing a loop and thiazide diuretic. The potential side effects of (20 min), dobutamine increased flow in cerebral, mesenteric,
diuretic therapy are well documented and include electrolyte and renal arteries (71). Dobutamine is a commonly used ino-
derangements, fluid depletion, hypotension, and azotemia. trope in adults with advanced heart failure and adults with
Appropriate monitoring is recommended for patients receiv- severe heart failure and ventricular dysfunction to ascertain
ing diuretic therapy in the both acute and chronic settings contractile reserve when considering transplantation or inten-
with correction of electrolytes and/or reduction in dosing as sive medical treatment (72). Scarce data exist about the con-
needed. 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 Inotropic agents have been associated with increased mor-
Inotropic agents are commonly used in heart failure, in the tality in adults with acutely decompensated heart failure.
both acute and chronic settings. However, it should be noted The mechanisms implicated on this effect have been associ-
that these agents are recommended for patients with evidence ated with increased oxygen consumption by the myocardium
if impaired perfusion (32). For patients with preserved perfu- and increased tachycardia. These medications should be used,
sion but symptoms of congestion, inotropic agents are not nec- in general, for a trial period to improve hemodynamics and
essary and may be harmful (2, 63, 64). further optimize patients for potential mechanical support
alternatives
DOPAMINE
Dopamine is a synthetic precursor to norepinephrine. There is MILRINONE
ample evidence that dopamine is effective in treating hypoten- Milrinone is commonly used for inpatient therapy of patients
sion in premature infants with and without cardiac disease (65). with chronic heart failure. Milrinone is a phosphodiesterase
In general, at doses less than 3 µg/kg/min, dopamine has been inhibitor that inhibits myocardial and vascular phosphodies-
shown to activate D1 receptors and produce vasodilatation terase activity resulting in improved myocardial contractility,
of the renal arteries. Controversy exists about this effect given increased lusitropy of the myocardium during diastole, and
that there is evidence that this low dose does not improve glo- afterload reduction from vasodilation.
merular filtration rate. In the Renal Optimization Strategies In IV form, its onset of action is within 5–15 minutes, with
Evaluation in Acute Heart Failure (ROSE AHF) trial neither a volume of distribution of 0.32–0.45 L/kg. Seventy percent of
low-dose dopamine nor nesiritide was better than placebo milrinone is bound to plasma protein and is metabolized in
(66). Doses of 3–10 µg/kg/min have been found to activate the liver (12%) with a half-life with normal renal function of
β1-adrenergic receptors in the myocardium-increasing inotropy approximately 2.5 hours, which is prolonged in patients with
and heart rate with additional promotion of norepinephrine renal failure and in patients on continuous venovenous hemo-
release and inhibition of its reuptake. At higher doses (10–20 filtration (74). It is excreted in the urine (85% as unchanged

