treatment, and prevention. Paediatr Drugs. 2008;10:75.
Gould JM, Matz PS. Otitis media. Pediatr Rev. 2010;31:102.
American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media. The diagnosis and
management of acute otitis media. Pediatrics. 2013;131:e964.
after the introduction of the pneumococcal conjugate vaccine. Clin Infect Dis. 2005;40:1738.
in children with acute otitis media. Pediatr Infect Dis J. 2012;31:297–301.
Moore MR et al. Effect of use of 13-valent pneumococcal conjugate vaccine in children on invasive
Lancet Infect Dis. 2015;15:301–309.
scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki
Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation. 2009;119:1541.
Respiratory distress syndrome (RDS) is a major cause of morbidity and
mortality in preterm neonates, resulting from pulmonary surfactant
deficiency; it is characterized by atelectasis, hypoxemia, decreased lung
compliance, small airway epithelial damage, and pulmonary edema.
Beractant, calfactant, poractant alfa, and lucinactant are exogenous
surfactants used in the prevention and treatment of RDS in preterm
neonates. These agents have been shown to improve oxygenation and
lung compliance and decrease the need for supplemental oxygen and
Bronchopulmonary dysplasia (BPD) is the most common form of
chronic pulmonary disease in infants; it is caused by lung immaturity,
surfactant deficiency, oxygen toxicity, barotrauma, and inflammation,
and is characterized by tachypnea, retractions, and wheezing.
The management of BPD includes supplemental oxygen therapy,
mechanical ventilation, and pharmacologic interventions including
diuretics, bronchodilators, and corticosteroids.
Infants with BPD are at higher risk for experiencing cardiorespiratory
problems including pneumonia, pulmonary hypertension, left ventricular
hypertrophy, and neurologic and developmental abnormalities.
Preterm neonates are at high risk for patent ductus arteriosus (PDA), a
serious cardiovascular disorder, which may present with tachycardia,
wide pulse pressure, bounding pulses, and systolic murmur.
Complications of PDA include pulmonary edema and heart failure.
PDA places the neonate at high risk for BPD, intraventricular
hemorrhage, and necrotizing enterocolitis.
Medical management of PDA includes fluid management, correction of
anemia, treatment of hypoxia and acidosis, and pharmacologic therapy
with prostaglandin inhibitors (indomethacin or ibuprofen) to close the
Necrotizing enterocolitis (NEC) is the most common life-threatening
nonrespiratory condition in newborns and is characterized by abdominal
distension, bloody stools, metabolic acidosis, and bowel perforation.
The management of NEC includes parenteral nutrition, intravenous
antibiotics, and bowel resection. Interventions including trophic feedings,
breast milk, probiotics, and a strict feeding protocol may be used to
decrease the incidence of NEC.
NEONATAL SEPSIS AND MENINGITIS
Bacterialsepsis can be classified as early-onset (caused by pathogens
colonized from the maternal genital tract) or late-onset sepsis (caused
by nosocomial pathogens). Clinicalsigns can be subtle and nonspecific
especially in preterm neonates.
Selection of empiric intravenous antibiotics is the same for sepsis and
meningitis and will depend on nosocomial pathogens commonly isolated
in the neonatal intensive care unit, antibiotic resistance patterns, and
underlying neonatal risk factors.
Congenital infections including herpes simplex virus, syphilis, and
cytomegalovirus may result in fetal death, congenital anomalies, serious
central nervous system sequelae, intrauterine growth retardation, or
preterm birth; if suspected, appropriate diagnostic tests and treatment
should be started immediately.
Pharmacologic treatment of apnea of prematurity includes the use of
methylxanthines, specifically caffeine and theophylline, which decrease
apneic episodes via both central and peripheral effects.
Caffeine offers several advantages over theophylline for the treatment
of apnea including a wider therapeutic index, fewer adverse effects,
prolonged half-life, once-daily dosing, and lack of the need for routine
serum drug concentration monitoring.
