Professional Documents
Culture Documents
Cvvs Therapy PDF
Cvvs Therapy PDF
Table of Contents
Introduction∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 507 II. Cardiovascular Complications of Kawasaki
General∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 508 Disease∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 511
I. Purpose of the Present Guideline Documents∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 508 III. Hyperlipidemia∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 515
II. Special Consideration of Clinical Trials in Children∙∙∙∙∙∙∙∙∙∙∙ 508 IV. Arrhythmia∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 516
III. Approval by Medical and Pharmaceutical Public V. Hypertension∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 517
Knowledge∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 508 VI. Hypotension∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 519
IV. Clinical Development of Pediatric Cardiovascular VII. Pulmonary Arterial Hypertension∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 520
Drugs∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 509 VIII. Myocardial Diseases∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 521
V. Basics of In Vivo Pharmacokinetics∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 509 IX. Infective Endocarditis∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 522
VI. Developmental Changes in Pediatric X. Premature and Newborn Medicine∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 522
Pharmacokinetics∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 510 XI. Radionuclide Imaging∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 522
1. Neonatal and Infantile Period∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 510 XII. Immunosuppressive for Organ Transplantation∙∙∙∙∙∙∙∙∙∙∙∙∙ 525
2. Early Childhood and After∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 510 XIII. Anesthetics and Sedatives∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 525
Specific Medications∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 510 Summary∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 527
I. Congesive Heart Failure Medications∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 510 I. List of Cardiovascular Drugs for Children∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 527
1. Renin-Angiotensin-Aldosterone System Inhibitors∙∙∙∙∙ 510 References∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 531
2. β-Blockers∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 510
3. Phosphodiesterase 3 Inhibitors∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 511 (Circ J 2014; 78: 507 – 533)
Introduction
The present guideline documents were developed with a focus and influences on lactation in patients with cardiovascu-
on appropriate drug therapy in pediatric patients with cardio- lar disease,
vascular diseases, under the principle of “the Right drug for 4. Coronary artery complications of Kawasaki disease, and
the Right pediatric patient at the Right time.” others.
The reason for this effort is that it has recently become more
common for not only pediatricians but also specialists in adult There are various developmental processes in childhood to
cardiovascular diseases to see the following diseases and con- adulthood, such as functional development of the cardiovas-
ditions: cular system and developmental changes in the liver, kidney,
endocrine system and density of receptors. Therefore, the
1. Cardiovascular diseases in children and youth, therapeutic dose for children should be determined by taking
2. Adult congenital heart disease patients with arrhythmia into account their complex modifiers, other than simply age,
or heart failure, and not by regarding children as “miniature adults”.1
3. Management of pregnancy and delivery, fetal therapy,
General
Indications for Drug Use in Pediatric Patients and II. Spcial Considerations of
Off-Label Use
Clinical Trials in Children
The limitations described in the package insert as “safety in
children has not been established (no clinical experience)” are
generally interpreted as follows: Clinical trials of new drugs in children and youth are limited
by the U.S. Food and Drug Administration (FDA) and the
1. There are no limitations about the use of the drug in European Medicines Evaluation Agency (EMEA) in terms of
children at the physician’s discretion. the following:
2. Because clinical experience with the drug is limited, and
therefore pharmacokinetics is unclear, the efficacy and 1. Selection of the therapeutic dose and the drug formulation
safety in children are not established as they are in adults. 2. Developmental and age-related changes in human organs
3. Appropriate dosage and administration have not been 3. Unexpected effects on normal developmental process
established. 4. Pharmacokinetics
4. The drug should be administered with caution. 5. Pharmacodynamics
5. Because proper usage cannot be determined, pediatric
patients are not covered by the national insurance for Therefore, considering the difficulties in clinical trials and
health hazards. corporate attitude toward drug development, incentives, Na-
6. However, complete prohibition of the use of the drug is tional Health Insurance (NHI) pricing formula, patent terms,
not intended. and others, off-label use is necessarily frequent in children and
youth, and it is often based on experience in a limited number
of patients. In addition, because there are age-related limita-
I. Purpose of the Present Guideline Documents tions in surgical manipulations and techniques, the importance
of medical therapy is higher in this population. In most cases,
Drugs used in clinical practice often do not have pediatric in- selection of the therapeutic dosage and treatment results de-
dications. Only about 30~40% of recently approved drugs are rived from experience with adult patients, and sometimes
permitted for pediatric use. trends in preceding use in overseas countries as well, are used
However, many pediatricians use off-label drugs in their as reference information.
practice when it is considered indispensable although they are Recently, guidelines of the clinical evaluation of new drugs
aware that the drugs are off-label, and they use these drugs in pediatric patients have been prepared, and the movement of
with caution, attaching importance to the safety as well as the new drug development for these patients has been accelerated.
usefulness of the drug and the balance of risk and benefit. In
recent years, it has been becoming apparent that the response
to the drugs, such as warfarin, varies among children accord-
III. Approval by Medical and
ing to the individual’s pharmacogenetic profile. The factors Pharmaceutical Public Knowledge
shown in Table 1 are involved in the pharmacokinetic vari-
ability of drugs used in children. Over the past decade, it has become possible to approve some
drugs for use in children without conducting additional clini-
Table 3. Recently Approved Cardiovascular Drugs for Pediatric Use (since January 2001 to November 2012)
1. Clinical studies conducted
- Palivizumab (anti-RS virus antibody)
2. Medical and pharmaceutical public knowledge (no newly conducted clinical studies)
- Immune globulin, aspirin (Kawasaki disease)
- Alprostadil (PGE1-αCD) (patent ductus arteriosus dependent cyanotic heart disease)
- Flecainide acetate (Tambocor) (tachyarrhythmia)
- Warfarin potassium (anticoagulation)
- Verapamil hydrochloride (Vasolan) (tachyarrhythmia)
3. Recently officially noticed and approved drugs
- Amlodipine (Norvasc), enalapril (Renivase), lisinopril (Longes), valsartan (Diovan) for hypertension
- Propranolol (Inderal) for tachyarrhythmia
αCD, α-cyclodextrin; PGE1, prostaglandin E1; RS, respiratory syncytial.
Table 4. Ontogeny of Hepatic Metabolism per Unit Organ Weight and Renal Excretion Activity in the Neonatal and Infantile Periods6
Hepatic metabolism
Oxidation
CYP1A2 Almost no activity at birth. Expression occurs 1~3 months after birth, and reaches the adult level at 4~5 months.