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 Supplement

drug) within 24 hours; active tubular secretion is a major elim- Levosimendan has a lusitropic effect by not eliciting an increase
ination pathway for milrinone. in intracellular calcium-preserving diastolic relaxation.
Although milrinone is commonly used in children with acute On infusion of levosimendan it is extensively metabolized,
and chronic heart failure, to date there are no published random- with a half-life of about 1 hour. Ninety-eight percent of levo-
ized trials testing IV milrinone therapy in children with chronic simendan bound to plasma proteins, mainly albumin, but the
or acute heart failure. In the Prophylactic intravenous use of active metabolites have much lower protein binding of about
milrinone after cardiac operation in pediatrics study of post- 40%. Its active metabolites OR-1855 and OR-1896 are inter-
operative low cardiac output in children, there was a significant converted by acetylation and de-acetylation and have half-lives
reduction in the prevalence of low cardiac output syndrome in of about 75 to 80 hours, producing a prolonged duration of
children who received high-dose milrinone (75-μg/kg bolus fol- action. Metabolites and a small amount of unchanged drug
lowed by a 0.75 μg/kg/min infusion for 35 hr) (75). Milrinone has are excreted in urine and feces. More than 95% of a dose is
been well studied in adults with heart failure. In the Short-term excreted within 1 week.
intravenous milirnone for acute exacerbation of chronic heart Like milrinone, the majority of data supporting the use of
failure (64) study, adults with acute decompensated heart failure levosimendan come from adult heart failure studies. In the
were randomized at hospital admission to placebo versus milri- Levosimendan Infusion versus Dobutamine (LIDO) study of
none. There was no benefit of milrinone therapy, an increased adults with cardiogenic shock, levosimendan was superior to
prevalence of hypotension and atrial arrhythmias, and a non- dobutamine in reducing pulmonary artery occlusion pressure
significant increase in in-hospital death. In the ADHERE (76) and decreased mortality at 6 months (82). However, in the
study of adults with acute decompensated heart failure patients Levosimendan vs Dobutamine for patients with acute decom-
who received inotrope (milrinone or dobutamine) had a higher pensated heart trial where these two agents were compared
in-hospital mortality than patients who received treatment with with acute decompensated heart failure in adults, there was no
a natriuretic peptide (nesiritide) or vasodilator (nitroglycerine). differences between groups in terms of symptomatic relief of
Milrinone, similar to other inotropes such as catecholamines, heart failure, death or days out of the hospital (83). In the more
increases cytosolic calcium concentration, increases myocardial recent REVIVE trial in adults with acute decompensated heart
oxygen consumption, and have no favorable remodeling effects, failure, although levosimendan had rapid and durable symp-
making its physiologically not the ideal agent for patients with tom relief, there was a greater risk of hypotension and cardiac
heart failure and adequate perfusion (77). 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
NATRIURETIC PEPTIDES with acute and chronic heart failure, levosimendan was safe,
Nesiritide, the recombinant form of the 32 amino acids of the decreased catecholamine requirements, and improved myo-
human B-type natriuretic peptide, has been shown to reduce cardial performance (85). A subsequent study from the same
left ventricular filling pressures and has variable effects on group in nine children with severe decompensated heart fail-
sodium and water excretion as well as cardiac output. The drug ure received a “rotating inotrope” regimen that included levo-
is administered in a continuous IV form and is currently has simendan, dobutamine, and in some cases milrinone, using
a class IIb indication in the adult heart failure guidelines as an levosimendan was safe, and this regimen allowed some patients
adjuvant to diuretic therapy for the treatment of dyspnea in to be weaned from positive pressure ventilation, get discharged
patients admitted for acute decompensated heart failure (58). from ICU and hospital, and successfully bridged to transplan-
The safety profile of nesiritide was studied in the Acute study tation (86). However, levosimendan is currently not Food and
of clinical effectiveness of nesiritde in decompensated heart Drug Administration approved for use in the United States.
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 PROMISING NEW THERAPIES
worsen renal function, the findings concluded that the drug There are no medications that are known to improve out-
should not be routinely used for the treatment of decompen- comes for acute heart failure. Serelaxin, recombinant human
sated heart failure. Several reports of nesiritide use in pediatric relaxin-2, is a naturally occurring peptide involved with mater-
patients have documented relative safety and potential efficacy nal adaptations to pregnancy. It can improve cardiac output as
of the drug, but no randomized data in children exist (79–81). 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-
LEVOSIMENDAN ciated with improved dyspnea score and decreased death at
Levosimendan is a calcium-sensitizing agent that has a unique 180 days (87). The Food and Drug Administration, however,
dual activity. It improves myocardial contractility by increasing did not approve serelaxin for use in the United States and rec-
cardiac troponin C calcium sensitivity, without increasing myo- ommended further studies of the drug’s efficacy.
cardial oxygen consumption. In addition, it provides additional There are several promising medications for chronic heart
peripheral and coronary vasodilatory effects by facilitation of failure. A chronically elevated baseline heart rate is a risk
potassium channel opening leading to afterload reduction. factor for mortality among adults. Ivabradine, an If current

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 Rossano et al

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