CASE 105-7, QUESTION 2: On rounds, the NICU medical team asks you how does caffeine compare with

theophylline with regard to its pharmacokinetics, efficacy, and toxicity? What treatment and dose should be

selected for S.M.? How do you reply to the team?

The plasma clearance of caffeine is considerably lower, and the half-life is

extremely prolonged in the premature newborn (72–96 hours).

2 The low clearance is

a reflection of the decreased neonatal hepatic metabolism and a resultant dependence

of elimination on the slow urinary excretion.

111 As a result, caffeine can be dosed

once daily (every 24 hours) in the neonate. The half-life of caffeine decreases with

increasing PMA,

112 and plasma clearance reaches adult levels after 3 to 4.5 months

of life.

113 As a result of the maturational changes, doses usually need to be adjusted

after 38 weeks’ PMA; however, most infants no longer require treatment of apnea

beyond 36 weeks’ PMA.

Protein binding of theophylline is decreased in term newborns compared with

adults.

114 The decreased protein binding along with an increased tissue distribution

results in a larger volume of distribution of theophylline in neonates. This larger

volume of distribution results in larger loading-dose requirements to attain similar

serum concentrations. Like caffeine, theophylline clearance in preterm newborns is

much slower than that observed in young children of 1 to 4 years of age.

114 As a

result, smaller theophylline maintenance doses are required in neonates.

Theophylline clearance and therefore maintenance doses increase with increasing

PMA. Adjustment of maintenance doses is especially important in infants at 40 to 50

weeks’ PMA when the greatest maturational changes in theophylline clearance

occur.

115

In adults, theophylline is eliminated primarily via hepatic metabolism.

116,117

In

contrast, the primary route of theophylline elimination in neonates is renal excretion

of unchanged drug (55%).

115 Hepatic metabolism of theophylline (especially

N-demethylation) is decreased in the neonate. As in adults, theophylline is

methylated to caffeine in the neonate. The neonate’s decreased demethylation

pathway, however, results in a decrease in caffeine elimination and significant serum

caffeine accumulation. On average, serum caffeine concentrations can be 40% of the

serum theophylline concentration.

115 The theophylline-derived caffeine may

contribute to the pharmacologic and toxic effects seen in neonates receiving

theophylline. After 50 weeks’ PMA, the theophylline-derived serum caffeine

concentrations become insignificant.

p. 2189

p. 2190

Comparative studies have found similar efficacy for theophylline and caffeine in

the control of apnea of prematurity. Caffeine, however, has several advantages over

theophylline, including a wider therapeutic index. Adverse effects such as

tachycardia, CNS excitation, and feeding intolerance are reported more frequently

with theophylline than with caffeine. Because the half-life is prolonged and dosing

requirements do not change quickly with time, caffeine serum concentrations do not

need to be routinely monitored. The great majority of preterm neonates achieve

caffeine plasma concentrations within the therapeutic range (5–20 mcg/mL) if they

receive standard doses.

113 Caffeine serum concentrations may be obtained in select

neonates (e.g., patients with clinical signs of toxicity or with intractable apnea). IV

loading doses of 20 mg/kg caffeine citrate (10 mg/kg caffeine base), followed 24

hours later by maintenance doses of 5 to 8 mg/kg caffeine citrate (2.5–4 mg/kg

caffeine base) given daily, are recommended. Loading doses of caffeine citrate

should be given IV for 30 minutes using a syringe infusion pump. Maintenance doses

can be administered IV for 10 minutes or given orally.

2 Because of the longer halflife, infants receiving caffeine must be monitored for a longer time (e.g., for 7–10

days) for adverse effects if toxicities occur and for apnea recurrence once the

medication is discontinued. It is important to remember that another IV caffeine

product is marketed in the United States as the sodium benzoate salt. Benzoic acid

has been associated with the gasping syndrome and may also displace bilirubin from

albumin-binding sites.

2 Because of these toxicities, the caffeine sodium benzoate

product should not be used in neonates.

The short- and long-term safety and efficacy of caffeine to treat apnea of

prematurity in VLBW infants were studied in a large, randomized, placebocontrolled trial.

45,118 Caffeine significantly decreased the frequency of BPD.

45

Infants

who received caffeine were able to have positive airway pressure discontinued 1

week sooner than those receiving placebo. Although caffeine reduced weight gain,

the effect was only temporary (during the first 3 weeks of therapy). In a follow-up

study at 18 to 21 months’ corrected age, caffeine significantly improved the rates of

survival without neurodevelopmental disability (e.g., CP, cognitive delay).