CYP2C9 Low activity at birth. Activity increases after birth, and reaches an almost adult level in half of infants by 5
months after birth.
CYP2C19 Low activity at birth. Expression increases slowly over a period of at least 5 months after birth.
CYP2D6 Almost no activity at birth. Activity is low until 2 weeks after birth, but develops after 3 weeks according to
the genotypes, showing distinct difference in activity by gene polymorphism. Activity reaches the adult level
by age 10 years.
CYP3A4 Low expression at birth. Increases slowly to an adult level over a period of 1~2 years after birth.
CYP3A7 Expression occurs in the early embryonic period, but decreases soon after birth, reaching almost nil by 1
year after birth.
Conjugation (transferase) metabolism enzymes
UGT1A1 Research in humans is insufficient.
UGT1A4 Expression at birth is less than 50% of the adult level, but reaches an almost adult level by about age 1.5 years.
UGT1A6 Activity is low through the neonatal to infantile period.
UGT2B7 Activity in the neonatal period is about 20% of the child level (at about age 10 years), and increases rapidly
2~6 months after birth.
Sulfatase Activity in the neonatal period is about 70% of the adult level.
N-acetylation enzyme Activity is low at birth and until 2 months after birth. Gene polymorphism-related difference is apparent 6
months after birth, and activity reaches the adult level 1~4 years after birth.
Methyl transferase Activity is already in the adult level at birth.
Renal excretion
Glomerular filtration rate (GFR) The rate in the neonatal period corresponds to 10~20% of the adult level, but reaches the adult level at about
age 1 year.
Active tubular transport The function level is low in the neonatal period, but reaches the adult level at about age 1 year, although its
development is slower than glomerular development.
CYP, cytochrome P450; UGT, UDP-glucuronosyltransferase.
Specific Medications
2. β-blockers (Table 7)12,13
I. Congestive-Heart Failure Medications7–11
A U.S. study of carvedilol for heart failure in children showed
no significant difference between placebo group and low- or
1. Renin-Angiotensin-Aldosterone System Inhibitors high-dose carvedilol groups for the composite end point (heart
(Table 5) failure outcomes).14 However, subgroup analysis demonstrated
The use of renin-angiotensin-aldosterone (RAA) system in- possible beneficial effect in patients with systemic left ventri-
hibitors is basic treatment for heart failure. Although these cle.15,16 Adverse reactions include bradycardia, complete atrio-
drugs are not approved for pediatric heart failure, enalapril, ventricular block, and exacerbation of heart failure. Character-
lisinopril, and valsartan have already been approved for hyper- istically in children, these drugs are reported to be less effective
tension in children. for cardiac disease in which the right ventricle is the systemic
Table 6 shows a comparison of the use of enalapril in adults ventricle (e.g., corrected transposition of the great arteries).
and children/youth. In children, the first-dose phenomenon at Propranolol is approved for pediatric tachyarrhythmia in
the starting of administration and adverse reactions such as Japan.
cough are not common. Caution is necessary in patients with Table 8 shows a comparison of carvedilol (covered by the
possible renal dysfunction. NHI) in adults and children/youth.
Table 5. Vasodilators
Mechanism of Action
- Inhibition of enhanced RAA system activity in heart failure
Target diseases
- Acute and chronic heart failure
Drug type (or class)
- Angiotensin-converting enzyme inhibitors: captopril, enalapril, lisinopril, cilazapril
- Angiotensin receptor antagonists: losartan, valsartan, candesartan
- Drugs approved for use in children and youth in Japan:
Enalapril, lisinopril, and valsartan are already approved for hypertension in children.
Captopril is covered by the National Health Insurance.
Precautions for pregnant women and fetuses
- Teratogenesis (some recent reports find that the primary disease, rather than the drug, is responsible.)
- Fetal growth retardation
RAA, renin-angiotensin-aldosterone.
Table 7. β-blockers
Mechanism of Action
- Inhibition of enhanced sympathetic nerve system activity in heart failure
Target diseases
- Chronic heart failure
Drug type (or class)
- Nonselective αβ ISA (–): carvedilol, 0.2~1.0 mg/kg/day (starting at a rate of 0.1 mg/kg, two divided doses)
- β selective ISA (–): bisoprolol, metoprolol
- Drugs approved for use in children and youth in Japan: propranolol (approved only for tachyarrhythmia)
Precautions for pregnant women and fetuses
- Contraindicated for pregnant women (fetal developmental toxicity)
ISA, intrinsic sympathetic activity.
of these patients have coronary artery sequelae in Japan. Tables 11,12, and 13 show a comparison of the use of as-
Table 10 shows treatments for coronary artery complica- pirin, clopidogrel, and warfarin, respectively, in adults and
tions of Kawasaki disease using antiplatelet and anticoagulant children/youth.
drug therapy. Long-term antiplatelet or anticoagulant drug When a concomitant coronary aneurysm is present, it is
therapy is often required for coronary artery complications, highly likely that thrombotic obstruction occurring in the an-
particularly when a concomitant giant aneurysm (at least 6 mm eurysm will result in acute myocardial infarction. Therefore,
in diameter) is present. acute thrombolytic therapy is attempted intravenously in chil-
Table 15. Prevention of Ischemic Heart Disease as the Coronary Artery Complications of Kawasaki Disease
Mechanism of Action
- Decrease of cardiac work, reduction of pre- and afterload, and increase of coronary blood flow
Target diseases
- Angina associated with coronary artery complications of Kawasaki disease
Drug type (or class)
- β-blockers: metoprolol (M), carvedilol (C) (covered by the NHI only for chronic heart failure)
- Calcium channel blockers: nifedipine (covered by the NHI) (N), amlodipine (A), diltiazem (D)
- Nitrates: isosorbide dinitrate (I), nitroglycerin (NT), nicorandil (NC) (hybrid of nitrate and ATP-sensitive potas-
sium channel opener)
- Drugs approved for use in children and youth in Japan: None
Precautions for pregnant women and fetuses
- Transfer into breast milk (M, C, N, A, D, I, NT), teratogenicity (N, D)
ATP, adenosine triphosphate; NHI, National Health Insurance.