Neonatalseizure activity is a common manifestation of a life-threatening
underlying neurologic process. Initial therapy is focused on the
treatment of the underlying cause (e.g., hypoglycemia, hypocalcemia,
infection) and may not include antiepileptic drug therapy.
Common antiepileptic medications used to treat neonatalseizure activity
are phenobarbital, phenytoin, and lorazepam.
The rational use of medications in neonates depends on an appreciation of both the
physiologic immaturity and the developmental maturation that influence neonatal drug
disposition and pharmacologic effects. Much progress has been made to decrease
neonatal mortality and improve survival of more premature and lower-birth-weight
newborns. Neonates, particularly those of extremely low birth weights (ELBW),
pose a pharmacotherapeutic challenge to the clinician. The alterations of body
composition, weight, and size, as well as physiologic and pharmacokinetic
parameters, which occur with normal growth and maturation during the first few
months of life, are greater than at any other time. Although the amount of neonatal
drug information is increasing, the overall lack of well-designed pharmacokinetic
and pharmacodynamic studies still hinders the clinical use of many drugs in this
population. This is especially true for newborns of the lowest birth weights (<750 g).
An understanding of common neonatal terminology (Table 105-1) is important
because every newborn is evaluated and classified at birth according to birth weight,
gestational age, and intrauterine growth status.
pharmacodynamics, and dosing recommendations often are specified according to
Important neonatal pharmacokinetic differences are reviewed in
Chapter 102, Pediatric Pharmacotherapy. This chapter focuses on the safe and
effective use of medications for common neonatal medical conditions.
Respiratory distress syndrome (RDS) is a major cause of morbidity and mortality in
3 This clinical syndrome is characterized by respiratory failure with
atelectasis, hypoxemia, decreased lung compliance, small airway epithelial damage,
and pulmonary edema. The principal cause of RDS is pulmonary surfactant
deficiency. Pulmonary surfactant decreases the surface tension at the air–fluid
interface in the alveoli and prevents alveolar collapse. Surfactant also facilitates the
clearance of pulmonary fluid, prevents pulmonary edema, and stabilizes alveoli
during aeration. At birth, the clearance of residual fetal lung fluid is accompanied by
an increase in pulmonary blood flow, which facilitates the transition from fetal to
Gestational age (GA) By dates: The number of weeks from the onset of the
mother’s last menstrual period until birth
By examination: Assessment of gestational maturity by
physical and neuromuscular examination; gestational age
estimates the time from conception until birth
Postnatal age (PNA) Chronologic age after birth
Postmenstrual age (PMA) Gestational age plus postnatal age. Postmenstrual age (rather
than postconceptional age) is the preferred term for use in
clinical practice. Postmenstrual age is considered to be a
more accurate term because gestational age is calculated
using the mother’s last menstrual period, and the exact date
of conception is generally not known.
Postconceptional age (PCA) Age since conception. This term is not recommended for use
in clinical practice and is currently reserved for cases when
the exact date of conception is known (i.e., assisted
reproductive technology). Older literature may use this term
to describe the sum of gestational age plus postnatal age;
thus, it is important to know how this term is defined when
Corrected age Postmenstrual age in weeks minus 40; represents postnatal
age if neonate had been born at term (40 weeks’ gestational
Neonate A full-term newborn 0 to 28 days postnatal age. Some may
also apply this term to a preterm neonate who is > 28 days
postnatal age, but with a postmenstrual age ≤ 42 to 46 weeks
Preterm <37 weeks’ gestational age at birth
Term 37 weeks’ 0 days to 41 weeks’ 6 days (average ˜ 40
weeks’) gestational age at birth
Post-term ≥42 weeks’ gestational age at birth
Extremely low birth weight (ELBW) Birth weight <1 kg
Very low birth weight (VLBW) Birth weight <1.5 kg
Low birth weight (LBW) Birth weight <2.5 kg
Small for gestational age (SGA) Birth weight <10th percentile for gestational age
Appropriate for gestational age (AGA) Birth weight between 10th and 90th percentiles for
Large for gestational age (LGA) Birth weight >90th percentile for gestational age
In the fetus, endogenous cortisol stimulates the synthesis and secretion of
pulmonary surfactant at 30 to 32 weeks’ gestational age.