118 These

benefits were not sustained at 5-year follow-up.

119 Although oral theophylline

(aminophylline) and caffeine are considered to be well absorbed in the neonate,

many neonates initially have feeding problems when apnea and bradycardia are

present. Therefore, therapy is usually initiated with the IV route, and an oral solution

can be used when the neonate is stable and tolerating enteral feedings. It should also

be remembered that, depending on the specific product used, aminophylline is a salt

containing 80% to 85% theophylline.

The generally accepted therapeutic range of theophylline for apnea of prematurity

is 6 to 12 mcg/mL. This range is lower than that which is normally accepted for the

treatment of asthma (5–15 mcg/mL) for several reasons: (a) The higher free fraction

of theophylline found in neonates results in a higher free concentration at any given

total concentration; (b) there is a significant accumulation of the unmeasured active

metabolite, caffeine; and (c) a different mechanism of action for theophylline is being

exploited for apnea (i.e., central stimulation vs. bronchodilation for asthma).

Aminophylline IV loading doses and maintenance doses of aminophylline and

theophylline can be found in appropriate pediatric references.

2 However, a large

variation in serum theophylline concentrations has been observed with some dosing

regimens.

120 Concomitant drug therapy and disease states (e.g., hepatic or renal

dysfunction) should also be taken into consideration when selecting initial

theophylline doses.

Serum theophylline concentrations should be monitored 72 hours after initiation of

therapy or after a change in dosage. Serum concentrations of theophylline should also

be measured if the infant experiences an increase in the number of apneic episodes,

signs or symptoms of toxicity, or a significant increase in weight. In asymptomatic

neonates, once steady state levels are obtained, theophylline concentrations may be

monitored every 2 weeks.

Because of the many advantages of caffeine over theophylline, S.M. should be

given 20 mg of caffeine citrate (10 mg caffeine base) as an IV loading dose for 30

minutes. Maintenance doses of 5 mg of caffeine citrate (2.5 mg caffeine base) every

24 hours should be started 24 hours after the loading dose.

CASE 105-7, QUESTION 3: The NICU medical resident asks you to outline a pharmacotherapeutic

monitoring plan for S.M. that includes monitoring parameters for efficacy and toxicity and duration of therapy.

What would you tell her?

The goal of methylxanthine therapy for S.M. is to decrease the number of episodes

of apnea and bradycardia. Continuous monitoring of HR and RR is required for

proper evaluation. The time, duration, and severity of episodes, activity of the infant,

and any necessary intervention performed should be documented. Relationships

between the apneic episodes and the feeding schedule and volume of feeds, as well

as the dosing schedule, should be examined. Apnea of prematurity usually resolves

by 34 to 36 weeks’ PMA; however, it may persist in some infants up to or beyond 40

weeks’ PMA.

107,109 Methylxanthine therapy usually is discontinued at 34 to 36 weeks’

PMA provided that the infant has not been having apneic spells. Infants requiring

therapy for longer periods may be discharged home on methylxanthines with apnea

monitors; however, this occurs very rarely.

Methylxanthine toxicities noted in neonates include tachycardia, agitation,

irritability, hyperglycemia, feeding intolerance, gastroesophageal reflux, and emesis

or occasional spitting up of food. Tachycardia is the most common toxicity and

usually responds to a downward adjustment of the dose. Tachycardia may persist for

1 to 3 days after dosage reductions owing to the decreased elimination of caffeine.

Seizures have also been reported with accidental overdoses. Methylxanthine toxicity

can be minimized with careful dosing and appropriate monitoring of theophylline

serum concentrations.

NEONATAL SEIZURES

CASE 105-8

QUESTION 1: F.H., a term female newborn (weight 3.5 kg), has a history of perinatal asphyxia. Apgar

scores were 0, 1, 4, and 7 at 1, 5, 10, and 15 minutes, respectively. Maternal history is negative for drug abuse.

Twenty-four hours after birth, F.H. begins to have rhythmic clonic twitching of the right hand, repetitive

chewing movements, fluttering of the eyelids, and occasional pendulum-like movements of the extremities that

resemble swimming motions. How should F.H.’s seizure activity be evaluated?

Seizure activity may be difficult to recognize in the term or premature neonate.