Table 17. Antihyperlipidemic Drugs
Mechanism of Action
- Inhibition of intracellular cholesterol (CH) production, inhibition of absorption and acceleration of excretion from
small intestine
Target diseases
- Familial hypercholesterolemia homozygote-apheresis (heterozygotes are limited in children)
- Autosomal recessive hypercholesterolemia (ARH) accompanied by xanthoma, β-sitosterolemia, and other conditions
Drug type
- Statins: pravastatin, sinvastatin, fluvastatin, atruvastatin, pitavastatin, rosuvastatin
- Non-statins: colestimide, ezetimibe
- Drugs approved for use in children and youth in Japan: None
Precautions for pregnant women and fetuses
- Statins require careful administration to women who wish to have a baby because they cause fetal anomaly.
Table 21. Antihypertensive Drugs for High Blood Pressure in Children (Calcium Channel Blockers)
Mechanism of Action
- Blocking calcium ion channel and relaxing the smooth muscle cells of peripheral blood vessels
Target diseases
- Hypertension (essential, renal, hypertensive emergency)
Drug type (or class)
- First-generation dihydropyridines: nifedipine*, nicardipine, perdipine hydrochloride
- Third-generation dihydropyridines: amlodipine
- Verapamil, diltiazem
Drugs approved for use in children and youth in Japan: amlodipine (approved for children aged 6 or older)
Precautions for pregnant women and fetuses
- Teratogenesis (nifedipine), increased fetal death, inhibition of body weight gain (nicardipine)
- Prolonged gestational period and duration of labor (amlodipine)
The drug with an asterisk (*) is covered by National Health Insurance.
Table 25. Antihypotensive Drugs
Mechanism of Action
- Elevating effect of systemic blood pressure by contraction of vascular smooth muscle
Target diseases
- Essential hypotension, orthostatic hypotension
Drug type (or class)
- α receptor agonists: phenylephrine hydrochloride, midodrine hydrochloride, ergotamine mesilate
- Sympathetic stimulant: amezinium metilsulfate
- Drugs approved for use in children and youth in Japan: midodrine hydrochloride
Precautions for pregnant women and fetuses
- Because ergotamine mesilate has uterotonic activity and placental and umbilical vasoconstrictor action, it is
contraindicated for pregnant or breast-feeding women.
[Amezinium metilsulfate]
Target diseases Essential hypotension, orthostatic hypotension
Presence/absence of indications Approved Off-label
Half-life T1/2 13.6±2.5 hours Unknown
Dosage 20 mg/day 5~20 mg/day according to age
Dosing method 2 divided oral doses per day
Major adverse reactions Palpitations, headache, nausea/vomiting, facial hot flashes, hypertension.
Contraindicated for hyperthyroidism and pheochromocytoma.
ceed the adult dose (overseas package inserts describe that there adults and children/youth. Nifedipine sustained-release tablets
has been no study that examined doses exceeding 5 mg/day in should be used without changing the formulation.
children). Table 24 shows a comparison of the use of nicardipine in
*However, the present guideline documents also refer to the adults and children/youth.
dosage “0.06~0.3 mg/kg/day, at one dose” as described in the
2009 guidelines of the European Society of Hypertension.36
Table 23 shows a comparison of the use of nifedipine in
Table 35. Prophylactic Drugs for Infective Endocarditis (All Unapproved for Pediatric Use)
Route, dose,
Generic name Half-life in blood Adverse reactions
method of administration
Amoxicillin (AMPC) Oral: 50 mg/kg (upper limit 2 g), 1 hour (renal) Gastrointestinal symptoms
given 1 hour prior to procedure
Ampicillin (ABPC) Intravenous injection: 50 mg/kg 1 hour (renal) Fever, rash, urticaria, convulsions, skin lesions
(upper limit 2 g), given within
30 min of procedure
Clindamycin phosphate Oral: 20 mg/kg (upper limit 600 mg), 2~3 hours (hepatic) Rash, neurological symptoms, hepatic damage,
(CLDM) given 1 hour prior to procedure renal dysfunction, pancytopenia
Cefalexin (CEX) Oral: 50 mg/kg (upper limit 2 g), 1.24 hours (renal) Fever, rash, urticaria
given 1 hour prior to procedure
Cefadroxil (CDX) Oral: 50 mg/kg (upper limit 3 g), NA Rash, hepatic damage, gastrointestinal symptoms,
given 1 hour prior to procedure pancytopenia, vitamin deficiencies
Azithromycin (AZM) Oral: 15 mg/kg (upper limit 500 mg), 66.2 hours Photosensitivity, eosinophilia, decreased blood
given 1 hour prior to procedure pressure, fainting, convulsions, gastrointestinal
symptoms, hearing difficulty, tinnitus
Clarithromycin (CAM) Oral: 15 mg/kg (upper limit 500 mg), 4.36 hours Rash, gastrointestinal symptoms, eosinophilia,
given 1 hour prior to procedure elevation of GOT
Cefazolin sodium (CEZ) Intravenous injection: 50 mg/kg 2.3 hours (renal) Hypersensitivity, thrombocytopenia, hepatic
(upper limit 1 g), given within dysfunction, gastrointestinal symptoms
30 min of procedure
Ceftriaxone sodium Intravenous injection: 50 mg/kg 4.7 hours (renal) Hypersensitivity, eosinophilia, vitamin deficiencies,
(CTRX) (upper limit 2 g), given within gastrointestinal symptoms
30 min of procedure Do not use in neonates and premature babies with
hyperbilirubinemia.
GOT, glutamic oxaloacetic transaminase; NA, not available.
born errors of metabolism, and mainly treated by enzyme re- initial inhalation concentration at 20 ppm, and maintained at
placement therapy. 20 ppm for subsequent 4 hours. When improved oxygenation
is achieved, the dose is decreased to 5 ppm, and therapy should
be discontinued after the dose is decreased gradually to 1 ppm.
IX. Infective Endocarditis (Table 33)46–48 Extracorporeal membrane oxygenation (ECMO) is indicated
for severe cases that do not respond to therapy.
Various antibacterial drugs are available. Tables 34 and 35
show therapeutic drugs and prophylactic drugs, respectively,
for bacterial endocarditis. XI. Radionuclide Imaging (Table 38)53–55
4. Sedatives
XIII. Anesthetic and Sedatives61–66 Sedatives are used for sedation in intensive care units, testing,
treatment, anesthetic premedication, and in the induction and
1. Inhalational Anesthetic Drugs maintenance of anesthesia (midazolam). The drugs used include
Inhalation anesthetic drugs approved for pediatric use are sevo- midazolam and dexmedetomidine. Midazolam is approved for
flurane, isoflurane, and nitrous oxide (See Table 40). use in children and youth in Japan (Table 46).