amounts of pulmonary surfactant for normal lung function are not present before 34 to
4,5 Therefore, the incidence and severity of RDS increase as
gestational age decreases. RDS occurs in approximately 25% of neonates born at 30
to 31 weeks’ gestation, but may occur in as high as 95% to 98% of neonates born at
Without adequate amounts of surfactant, the surface tension within the alveoli is so
great that the alveoli collapse (atelectasis), resulting in poor gas exchange (e.g.,
hypoxemia, hypercapnia). Low lung compliance also results, and large inspiratory
pressures are needed to aerate the lungs. Unfortunately, the extremely compliant
neonatal chest wall makes it difficult to create the large negative inspiratory
pressures necessary to open the alveoli. This results in an increased work of
breathing and alterations of ventilation and perfusion.
Aeration of the surfactant-deficient lung also results in the cyclic collapse and
distension of bronchioles, with resultant bronchiolar epithelial injury and necrosis.
This epithelial damage causes pulmonary edema by allowing fluid and proteins to
leak from the intravascular space into the airspaces and interstitium of the lung. The
necrotic epithelial debris and proteins then form fibrous hyaline membranes.
Hyaline membranes and pulmonary edema further impair gas exchange.
The inadequate oxygenation and ventilation and increased work of breathing
caused by RDS may result in the need for assisted positive-pressure ventilation.
Complications of RDS may be related to mechanical ventilation and include
pulmonary barotrauma (e.g., pneumothorax, pulmonary interstitial emphysema [PIE]),
intraventricular hemorrhage (IVH), patent ductus arteriosus (PDA), retinopathy of
prematurity (ROP), and chronic lung disease or bronchopulmonary dysplasia (BPD).
ventilation (NIPPV) is as follows:
is inserted for central venous access. L.D.’s chest radiographic shows RDS (see
http://www.adhb.govt.nz/newborn/teachingresources/radiology/CXR/RDS/RDS.jpg for a radiograph of
What signs and laboratory data are consistent with RDS?
An Apgar score is a method of evaluating the physical condition of a newborn
infant immediately after birth. It consists of
five clinical signs including HR, respiratory effort, muscle tone, skin color, and
reflex irritability. Each sign can receive a score of 0 to 2 points with a total possible
score of 10 points. A score of 7 to 10 is considered normal, whereas scores of 0 to 3
require immediate resuscitation. The Apgar score is routinely done at 1 and 5
minutes of life and is repeated every 5 minutes until a total score of at least 7 is
achieved. (For a video of how to assign an Apgar score to newborns, go to
http://online.wsj.com/video/assigning-an-apgar-score-to-newborns/9B7B09A9-
1B12-4C65-92BA-D4C6DFA35BBA.html?mod=googlewsj.) L.D.’s Apgar scores
of 3 and 5 at 1 and 5 minutes indicate that he may have experienced some perinatal
asphyxia, most likely secondary to maternal placenta abruption. L.D.’s risk factors
for RDS are prematurity, male sex, perinatal asphyxia, cesarean section, and
maternal gestational diabetes. Other risk factors include second-born twins and
3 Clinical signs and laboratory data consistent with RDS
in L.D. include tachypnea, cyanosis, retracting respirations, grunting, nasal flaring,
hypoxemia, hypercapnia, and a mixed respiratory and metabolic acidosis.
manifestations classically present within the first 6 hours of life.
Tachypnea, the first sign of respiratory distress, is an attempt to compensate for the
inadequate ventilation, hypercapnia, and acidosis. L.D.’s retracting respirations (the
use of intercostal, subcostal, suprasternal, or sternal accessory muscles) reflect the
increased work of breathing necessary to maintain ventilation. His nasal flaring
decreases resistance during inspiration and increases oxygenation. Grunting is the
result of forceful exhalation against a partially closed glottis in an effort to prolong
expiration and maximize oxygenation. Grunting also increases intrathoracic pressure
during expiration in an attempt to stabilize the alveoli and prevent atelectasis. L.D.’s
cyanosis, hypoxemia, hypercapnia, and mixed respiratory and metabolic acidosis are
consequences of inadequate oxygenation and poor ventilation and are consistent with
CASE 105-1, QUESTION 2: What treatments should be initiated for L.D.’s respiratory insufficiency?