Because of the immaturity of the cortex, neonatal seizures rarely are generalized

tonic-clonic events, but can be clonic (focal or multifocal), tonic (focal or

generalized), myoclonic (focal, multifocal, or generalized), or subtle in nature.

121,122

For videos of neonatalseizures, go to https://www.youtube.com/watch?v=Igj1HBT6oCQ.

Subtle seizures include activities such as abnormal oral-buccal- lingual

movements; ocular movements; swimming, pedaling, or stepping movements; and

occasionally apnea. In addition, autonomic nervous system signs such as changes in

HR, BP, respirations,

p. 2190

p. 2191

skin color, oxygenation, salivation, or pupil size may occur.

121,122 Clinical neonatal

seizures may or may not be associated with EEG changes. In addition, electrographic

seizure activity may occur in neonates without clinical manifestations (i.e.,

subclinical seizures).

Neonatal seizure activity is a common manifestation of a life-threatening

underlying neurologic process. Etiologies may include metabolic or electrolyte

imbalances (e.g., alterations in glucose, calcium, magnesium, or sodium),

cerebrovascular injury, CNS infection, genetic disorders, or drug-related causes

(e.g., withdrawal after maternal drug use or adverse effects from drugs administered

before, during, or after delivery).

121–126 Therefore, initial efforts may not include

antiepileptic drug therapy. Definitive treatment is directed toward specific identified

etiologies. The acute evaluation of neonatal seizures includes assessment of the

infant’s airway, breathing, and circulation and a review of the infant’s history,

physical examination, and laboratory studies. Every neonate with seizure activity

should have a bedside determination of glucose; laboratory determinations of serum

electrolytes, including sodium, BUN, glucose, calcium, and magnesium; blood gases;

bilirubin; and an infectious disease workup, including complete blood cell count with

platelets, CRP level, blood culture, urine culture, lumbar puncture with CSF analysis

(cell count, protein, glucose), and CSF culture.

121–124 Treatment with antiepileptic

drugs is indicated after correction of known electrolyte abnormalities. Antiepileptic

drug therapy can be initiated while laboratory test results are pending, as long as

hypoglycemia has been corrected.

If these tests do not reveal any abnormalities, an EEG, metabolic disease workup

(e.g., serum ammonia, lactate, and pyruvate; serum and urine amino and organic

acids), and screening of blood and urine for drugs can be performed.

121–124

Intrauterine infections associated with congenital neurologic abnormalities and

seizures can be identified by obtainment of TORCH titers or PCR for specific

viruses (e.g., CMV, HSV). Cranial ultrasounds, computed tomography scans, and

magnetic resonance images may be obtained to identify infarcts, hemorrhages,

calcifications, or cerebral malformations that may cause seizure activity.

121,122,124

CASE 105-8, QUESTION 2: F.H. is found to have adequate ventilation and circulation. An IV line is

established; blood cultures and serum chemistries, including calcium and magnesium, are obtained. A bedside

blood glucose determination reveals a blood glucose of 20 mg/dL. What is your assessment and

recommendation at this time?

Hypoglycemia seems to be the cause of F.H.’s seizure activity. Hypoxic ischemic

encephalopathy secondary to asphyxia, however, is the most common cause of

neonatal seizures.

121,123 Hypoxic ischemic encephalopathy can be associated with

metabolic abnormalities such as hypoglycemia, hypocalcemia, and hyponatremia

(owing to inappropriate secretion of antidiuretic hormone). The definition of

clinically significant hypoglycemia in neonates remains controversial, because

normal blood glucose depends on a variety of factors, including gestational age, birth

weight, feeding status, body stores, and other disease states.

125 Historically,

hypoglycemia was defined as a whole blood glucose less than 20 mg/dL for

premature infants and less than 30 mg/dL for term infants during the first 72 hours of

life and less than 40 mg/dL for any neonate after 72 hours of age. However, in

clinical practice, a blood glucose less than 40 mg/dL in a neonate of any age would

be treated.

121 F.H. should receive an IV bolus dose of 7 mL (2 mL/kg) of dextrose

10% (200 mg/kg) given in 2 to 3 minutes, followed by a continuous infusion of

dextrose 10% at an initial dose of 12.6 to 16.8 mL/hour (6–8 mg/kg/minute or 3.6–

4.8 mL/kg/hour).

121,125 Serum glucose levels should be monitored, and the dextrose

infusion should be titrated as needed. If hypoglycemia persists, possible causes such

as islet tumor of the pancreas, adrenal insufficiency, and inborn errors of metabolism

should be investigated. Corticosteroids, glucagon, diazoxide, and octreotide have

been used to treat persistent hypoglycemia.