5. Muscle Relaxants is indicated for use in neonates, infants, and young and older
Muscle relaxants are used for muscle relaxation during gen- children) (Table 47). More details are available in “Guidelines
eral anesthesia and tracheal intubation. There are three types for Use of Anesthetics and Anesthesia-Related Drugs, 3rd
of muscle relaxants: rocuronium, vecuronium, and suxametho- revised edition (2012. 10. 31), Chapter X. Pediatric Anesthesia
nium. Among these drugs, the one approved for use in chil- Drugs,” by the Japanese Society of Anesthesiologists.68
dren and youth in Japan is rocuronium (careful administration
Summary (Table 48)
As for medical products used in the field of pediatric cardio- cal evaluation of drugs of this kind worldwide, resulting in a
vascular diseases, data from well-designed clinical studies lack of high-quality evidence in this field. Therefore, many
have been limited. Instead, evidence is restricted to experts’ drugs that are indicated for adult diseases remain to be devel-
opinions. Consideration for risk/benefit and informed consent oped for pediatric use. Table 49 shows a list of cardiovascular
are important, and it is necessary to refer severe cases to insti- drugs used for children around the world.69 This list includes
tutions where pediatric cardiologists are available. a number of globally recognized drugs, although some have
Table 49 shows the doses of major drugs used for pediatric yet to be approved for pediatric use in Japan. This table has
cardiovascular diseases described in a representative textbook been cited from Anderson’s basic textbook of pediatric cardi-
(Anderson RH, et al. Pediatric Cardiology, third edition, 2009).69 ology. The dosing basically covers neonates to 10-year-old
children. However, this table provides rough standards, and
the doses should be chosen appropriately by the doctor in
I. List of Cardiovascular Drugs for Children69 charge who considers the risk/benefit based on the physical
development, immaturity, race difference, renal and hepatic
Conclusion function, dehydration status, presence/absence of fever, sever-
Clinical studies of new drugs for pediatric use have been lim- ity of the disease, complications, and concomitant medications
ited, and there have been few established guidelines for clini- in individual patients and other factors.
Table 48. Summary
1. Drugs that can be used clinically in children are limited.
2. Currently many drugs are lacking definitive evidence for safety.
3. However, usefulness has been reported frequently in guidelines of relevant academic societies, textbooks, and
medical journals.
4. A number of drugs are already usable through application by medical and pharmaceutical public knowledge, and
several drugs are covered by the National Health Insurance.
5. When the use of drugs that have not been examined in clinical studies is attempted, it is necessary to chose safe
drugs that are less likely to affect the fetus, breast milk, and “growth and development” after the neonatal stage,
based on consideration for the risk/benefit and characteristics of Japanese people.
6. It should be noted that adults and children may slightly differ in their therapeutic dose, pharmacokinetics, pharma-
codynamics, and adverse reactions. Physicians should take great care when they prescribe drugs for children by
simply converting the therapeutic dose for adults on the basis of body weight alone.
Drug
Serious adverse General dosage and
generic name Indications Contraindications Comments
reactions dosing method
[trade name]#
Amiloride - Potassium - Hyperkalemia - Hyponatremia - 200 μg/kg orally twice per - Diuretic effect will be
[No approved drug sparing - Renal failure - Hyperkalemia day decreased by concomitant
products in Japan] diuretic - Hypotension - Maximum daily dose 20 mg use with thiazide or loop
diuretics.
Amiodarone - Supraventricu- - Bradycardia - Bradycardia, [Oral] - To suppress development
[Ankaron] lar arrhythmias - AV block torsades de - Initial dose: 5 mg/kg 2~3 of adverse reactions, long-
- Ventricular - Hypotension pointes times per day for 7 days, term use should be avoided.
arrhythmias - Thyroid disorder then decreased to mainte- - Careful monitoring of liver
- Interstitial pneu- nance dose function, thyroid function,
monia, pulmo- - Maintenance dose: 5 mg/kg interstitial pneumonia,
nary fibrosis once per day, or adjustment aggravation of arrhythmias,
- Alveolar hemor- based on measurement of bradycardia, and vision is
rhage, ARDS blood concentrations necessary.
- Hepatic dysfunc- [Intravenous] - Because photosensitivity
tion, hepatitis - 25 μg/kg/min for the first and depigmentation of skin
- Corneal pigmen- 4 hours, then decreased to are severe, sun block is
tation 5~15 μg/kg/min necessary.
- Photosensitivity, - Maximum daily dose 1.2 g - Monitor the heart rate
depigmentation during intravenous infu-
of skin sions, and adjust the dose if
- Neurological necessary.
disorder, anemia - Effective blood concentra-
- SIADH tions of amiodarone and
active metabolites:
0.6~2.5 mg/L
Aspirin - Low dose: - Viral infection - Reye’s - Low dose: 5 mg/kg once per - High dose is aspirin is also
[Aspirin] antiplatelet with the risk of syndrome day (maximum 75 mg) used in rheumatic fever and
prophylaxis Reye’s syndrome - Hemorrhage - High dose: 20~25 mg/kg 4 post-pericardiotomy
against throm- - Hemorrhagic (particularly time per day for approxi- syndrome.
bosis gastric ulcer gastrointestinal mately 14 days, then
- High dose: tract) decreased to the low dose
anti-inflamma- - Bronchospasm
tory agent for
Kawasaki
disease
Atenolol - Hypertension - Bronchial asthma - Bradycardia - 1~2 mg/kg orally once per - Administration may be
[Tenormin] - Supraventricu- - AV block - Heart failure day started at a low dose if there
lar tachycardia - Hypotension - Bronchospasm - Maximum daily dose 100 mg is renal or hepatic dysfunc-
- Ventricular - Cardiac dysfunc- - AV block tion.
tachycardia tion - Peripheral vaso-
constriction
- Fatigue
Captopril - Heart failure - Renal dysfunction - Hypotension - Starting at a rate of - ACE inhibitor
[Captoril] - Hypertension - Renovascular (particularly with 0.1 mg/kg orally 3 times per - Usually used with loop
disease initial doses) day diuretics for heart failure.
- Coarctation of - Renal dysfunc- - The dose can be increased - Do not use with potassium
the aorta tion up to 1 mg/kg orally 3 times sparing diuretics.
