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848  Part XII  ◆  The Fetus and the Neonatal Infant

Chapter 101 
Respiratory Tract
Disorders
Waldemar A. Carlo and
Namasivayam Ambalavanan

Respiratory disorders are the most frequent cause of admission for


neonatal intensive care in both term and preterm infants. Signs and
symptoms of respiratory distress include cyanosis, grunting, nasal
flaring, retractions, tachypnea, decreased breath sounds with or
without rales and/or rhonchi, and pallor. A wide variety of pathologic
lesions may be responsible for respiratory disturbances, including pul-
monary, airway, cardiovascular, central nervous, infection, and other
disorders (Fig. 101-1).

Neonate with acute respiratory distress

Yes Abnormal No
lungs by chest
radiograph
Abnormalities in

Common Uncommon
Respiratory distress Diapragmatic hernia Perfusion Neuro- Diaphragm
syndrome Tracheoesophageal
Transient fistula
BP muscular or chest
tachypnea Cysts and tumors HCT findings wall
Pneumonia Congenital lobar
aspiration emphysema
syndromes Pulmonary hypoplasia Anemia Asphyxia Chest wall
Pneumothorax and Accessory or sequestered lobes Polycythemia Intracranial disorders
air leaks Pulmonary Hypotension hemorrhage Diaphragmatic
Pulmonary edema lymphangiectasia Hypovolemia Neuromuscular disorders
Pleural effusion Pulmonary disorders
Pulmonary hemorrhage arteriovenous fistula Drugs

CVS Other
Airway Abdominal
findings or mixed
findings findings
or echo findings

Upper airway Persistent fetal Ascites Sepsis


Laryngeal circulation Necrotizing Acidosis
Lower airway Cyanotic congenital enterocolitis Hypothermia,
heart disease Abdominal mass cold stress
Congestive heart Omphalocele Hyperthermia
failure Gastroschisis Hypoglycemia
Methemoglobinemia

Figure 101-1 Neonate with acute respiratory distress. BP, blood pressure; CVS, cardiovascular system; HCT, hematocrit. (From Battista MA,
Carlo WA: Differential diagnosis of acute respiratory distress in the neonate. In Frantz ID, editor: Tufts University of School of Medicine and
Floating Hospital for Children reports on neonatal respiratory diseases, vol 2, issue 3, Newtown, PA, 1992, Associates in Medical Marketing Co.)

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Chapter 101  ◆  Respiratory Tract Disorders  849