125

Treatment of Hypocalcemia and Hypomagnesemia

CASE 105-8, QUESTION 3: F.H. receives 7 mL (700 mg) of 10% dextrose solution IV, and an IV infusion

of glucose at 8 mg/kg/minute is initiated. A repeat bedside blood glucose determination reveals a blood glucose

of 80 mg/dL, but F.H. continues to have seizure activity. F.H.’s laboratory results come back with the following

results:

Sodium, 137 mEq/L

Potassium, 4.3 mEq/L

CO2

, 22 mEq/L

Chloride, 104 mEq/L

BUN, 7 mg/dL

SCr, 0.7 mg/dL

Glucose, 25 mg/dL

Magnesium, 1.0 mEq/L

Calcium, 6.5 mg/dL

What should be done next to control F.H.’s seizures?

F.H. also has hypocalcemia and hypomagnesemia, both of which may cause

seizure activity. Neonatal hypocalcemia is defined as a serum calcium less than 7.5

mg/dL in preterm and less than 8 mg/dL in term infants

123 or an ionized serum calcium

less than 3 mg/dL. Hypomagnesemia (defined as a serum magnesium <1.5 mEq/L) is

rare but may coexist with hypocalcemia. Hypomagnesemia should be suspected when

hypocalcemia cannot be corrected despite large doses of calcium.

F.H. should receive calcium gluconate 700 mg (200 mg/kg) given slowly IV as a

10% solution

121,123 and magnesium sulfate 25 to 50 mg/kg/dose (0.2–0.4

mEq/kg/dose) IM as a 20% solution or IV as a dilute solution (maximal

concentration, 100 mg/mL) administered for 2 to 4 hours.

2 Doses of calcium

gluconate and magnesium sulfate may be repeated based on serum determinations. If

IV calcium is administered too quickly, vasodilation, hypotension, bradycardia,

cardiac arrhythmias, and cardiac arrest may occur. Calcium gluconate may be

administered slowly IV at a maximal rate of 50 mg/minute while monitoring HR, BP,

and electrocardiogram.

2 The IV site should be closely monitored for signs of

infiltration because extravasation may result in severe dermal necrosis.

Treatment with Antiepileptic Drugs

CASE 105-8, QUESTION 4: Despite normalization of her laboratory tests, F.H. continues to have seizure

activity. Phenobarbital 35 mg IV push for 1 minute is administered. Ten minutes later, F.H. continues to have

intermittent seizure activity. Describe a pharmacotherapeutic plan to control F.H.’s seizure activity.

Phenobarbital is the initial antiepileptic drug of choice for neonatal seizures;

phenytoin and lorazepam usually are considered the second and third drugs of

choice.

121,124,126–130 Because of the large volume of distribution of phenobarbital in

neonates (0.8–1 L/kg), large initial loading doses of 20 mg/kg are required to

produce therapeutic serum concentrations.

2,121,124 Because F.H. received only a 10-

mg/kg dose (35 mg) of phenobarbital, an additional 10 mg/kg should be given now.

Phenobarbital should be administered IV at a rate of 1 mg/kg/minute or less,

2

p. 2191

p. 2192

so a 35-mg dose should be given for at least 10 minutes, not in 1 minute. Rapid

administration of phenobarbital may cause respiratory depression, apnea, or

hypotension. If F.H. continues to have seizure activity after a total phenobarbital

loading dose of 20 mg/kg, additional 5- to 10-mg/kg loading doses may be given

every 15 to 20 minutes as needed up to a total loading dose of 40 mg/kg. Ventilatory

support may be required when using these higher doses, and serum phenobarbital

concentrations should be monitored. Phenobarbital’s therapeutic effect of controlling

neonatal seizures plateaus at serum concentrations of 40 mcg/mL; adverse effects

increase at higher serum concentrations.

131

If seizure activity is not controlled in F.H. (despite optimal phenobarbital loading

doses), a phenytoin loading dose of 70 mg (20 mg/kg) should be administered IV at a

rate of 0.5 to 1 mg/kg/minute or less.

2,121,124 Rapid IV administration of phenytoin may

cause cardiac arrhythmias, bradycardia, or hypotension. Phenytoin may cause severe

damage to tissues if extravasation occurs. Therefore, BP, HR, electrocardiogram, and

the IV site of infusion should be monitored. Fosphenytoin, the diphosphate ester salt

of phenytoin, is available in the United States for IV and IM use in adults.