- Left ventricular - Tachycardia per day. - Careful observation is
outflow tract - Photosensitivity required at the initial induc-
obstruction - Persistent dry tion.
- Left ventricular cough - Usually, in an in-patient to
inflow obstruction ensure monitoring of blood
pressure and renal function.
Carvedilol - Heart failure - Bronchial asthma - Bradycardia - Starting at a rate of - Used as a third-line therapy
[Artist] - AV block - Heart failure 0.05 mg/kg orally twice per for chronic heart failure that
- Cardiac dysfunc- - Bronchospasm day (maximum daily dose can be added after diuretics
tion - AV block 3.125 mg) and ACE inhibitors
- Periphreal vaso- - The dose can be increased - No evidence of long-term
constriction every 2 weeks to a final usefulness in children has
- Fatigue dose of 0.35 mg/kg orally been available.
twice per day (maximum
daily dose 25 mg)
Clopidogrel - Antiplatelet - Hemorrahage - 1 mg/kg orally once per day - Used as a second-line
[Plavix] prophylaxis - Thrombocytope- (maximum daily dose therapy after aspirin
against throm- nia 75 mg)
bosis as an
alternative to
low-dose
aspirin
Drug
Serious adverse General dosage and
generic name Indications Contraindications Comments
reactions dosing method
[trade name]#
Digoxin - Supraventricu- - AV block - Anorexia [Oral] - In urgent circumstances,
[Digosin] lar arrhythmias - Renal failure - Abdominal pain - Neonates to age less than 5 loading doses (digitaliza-
- Heart failure - WPW syndrome - AV block years: 10 μg/kg/day, age tion) may be required over
- Ventricular tachy- - Arrhythmias 5~10 years: 6 μg/kg/day the first 24 hours.
cardia - Maximum daily dose 250 μg - The dose should be
decreased in preterm
neonates and children with
renal failure.
- Because of limited useful-
ness in heart failure, rarely
used as first-line therapy.
- Intravenous administration
is rare.
- Effective blood concentra-
tions of digoxin are
0.8~2.0 μg/L.
Dinoprostone - Patent ductus - Apnea - Drip infusion starting at a - Monitoring of heart rate,
(Prostaglandin E2) arteriosus in - Tchypnea rate of 5 ng/kg/min breathing, and body temper-
[Prostandin E2] neonates - Hypotension - The dose can be increased ature is necessary.
- (In Japan, - Fever up to 20 ng/kg/min accord- - Artificial ventilation for
uterine - Cortical prolifer- ing to response. apnea may be necessary.
constriction) ation of long
bones
- Necrotizing
enterocolitis
Dipyridamole - Antiplatelet - Heart failure - Hypotension - 2.5 mg/kg orally twice per - Dipyridamole has also been
[Anginal] prophylaxis - Aortic stenosis - Tachycardia day used for ischemic heart
[Persantin] against throm- - Bronchospasm - Age 12 years or older: disease and steroid-resis-
bosis as an 100~200 mg orally 3 times tant nephrosis.
alternative to per day - The antiplatelet action may
low-dose be synergistic with aspirin.
aspirin
Dobutamine - Inotropic - Left ventricular - Tachycardia - 2~20 μg/kg/min by continu-
[Dobutrex] support in low outflow tract - Hypotension ous intravenous infusion
cardiac output obstruction
Dopamine - Hypotension - Tachycardia - Hypertension - 2~20 μg/kg/min by continu- - No evidence of effective
[Inovan] - Low cardiac - Arrhythmia - Tachycardia ous intravenous infusion vasodilatory activity of low
output - Arrhythmias doses dopamin in clinical
settings.
Enalapril - Heart failure - Renal failure - Hypotension - Starting at a rate of - ACE inhibitor
[Renivace] - Hypertension - Renovascular (particularly with 0.1 mg/kg/day orally - Usually used with loop
disease initial doses) - The dose can be increased diuretics for heart failure.
- Coarctation of - Renal dysfunc- to 1 mg/kg/day according to - Do not use with potassium
aorta tion response. sparing diuretics.
- Left ventricular - Tachycardia - Careful observation is
outflow tract - Raynaud’s required at the initial induc-
obstruction symptoms tion.
- Left ventricular - Stevens-Johnson - Usually, in an in-patient to
inflow stenosis syndrome ensure monitoring of blood
obstruction - Alopecia pressure and renal function.
- Muscle cramp
- Persistent dry
cough
Epinephrine - Acute hypo- - Hypertension - Tachycardia - 0.1 μg/kg/min intravenously
(Adrenaline) tension - Hypertension - The dose can be increased
[Bosmin] - Arrhythmias up to 1.5 μg/kg/min.
Esmolol - Emergency - Bronchial asthma - Bradycardia - Initial dose: slow intrave- - Relatively cardioselective
[Brevibloc] management of - AV block - Heart failure nous infusion of 500 μg/kg β-blocker
arrhythmias and - Hypotension - Bronchospasm over 1~2 min; subsequently, - Decrease dose if hypoten-
hypertension - Cardiac dysfunc- - AV block continuous intravenous infu- sion or bradycardia occurs.
- Anoxic spells tion sion of 25~50 μg/kg/min is - Higher doses are required
in tetralogy of applicable. to relieve severe anoxic
Fallot - The dose can be increased spell in tetralogy of Fallot
(unapproved in up to 200 μg/kg/min in resis- (no clinical experience in
Japan) tant cases. Japan).
Drug
Serious adverse General dosage and
generic name Indications Contraindications Comments
reactions dosing method
[trade name]#
Flecainide - Ventricular - Heart failure - Precipitation of [Oral] - ECG monitoring is neces-
[Tambocor] tachycardia - Heart block life-threatening - 2~3 mg/kg 2~3 times per sary during slow intrave-
- Arrhythmias in - Hypokalemia arrhythmias day nous infusion.
WPW (particularly in - Adjust dose according to - Blood concentrations is
syndrome patients with blood concentrations monitored during intrave-
- AV reentry structural heart [Intravenous] nous infusion continued for
tachycardia disease) - Single dose 2 mg/kg more than 24 hours (effec-
- Cardiac dysfunc- - 0.1~0.25 mg/kg/h until reso- tive blood concentrations
tion (particularly lution of arrhythmias 200~800 μg/L)
when used with (maximum total dose of
β-blockers or 600 mg in first day)
calcium channel
blockers)
Furosemide - Heart failure - Hypokalemia - Hyponatremia [Oral] - In case of oliguria, higher
[Lasix] - Pulmonary - Hypotension - Hypokalemia - 0.5~2 mg/kg 2 or 3 times per doses may be required, and
congestion - Hypomagnesemia day (maximum daily dose: increased gradually accord-
- Hypertension - Nephrocalcinosis 12 mg/kg or 80 mg/day in ing to urine output.