Before L.D. is treated for RDS, other causes of respiratory distress must be ruled
out. For example, infections (particularly group B streptococcal sepsis or
pneumonia) often present with respiratory distress. Because it is difficult to
distinguish between RDS and infection, all neonates with severe RDS should receive
antibiotics. L.D. was started empirically on antibiotics, and a complete evaluation of
possible sepsis should be performed.
Neonates should be treated for RDS as soon as possible and may require
ventilatory support. Noninvasive ventilator support such as NIPPV or nasal
continuous positive airway pressure (CPAP) has been shown to reduce barotrauma,
volutrauma, and airway damage compared to intubation with mechanical ventilation.
However, some extremely preterm neonates may require intubation with mechanical
ventilation due to persistent symptoms of RDS. Because L.D. failed NIPPV and
required intubation, exogenous surfactant should be administered intratracheally as
soon as possible. Human surfactant is synthesized and secreted by type II alveolar
epithelial cells of the lung. It contains 80% phospholipids, 8% neutral lipids, and
5 The major surface-active component is
dipalmitoylphosphatidylcholine (DPPC), also known as colfosceril or lecithin.
However, this phospholipid slowly adsorbs to the air–fluid interface in the alveoli.
Other phospholipids (e.g., phosphatidylcholine, phosphatidylglycerol) and four
surfactant apoproteins (SP-A, SP-B, SP-C, and SP-D) enhance spreadability and
5 Adsorption and surface spreading of the surfactant in the alveoli
are important determinants of surface tension activity. SP-A and SP-D both play a
role in immune regulation and providing host defense. SP-A may also help to regulate
alveolar surfactant reuptake and metabolism.
5 SP-B and SP-C are the two most
important apoproteins responsible for promoting adsorption and surface spreading of
the surfactant in the alveoli to form a phospholipid monolayer.
the most critical protein for surfactant activity.
Natural surfactants are derived from bovine or porcine lung lipid or lavage
extracts. Modified natural surfactants are lung lipid extracts supplemented with
phospholipids or other components.
3 Currently, four surfactant products are
commercially available for clinical use in the United States (US): beractant
(Survanta), calfactant (Infasurf), poractant alfa (Curosurf), and lucinactant (Surfaxin).
Beractant, calfactant, and lucinactant are US Food and Drug Administration (FDA)-
approved for the prevention (i.e., prophylaxis) of RDS, whereas beractant,
calfactant, and poractant alfa are approved for treatment (i.e., rescue therapy).
Animal-derived products contain variable amounts of SP-B and SP-C, lipids, and
phospholipids. Lucinactant, a new synthetic surfactant, contains not only
phospholipids but also high concentrations of sinapultide (KL4), a synthetic peptide
that mimics human SP-B. (see Table 105-2 for comparisons).
CASE 105-1, QUESTION 3: What are the effects of exogenously administered surfactant that can be
Oxygenation and lung compliance rapidly and markedly improve after the
administration of surfactant. It should be expected that supplemental oxygen and
mechanical ventilation may need to be significantly reduced. The increased lung
compliance and decreased need for high inspiratory pressures result in a dramatic
decrease in the incidence of pneumothorax and PIE. Survival in treated infants
increases by approximately 40% regardless of birth weight or gestational age, and
neonatal mortality from RDS is decreased to approximately 20%.
complications of RDS such as severe BPD, IVH, NEC, ROP, and PDA have not been
decreased consistently with surfactant therapy.
CASE 105-1, QUESTION 4: Which surfactant is appropriate and when should it be administered to L.D.?