2

Fosphenytoin is a water-soluble prodrug of phenytoin that undergoes conversion by

plasma and tissue esterases to phenytoin, phosphate, and formaldehyde. Because of

its greater water solubility, the IV preparation does not contain propylene glycol, and

thus fosphenytoin may have fewer cardiovascular adverse effects associated with IV

administration. In addition, it can be safely administered intramuscularly and may

cause less dermal necrosis if extravasated. Unfortunately, appropriate clinical

studies of fosphenytoin in neonates have not yet been conducted. Unanswered

concerns about the neonatal handling of formaldehyde also exist. Despite the lack of

neonatal studies, some clinicians prefer to use fosphenytoin instead of phenytoin, due

to the aforementioned advantages. Studies assessing the safety, efficacy, and optimal

dosing of fosphenytoin in neonates are needed.

Lorazepam IV (0.05 to 0.1 mg/kg) should be used to treat F.H.’s seizures if they

are unresponsive to phenobarbital and phenytoin.

2,126,127 Lorazepam is preferred over

diazepam owing to its longer duration of effect and fewer pharmaceutical adjuvants.

Lorazepam (especially in combination with phenobarbital) may cause respiratory and

CNS depression. RR, BP, and HR should be monitored. Doses should be diluted

with an equal volume of 5% dextrose in water, normal saline, or sterile water for

injection before IV use and administered slowly for 2 to 5 minutes.

2

If seizure activity continues in F.H., continuous IV infusion of midazolam or IV or

oral levetiracetam should be considered.

121,124,128–130,132 Levetiracetam may be

preferred over continuous infusion midazolam due to less adverse neurologic effects.

In fact, some clinicians prefer levetiracetam to phenytoin as a second-line agent.

Although the IV formulation of levetiracetam is not approved for use in neonates,

some neonatal centers use the pediatric oral dosing recommendations for the IV route

because the two forms are bioequivalent.

2 However, the optimal neonatal dose of

levetiracetam has not been established. Neonatal reports have used doses based on

studies in pediatric patients.

128 Given that levetiracetam is primarily excreted via the

kidney (66% of a dose is excreted as unchanged drug in the urine) and that the renal

function of neonates is decreased compared with that of older infants, one would

expect a lower clearance and the use of lower levetiracetam doses in neonates.

However, recent neonatal pharmacokinetic studies

124,129,130 have identified a larger

volume of distribution per kg (compared to children) and a more rapid clearance than

expected based on immature renal function. A significant increase in levetiracetam

clearance also occurred during the first week of life, reaching the clearance seen in

children. These findings indicate that in neonates, larger loading doses and

maintenance doses, with an adjustment of maintenance doses after the first 7 days of

life, would be required. Phase 2 trials of higher doses have not yet been

completed.

124,129 Thus, currently the clinical use of levetiracetam in neonates requires

careful dose titration and close monitoring of adverse effects. Oral carbamazepine,

clonazepam, lamotrigine, topiramate, and valproic acid (IV, oral) have also been

used to treat refractory neonatal seizures in limited numbers of patients.

121,124,126,129

Because the risk of valproic acid-associated hepatotoxicity is higher for patients

younger than 2 years of age, this drug is not a preferred agent for use in neonates.

2

IV

pyridoxine (50 to 100 mg) should be considered when seizure activity persists.

Pyridoxine is a cofactor required for the synthesis of the inhibitory neurotransmitter

γ-aminobutyric acid (GABA). Patients with pyridoxine dependency require higher

amounts of pyridoxine for proper GABA synthesis. Pyridoxine dependency is a rare

disorder, but should be considered in neonates with seizure activity unresponsive to

antiepileptic drug therapy. Lifelong supplementation of pyridoxine is required in

these patients.

123

CASE 105-8, QUESTION 5: F.H.’s seizure activity stopped after receiving a total loading dose of 105 mg of

phenobarbital and 70 mg of phenytoin. A serum phenobarbital concentration of 35 mcg/mL and a phenytoin

concentration of 17 mcg/mL were measured 1 hour after the phenytoin loading dose (2 hours after the last

phenobarbital loading dose). How should maintenance doses of antiepileptic drugs be instituted in F.H.?