- Hypotension total, whichever is lower)
- Hearing loss [Intravenous]
(with rapid intra- - 0.5~1 mg/kg up to 4 times
venous infusion) per day, or continuous infu-
sion of 0.1~2 mg/kg/h
Ibuprofen - Patent ductus - Hepatic dysfunction - Hemorrhage - 10 mg/kg by slow intrave- - Decrease dose in cases of
[Brufen] arteriosus in - Pulmonary (particularly, nous infusion renal dysfunction.
preterm hypertension intracranial) - The 2nd (at 24 hours) and - Monitoring of hepatic func-
infants (no - Hemorrhage - Renal dysfunc- 3rd (at 48 hours) doses are tion is necessary.
indication for - Necrotizing tion 5 mg/kg.
neonates in enterocolitis - Necrotizing
Japan) - Infection enterocolitis
Indomethacin - Patent ductus - Renal dysfunction - Hemorrhage - Drip infusion over 30 minutes - Monitor urine output, and
[Indacin] arteriosus in - Infection including intra- - Neonates under 48 hours after the 2nd and 3rd doses be
preterm - Hemorrhage cranial hemor- birth: 200 μg/dose, followed given until urine output
infants (particularly, rhage by two doses of 100 μg recovers.
intracranial) - Oliguria, anuria separated by 12~24 hours - Indomethacin is used as an
- Necrotizing - Fluid retention - Neonates 2~7 days after anti-inflammatory drug for
enterocolitis birth: 200 μg/dose, followed post-pericardiotomy
by two doses of 200 μg syndrome.
separated by 12~24 hours
- Neonates over 7 days after
birth: 200 μg/dose, followed
by two doses of 250 μg
separated by 12~24 hours
Isoprenaline - Bradycardia - Hypotension - Hypotension - 0.02 μg/kg/min, maximum
[Proternol] - Complete AV - Tachycardia 0.5 μg/kg/min (maximum
block - Arrhythmias 0.2 μg/kg/min in neonates)
Lidocaine - Ventricular - AV block - Central nervous - 0.5~1 mg/kg intravenously - ECG monitoring is neces-
[Xylocaine] fibrillation - Cardiac dysfunc- system depression over 1 minute. sary during therapy.
- Ventricular tion - Respiratory - Repeat at 5-minute intervals - Decrease dose when there
tachycardia - Hepatic failure depression up to 3 mg/kg, followed by is hepatic or renal dysfunc-
- Renal failure - Hypotension continuous infusion of tion.
- Bradycardia 1~3 mg/kg/h.
Lisinopril - Heart failure - Renal dysfunction - Hypotension - Starting at a rate of - ACE inhibitor
[Zestril, Longes] - Hypertension - Renovascular (particularly with 0.1 mg/kg/day orally - Usually used with loop
disease initial doses) - The dose can be increased diuretics for heart failure.
- Coarctation of - Renal dysfunc- up to 0.5~1 mg/kg/day - Do not use with potassium
aorta tion according to response. sparing diuretics.
- Left ventricular - Tachycardia - Maximum daily dose 40 mg - Careful observation is
outflow tract - Alopecia required at the initial induction.
obstruction - Persistent dry - Usually, in an in-patient to
- Left ventricular cough ensure monitoring of blood
inflow obstruction pressure and renal function.
Losartan - Heart failure - Renal dysfunction - Hypotension - 0.5 mg/kg orally once per - Angiotensin II receptor blocker
[Nu-Lotan] - Hypertension - Renovascular (particularly with day - This drug is similar to ACE
disease initial doses) - The dose can be increased inhibitors in drug efficacy,
- Coarctation of - Hypokalemia up to 2 mg/kg once per day. but does not cause dry
aorta cough characteristic of ACE
- Left ventricular inhibitor therapy.
outflow tract - Decrease dose when there
obstruction is renal or hepatic dysfunction.
- Left ventricular - Introduce with caution
inflow obstruction because of the risk of hypo-
tension.
Drug
Serious adverse General dosage and
generic name Indications Contraindications Comments
reactions dosing method
[trade name]#
Milrinone - Heart failure - Renal failure - Arrhythmias - Continuous intravenous - PDE inhibitor with both posi-
[Milrila] - Low cardiac - Hypotension - Hypotension infusion of 30~45 μg/kg/h tive inotropic and dilative
output vasodilator actions
- Shock - Administer 50~75 μg/kg by
drip infusion over the first
1-hour period if there is no
hypotension.
- Decrease dose if there is
renal failure.
- Short-term use only.
Norepinephrine - Hypotension - Hypertension - Hypertension - Continuous intravenous
(Noradrenaline) secondary to - Severe vasocon- infusion of 20~100 ng/kg/min
[Noradrenaline] severe vasodi- striction and - The dose can be increased
lation peripheral isch- up to 1 μg/kg/min.
emia
- Arrhythmias
Propranolol - Hypertension - Bronchial asthma - Bradycardia - Tetralogy of Fallot: - Contraindicated for use with
[Inderal] - Supraventricu- - AV block - Heart failure 15~20 μg/kg intravenously; verapamil. Decrease dose if
lar tachycardia - Hypotension - AV block the dose can be increased there is renal or hepatic
- Ventricular - Cardiac dysfunc- - Peripheral vaso- slowly up to 100~200 μg/kg dysfunction.
tachycardia tion constriction under ECG monitoring.
- Anoxic spell in - Fatigue - Arrhythmias: 0.25~0.5 mg/kg
tetralogy of orally 3 times per day; the
Fallot dose can be increased up to
1 mg/kg 3 times per day.
Slow intravenous infusion of
10~50 μg/kg under ECG
monitoring
Sildenafil - Pulmonary - Hypotension: - Dyspnea - 0.5 mg/kg/dose orally every - Decrease dose if there is
[Revatio] hypertension Coronary artery - Headache 4~6 hours. hepatic or renal dysfunction.
disease - Visual distur- - The dose can be increased - This drug is also used for
bances up to 2 mg/kg every 4 hours pulmonary hypertension
- Erection according to response. following cardiac surgery
and for weaning from
inhaled nitric oxide therapy.