Trials comparing natural surfactant products (poractant alfa vs. beractant, calfactant
vs. beractant, poractant alfa vs. calfactant) have demonstrated that poractant alfa and
calfactant result in a significantly faster weaning of supplemental oxygen and mean
airway pressure compared to beractant. Furthermore, a lower mortality rate at 36
weeks’ PMA was seen with a higher initial dose of poractant alfa 200 mg/kg. No
differences were seen with the duration of mechanical ventilation and supplemental
oxygen, the incidence of BPD, and other secondary outcomes.
only one trial comparing the three natural surfactant products for the treatment of
RDS. Overall, there were no significant differences in the incidence of
pneumothorax, PIE, death, and the combined variable of BPD or death among the
Trials comparing synthetic (lucinactant) to a natural surfactant product (beractant
or poractant alfa) found no difference in the incidence of RDS at 24 hours; however,
one study reported a significantly higher incidence of RDS-related death by 14 days
of life and NEC in the beractant group.
In addition, no significant differences were
found with mortality, BPD, IVH, PDA, and ROP between synthetic and natural
Studies assessing the long-term neurodevelopmental outcomes (at 1 year and at 18
to 24 months of corrected age) of infants receiving surfactants (beractant vs.
poractant alfa and lucinactant vs. beractant or poractant alfa) for RDS found no
significant difference between products.
Comparison of Currently Marketed Surfactant Products
Variable Calfactant (Infasurf)
(Curosurf) Beractant (Survanta) Lucinactant (Surfaxin)
Proteins SP-B and SP-C SP-B and SPC
SP-B and SP-C Sinapultide (KL4
Indications Prophylaxis and rescue
Not approved Birth weight <1,250 g or
3 mL/kg (PL 105 mg/kg) Initial dose: 2.5
4 mL/kg (PL 100 mg/kg) 5.8 mL/kg (PL 175
Not approved Give first dose ASAP
Cost per vial $455.00 (3 mL), $805.33
aAverage wholesale price according to 2015 Red Book.
fractional inspired oxygen; Pao2
, partial pressure of oxygen; PL, phospholipids; RDS, respiratory distress
Cost-effectiveness studies of different natural surfactant products for the treatment
of RDS reported significant cost savings associated with poractant alfa (due to fewer
required additional doses) compared with beractant.
12,13 A recent pharmacoeconomic
analysis of costs associated with reintubation in preterm infants treated with either
lucinactant, beractant, or poractant alfa utilized data from two multicenter trials.
Reintubation rates were significantly lower in the lucinactant-treated group.
However, it is important to note that one of the studies compared lucinactant to
colfosceril palmitate, a product no longer available in the US. Furthermore, the
second trial was terminated before achieving enrollment goal. Therefore, these
limitations may have affected respiratory outcomes and healthcare costs associated
with reintubation and mechanical ventilation.
Based on these comparative trials, it appears there are no significant differences in
the short-term (e.g., air leaks, duration of mechanical ventilation/oxygenation) and
long-term outcomes (e.g., death, BPD, and other secondary outcomes) between the
four surfactant products. Poractant alfa, given at a dose of 200 mg/kg, may be the
favorable surfactant therapy because it resulted in a faster weaning of oxygen and
mean airway pressure, a decrease in mortality at 36 weeks’ PMA, and a lower cost.
TIME AND METHOD OF ADMINISTRATION
Surfactant therapy can be administered as prophylactic (i.e., within 10–30 minutes
after birth) or rescue treatment (given to those with established RDS within 12 hours
of life). Early rescue is defined as the administration of surfactant within the first 2
hours of life; late rescue is defined as treatment after more than 2 hours of life.
Theoretically, the first dose of surfactant should be given before the newborn’s first
breath or before positive-pressure ventilation.
10 This would avoid the early lung
injury in RDS that can interfere with surfactant distribution, bioavailability, and
effectiveness. This strategy, however, increases the cost of care because newborns
that might never experience RDS would be intubated and treated unnecessarily. In
addition, delivery room treatment may interfere with resuscitation and stabilization of
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