It is not surprising that F.H. required both phenobarbital and phenytoin to control

her seizures. Although phenobarbital and phenytoin are equally effective, neonatal

seizures are controlled in fewer than 50% of neonates with either agent alone. When

both agents are used together, neonatal seizures are controlled in approximately 60%

of neonates.

133

F.H. should be placed on maintenance doses of both phenobarbital and phenytoin

because both drugs were needed to control her seizure activity. Because the half-life

of phenobarbital is prolonged in neonates (about 100–150 hours), maintenance doses

can be instituted 24 hours after the loading dose at 3 to 4 mg/kg/day

2,123,134 as a single

daily dose. Although this newborn is term, she should receive a lower dose of

phenobarbital (2.5– 3 mg/kg/day) because of her history of asphyxia. Asphyxiated

neonates have impaired phenobarbital clearance and therefore require lower

maintenance doses than nonasphyxiated neonates to achieve similar phenobarbital

serum concentrations.

135 Maintenance doses of phenytoin (3–4 mg/kg/day given in

divided doses every 12 hours) may be initiated 12 to 24 hours after the loading dose.

Serum concentrations of these agents should be monitored periodically because

maintenance dose requirements increase with time, usually by weeks 2 to 4 of

therapy.

134 This may be related to a normal maturation of hepatic enzyme systems

with age or induction of cytochrome P-450 enzymes. In neonates, oral phenytoin is

poorly absorbed and should be avoided in the acute setting. A routine 25% increase

in the dose is needed when converting IV phenytoin to oral to attain similar serum

concentrations. In addition, after 2 to 4 weeks of age, dosing intervals of every 8

hours may be needed.

It should be remembered that phenytoin is a highly protein-bound drug. In neonates,

protein binding of phenytoin is decreased. This results in an increased free fraction

and suggests that total phenytoin therapeutic serum concentrations in newborns should

be 8 to 15 mcg/mL rather than the 10 to 20 mcg/mL as accepted in children and

adults.

2

In addition, bilirubin can displace phenytoin from albumin binding sites. A

positive correlation between total bilirubin concentrations and free fraction of

phenytoin has been described. Unbound phenytoin was reported to be approximately

20% in neonates when bilirubin concentrations were 20 mg/dL

p. 2192

p. 2193

(compared with 10% normally).

136 Thus, total phenytoin serum concentrations must

be interpreted carefully in neonates, and measurement of unbound phenytoin may be

required in neonates with hyperbilirubinemia.

The optimal duration of anticonvulsant treatment of neonatal seizures has not been

clearly established. Because of the potential long-term toxicities of these medications

and the low risk of seizure recurrence, anticonvulsants are generally discontinued

before discharge if the neonate’s neurologic examination and EEG are normal.

Neonates who continue receiving anticonvulsants are reassessed periodically after

discharge (e.g., at 1 and 3 months of age and then every 3 months). Thus, the duration

of anticonvulsant medications is individualized based on the infant’s neurologic

examination and EEG.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

after the reference.

Key References

Glass HC. Neonatalseizures: advances in mechanisms and management. Clin Perinatol. 2014;41:177–190. (124)

Hall N et al. Necrotizing enterocolitis: prevention, treatment, and outcome. J Pediatr Surg. 2013;48(12):2359–2367.

(75)

Pickering LK et al, eds. 2012 Red Book: Report of the Committee on Infectious Diseases. 29th ed. Elk Grove

Village, IL: American Academy of Pediatrics; 2012. (84)

Polin R, Carlo W. Committee on Fetus and Newborn. Clinical Report. Surfactant replacement therapy for preterm

and term neonates with respiratory distress. Pediatrics. 2014;133:156–163. (11)

Taketomo CK et al. Pediatric and Neonatal Dosage Handbook. 21st ed. Hudson, OH: Lexi-Comp; 2014. (2)

Watterberg K et al. Policy statement—postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia.

Pediatrics. 2010;126:800. (39)

Key Websites

American Heart Association, Congenital Heart Defects.

http://www.heart.org/HEARTORG/Conditions/CongenitalHeartDefects/Congenital-HeartDefects_UCM_001090_SubHomePage.jsp.

Cochrane Neonatal Group. http://neonatal.cochrane.org/.

Neonatology on the Web. http://www.neonatology.org/.

NICHD—The Eunice Kennedy Shriver National Institute of Child Health & Human Development.

http://www.nichd.nih.gov/cochrane/.

The Congenital Heart Information Network. http://www.tchin.org/.

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