Sotalol - Atrial flutter - Bronchial asthma - Bradycardia - 1 mg/kg orally twice per day - Monitor the QT interval.
[Sotacor] - Supraventricu- - AV block - Heart failure - The dose can be increased - Avoid use with other drugs
lar tachycardia - Hypotension - Bronchospasm every 3~4 days up to that induce QT prolonga-
- Ventricular - Cardiac dysfunc- - AV block 4 mg/kg orally twice per day tion.
tachycardia tion - Arrhythmias if necessary - Effective blood concentra-
- Hypokalemia - QT prolongation (maximum daily dose tions are 0.04~2.0 mg/L.
- Hypomagnese- - Torsades de 160 mg).
mia pointes
- QT prolongation
Spironolactone - Potassium - Hyperkalemia - Hyperkalemia - 0.5~1 mg/kg orally 3 times - Usually used with loop
[Aldactone-A] sparing - Hyponatremia - Hyponatremia per day diuretics.
diuretic (Anti- - Hepatic dysfunc- - Should not be given simul-
aldosterone tion taneously with ACE inhibi-
drug) - Gynecomastia tors.
- Osteomalacia
ACE, angiotensin converting enzyme; ARDS, acute respiratory distress syndrome; AV, atrioventricular; PDE, phosphodiesterase; SIADH,
syndrome of inappropriate antidiuretic hormone secretion; WPW, Wolff-Parkinson-White.
Adapted from, Anderson RH, et al. Paediatric cardiology, 3rd edn, 2009: 1299–1303,69 with permission from Elsevier Inc., modified for Japa-
nese pediatric patients.
#Added to this table.
phosphodiesterase inhibitors after arterial switch operation. Cincin- et al. A systematic review and meta-analysis of statin therapy in chil-
nati: Cincinnati Children’s Hospital Medical Center, 2006 Aug. dren with familial hypercholesterolemia. Arterioscler Thromb Vasc
10. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, et al. Biol 2007; 27: 1803 – 1810.
A comparison of enalapril with hydralazine-isosorbide dinitrate in 30. McGill HC Jr, McMahan CA, Gidding SS. Preventing heart disease
the treatment of chronic congestive heart failure. N Engl J Med 1991; in the 21st century: Implications of the Pathobiological Determinants
325: 303 – 310. of Atherosclerosis in Youth (PDAY) study. Circulation 2008; 117:
11. Mori Y, Nakazawa M, Tomimatsu H, Momma K. Long-term effect 1216 – 1227.
of angiotensin-converting enzyme inhibitor in volume overloaded 31. Vignati G. Pediatric arrhythmias: Which are the news? J Cardiovasc
heart during growth: A controlled pilot study. J Am Coll Cardiol Med (Hagerstown) 2007; 8: 62 – 66.
2000; 36: 270 – 275. 32. Guccione P, Paul T, Garson A Jr. Long-term follow-up of amioda-
12. Wu JR, Chang HR, Huang TY, Chiang CH, Chen SS. Reduction in rone therapy in the young: Continued efficacy, unimpaired growth,
lymphocyte beta-adrenergic receptor density in infants and children moderate side effects. J Am Coll Cardiol 1990; 15: 1118 – 1124.
with heart failure secondary to congenital heart disease. Am J Car- 33. Pfammatter JP, Stocker FP. Re-entrant supraventricular tachycardia
diol 1996; 77: 170 – 174. in infancy: Current role of prophylactic digoxin treatment. Eur J Pe-
13. Läer S, Mir TS, Behn F, Eiselt M, Scholz H, Venzke A, et al. diatr 1998; 157: 101 – 106.
Carvedilol therapy in pediatric patients with congestive heart failure: 34. Bendayan R, McKenzie MW. Digoxin pharmacokinetics and dosage
A study investigating clinical and pharmacokinetic parameters. Am requirements in pediatric patients. Clin Pharm 1983; 2: 224 – 235.
Heart J 2002; 143: 916 – 922. 35. National High Blood Pressure Education Program Working Group on
14. Shaddy RE, Boucek MM, Hsu DT, Boucek RJ, Canter CE, Mahony High Blood Pressure in Children and Adolescents. The fourth report
L, et al; Pediatric Carvedilol Study Group. Carvedilol for children on the diagnosis, evaluation, and treatment of high blood pressure in
and adolescents with heart failure: A randomized controlled trial. children and adolescents. Pediatrics 2004; 114(2 Suppl 4th Report):
JAMA 2007; 298: 1171 – 1179. 555 – 576.
15. Azeka E, Franchini Ramires JA, Valler C, Alcides Bocchi E. Delist- 36. Lurbe E, Cifkova R, Cruickshank JK, Dillon MJ, Ferreira I, Invitti
ing of infants and children from the heart transplantation waiting list C, et al; European Society of Hypertension. Management of high
after carvedilol treatment. J Am Coll Cardiol 2002; 40: 2034 – 2038. blood pressure in children and adolescents: Recommendations of the
16. Bajcetic M, Kokic Nikolic A, Djukic M, Kosutic J, Mitrovic J, European Society of Hypertension. J Hypertens 2009; 27: 1719 – 1742.
Mijalkovic D, et al. Effects of carvedilol on left ventricular function 37. Litwin M, Grenda R, Sladowska J, Antoniewicz J. Add-on therapy
and oxidative stress in infants and children with idiopathic dilated with angiotensin II receptor 1 blocker in children with chronic kidney
cardiomyopathy: A 12-month, two-center, open-label study. Clin Ther disease already treated with angiotensin-converting enzyme inhibi-
2008; 30: 702 – 714. tors. Pediatr Nephrol 2006; 21: 1716 – 1722.
17. Yan C, Miller CL, Abe J. Regulation of phosphodiesterase 3 and in- 38. Messerli FH, Bangalore S, Julius S. Risk/benefit assessment of beta-
ducible cAMP early repressor in the heart. Circ Res 2007; 100: 489 – blockers and diuretics precludes their use for first-line therapy in hy-
501. pertension. Circulation 2008; 117: 2706 – 2715, discussion 2715.
18. Amsallem E, Kasparian C, Haddour G, Boissel JP, Nony P. Phos- 39. Ogihara T, Kikuchi K, Matsuoka H, Fujita T, Higaki J, Horiuchi M,
phodiesterase III inhibitors for heart failure. Cochrane Database Syst et al; Japanese Society of Hypertension Committee. The Japanese
Rev 2005: CD002230. Society of Hypertension Guidelines for the Management of Hyperten-
19. Duggal B, Pratap U, Slavik Z, Kaplanova J, Macrae D. Milrinone sion (JSH 2009). Hypertens Res 2009; 32: 3 – 107.
and low cardiac output following cardiac surgery in infants: Is there 40. Kliegman RM, Behrman RE, Stanton BF, St. Geme J, Schor N, editors.
a direct myocardial effect? Pediatr Cardiol 2005; 26: 642 – 645. Nelson textbook of pediatrics, 19th edn. Philadelphia: W.B.Saunders,
20. Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, 2011.
Burns JC, et al. Diagnosis, treatment, and long-term management of 41. Barst RJ, Ertel SI, Beghetti M, Ivy DD. Pulmonary arterial hyperten-
Kawasaki disease: A statement for health professionals from the sion: A comparison between children and adults. Eur Respir J 2011;
Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, 37: 665 – 677.
Council on Cardiovascular Disease in the Young, American Heart 42. Paul GA, Gibbs JS, Boobis AR, Abbas A, Wilkins MR. Bosentan
Association. Circulation 2004; 110: 2747 – 2771. decreases the plasma concentration of sildenafil when coprescribed
21. Onouchi Z, Hamaoka K, Sakata K, Ozawa S, Shiraishi I, Itoi T, et al. in pulmonary hypertension. Br J Clin Pharmacol 2005; 60: 107 – 112.
Long-term changes in coronary artery aneurysms in patients with 43. Barst RJ, Ivy DD, Gaitan G, Szatmari A, Rudzinski A, Garcia AE,
Kawasaki disease: Comparison of therapeutic regimens. Circ J 2005; et al. A randomized, double-blind, placebo-controlled, dose-ranging
69: 265 – 272. study of oral sildenafil citrate in treatment-naive children with pul-
22. Li JS, Yow E, Berezny KY, Bokesch PM, Takahashi M, Graham TP monary arterial hypertension. Circulation 2012; 125: 324 – 334.
Jr, et al; PICOLO Investigators. Dosing of clopidogrel for platelet 44. Venugopalan P, Agarwal AK, Worthing EA. Chronic cardiac failure
inhibition in infants and young children: Primary results of the Plate- in children due to dilated cardiomyopathy: Diagnostic approach,
let Inhibition in Children On cLOpidogrel (PICOLO) trial. Circula- pathophysiology and management. Eur J Pediatr 2000; 159: 803 – 810.
tion 2008; 117: 553 – 559. 45. Ostman-Smith I. Hypertrophic cardiomyopathy in childhood and ado-
23. Monagle P, Chalmers E, Chan A, DeVeber G, Kirkham F, Massicotte lescence - strategies to prevent sudden death. Fundam Clin Pharma-
P, et al. Antithrombotic therapy in neonates and children: American col 2010; 24: 637 – 652.
College of Chest Physicians Evidence-Based Clinical Practice 46. Day MD, Gauvreau K, Shulman S, Newburger JW. Characteristics of
Guidelines (8th Edition). Chest 2008; 133(6 Suppl): 887S – 968S. children hospitalized with infective endocarditis. Circulation 2009;
24. Taki M, Kobayashi M, Ohi C, Shimizu H, Goto K, Aso K, et al. 119: 865 – 870.
Spontaneous platelet aggregation in Kawasaki disease using the 47. Ishiwada N, Niwa K, Tateno S, Yoshinaga M, Terai M, Nakazawa M.
particle counting method. Pediatr Int 2003; 45: 649 – 652. Causative organism influences clinical profile and outcome of infec-
25. Meschengieser SS, Fondevila CG, Frontroth J, Santarelli MT, Lazzari tive endocarditis in pediatric patients and adults with congenital heart
MA. Low-intensity oral anticoagulation plus low-dose aspirin versus disease. Circ J 2005; 69: 1266 – 1270.
high-intensity oral anticoagulation alone: A randomized trial in pa- 48. Wilson W, Taubert KA, Gewitz M, Lockhart PB, Baddour LM,
tients with mechanical prosthetic heart valves. J Thorac Cardiovasc Levison M, et al. Prevention of infective endocarditis: Guidelines from
Surg 1997; 113: 910 – 916. the American Heart Association: A guideline from the American Heart
26. Arambepola C, Farmer AJ, Perera R, Neil HA. Statin treatment for Association Rheumatic Fever, Endocarditis, and Kawasaki Disease
children and adolescents with heterozygous familial hypercholester- Committee, Council on Cardiovascular Disease in the Young, and the
olaemia: A systematic review and meta-analysis. Atherosclerosis Council on Clinical Cardiology, Council on Cardiovascular Surgery
2007; 195: 339 – 347. and Anesthesia, and the Quality of Care and Outcomes Research In-
27. Haney EM, Huffman LH, Bougatsos C, Freeman M, Steiner RD, terdisciplinary Working Group. Circulation 2007; 116: 1736 – 1754.
Nelson HD. Screening and treatment for lipid disorders in children 49. Malviya M, Ohlsson A, Shah S. Surgical versus medical treatment with
and adolescents: Systematic evidence review for the US Preventive cyclooxygenase inhibitors for symptomatic patent ductus arteriosus
Services Task Force. Pediatrics 2007; 120: e189 – e214. in preterm infants. Cochrane Database Syst Rev 2008; 1: CD003951.
28. de Jongh S, Ose L, Szamosi T, Gagné C, Lambert M, Scott R, et al; 50. Fowlie PW, Davis PG. Prophylactic intravenous indomethacin for
Simvastatin in Children Study Group. Efficacy and safety of statin preventing mortality and morbidity in preterm infants. Cochrane
therapy in children with familial hypercholesterolemia: A random- Database Syst Rev 2002; 3: CD000174.
ized, double-blind, placebo-controlled trial with simvastatin. Circu- 51. Van Overmeire B, Smets K, Lecoutere D, Van de Broek H, Weyler
lation 2002; 106: 2231 – 2237. J, Degroote K, et al. A comparison of ibuprofen and indomethacin
29. Avis HJ, Vissers MN, Stein EA, Wijburg FA, Trip MD, Kastelein JJ, for closure of patent ductus arteriosus. N Engl J Med 2000; 343: 674 –