It is occasionally difficult to distinguish respiratory from nonrespira- shunting is common soon after birth; if pulse oximetry is performed
tory etiologies on the basis of clinical signs alone. Signs of respiratory soon after birth, the recommendation is to measure oxygen saturation
distress are an indication for a physical examination and diagnostic in the right upper extremity.
evaluation, including a blood gas or pulse oximetry determination
and chest x-ray. Timely and appropriate therapy is essential to improve BREATHING PATTERNS IN NEWBORNS
outcome. During sleep in the 1st few mo after birth, normal full-term infants
may have episodes when regular breathing is interrupted by short
pauses. This periodic breathing pattern, which shifts from a regular
rhythmicity to cyclic brief episodes of intermittent apnea, is more
101.1  Transition to Pulmonary Respiration common in preterm infants, who may have apneic pauses of 5-10 sec
Waldemar A. Carlo followed by a burst of rapid respirations at a rate of 50-60 breaths/min
for 10-15 sec. They rarely have an associated change in color or heart
Successful establishment of adequate lung function at birth depends rate, and periodic breathing often stops without apparent reason. Peri-
on airway patency, functional lung development, and maturity of respi- odic breathing, a normal characteristic of neonatal respiration, has no
ratory control. Fetal lung fluid must be removed and replaced with gas. prognostic significance.
This process begins before birth as active sodium transport across the
pulmonary epithelium drives liquid from the lung lumen into the
interstitium with subsequent absorption into the vasculature. Increased
levels of circulating catecholamines, vasopressin, prolactin, and gluco- 101.2  Apnea
corticoids enhance lung fluid adsorption and trigger the change in lung Waldemar A. Carlo
epithelia from a chloride-secretory to a sodium-reabsorptive mode.
Functional residual capacity (FRC) must be established and main- Apnea is a common problem in preterm infants that may be the result
tained in order to develop a ventilation–perfusion relationship that will of prematurity or an associated illness. In term infants, apnea is always
provide optimal exchange of oxygen and carbon dioxide between worrisome and demands prompt diagnostic evaluation. Periodic
alveoli and blood (see Chapter 421). breathing must be distinguished from prolonged apneic pauses,
because the latter may be associated with serious illnesses. Apnea is a
THE FIRST BREATH feature of many primary diseases that affect neonates (Table 101-1).
During vaginal delivery, intermittent compression of the thorax facili- These disorders produce apnea by direct depression of the central
tates removal of lung fluid. Surfactant lining the alveoli enhances the nervous system’s control of respiration (hypoglycemia, meningitis,
aeration of gas-free lungs by reducing surface tension, thereby lower- drugs, hemorrhage, seizures), disturbances in oxygen delivery (shock,
ing the pressure required to open alveoli. Although spontaneously sepsis, anemia), or ventilation defects (obstruction of the airway, pneu-
breathing infants do not need to generate an opening pressure to create monia, muscle weakness).
airflow, infants requiring positive-pressure ventilation at birth need an Idiopathic apnea of prematurity occurs in the absence of identifi-
opening pressure of 13-32 cm H2O and are more likely to establish able predisposing diseases. Apnea is a disorder of respiratory control
FRC if they generate a spontaneous, negative pressure breath. Expira- and may be obstructive, central, or mixed. Obstructive apnea (pha-
tory esophageal pressures associated with the first few spontaneous ryngeal instability, neck flexion) is characterized by absence of airflow
breaths in term newborns range from 45-90 cm H2O. This high pres- but persistent chest wall motion. Pharyngeal collapse may follow the
sure, due to expiration against a partially closed glottis, may aid in the negative airway pressures generated during inspiration or it may result
establishment of FRC but would be difficult to mimic safely with use from incoordination of the tongue and other upper airway muscles
of artificial ventilation. The higher pressures needed to initiate respira-
tion are required to overcome the opposing forces of surface tension
(particularly in small airways) and the viscosity of liquid remaining in Table 101-1 Potential Causes of Neonatal Apnea and
the airways, as well as to introduce about 50 mL/kg of air into the Bradycardia
lungs, 20-30 mL/kg of which remains after the first breath to establish
FRC. Air entry into the lungs displaces fluid, decreases hydrostatic Central nervous system Intraventricular hemorrhage, drugs,
pressure in the pulmonary vasculature, and increases pulmonary blood seizures, hypoxic injury, herniation,
neuromuscular disorders, Leigh
flow. The greater blood flow, in turn, increases the blood volume of the
syndrome, brainstem infarction or
lung and the effective vascular surface area available for fluid uptake. anomalies (e.g., olivopontocerebellar
The remaining fluid is removed via the pulmonary lymphatics, upper atrophy), spinal cord injury after general
airway, mediastinum, and pleural space. Fluid removal may be impaired anesthesia
after cesarean section or as a result of surfactant deficiency, endothelial
Respiratory Pneumonia, obstructive airway lesions,
cell damage, hypoalbuminemia, high pulmonary venous pressure, or
upper airway collapse, atelectasis,
neonatal sedation. extreme prematurity, laryngeal reflex,
Initiation of the first breath is caused by a decline in Pao2 and pH phrenic nerve paralysis, pneumothorax,
and a rise in Paco2 as a result of interruption of the placental circula- hypoxia
tion, a redistribution of cardiac output, a decrease in body temperature,
and various tactile and sensory inputs. The relative contributions of Infectious Sepsis, meningitis (bacterial, fungal, viral),
respiratory syncytial virus, pertussis
these stimuli to the onset of respiration are uncertain.
When compared with term infants, preterm infants have a very Gastrointestinal Oral feeding, bowel movement,
compliant chest wall and may be at a disadvantage in establishing FRC. necrotizing enterocolitis, intestinal
The FRC is lowest in the most immature infants because of the decrease perforation
in alveolar number. Abnormalities in ventilation : perfusion ratio are Metabolic ↓ Glucose, ↓ calcium, ↓/↑ sodium,
greater and persist for longer periods in preterm infants and may lead ↑ ammonia, ↑ organic acids,
to hypoxemia and hypercarbia as a result of atelectasis, intrapulmonary ↑ ambient temperature, hypothermia
shunting, hypoventilation, and gas trapping. The smallest immature Cardiovascular Hypotension, hypertension, heart failure,
infants have the most profound disturbances as a consequence of respi- anemia, hypovolemia, vagal tone
ratory distress syndrome (RDS). However, even in healthy term infants,
oxygenation is impaired immediately after birth, and oxygen saturation Other Immaturity of respiratory center, sleep
state
improves to exceed 90% only around 5 min. In addition, right-to-left

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850  Part XII  ◆  The Fetus and the Neonatal Infant

involved in maintaining airway patency. In central apnea, which is using nasal cannula (1-2.5 L/min) are therapies for mixed or obstruc-
caused by decreased central nervous system (CNS) stimuli to respira- tive apnea, but CPAP is preferred because of its proven efficacy and
tory muscles, both airflow and chest wall motion are absent. Gesta- safety. The efficacy of CPAP is related to its ability to splint the upper
tional age is the most important determinant of respiratory control, airway and prevent airway obstruction.
with the frequency of apnea being inversely related to gestational age.
The immaturity of the brainstem respiratory centers is manifested by PROGNOSIS
an attenuated response to carbon dioxide and a paradoxical response Apnea of prematurity does not alter an infant’s prognosis unless it is
to hypoxia that results in apnea rather than the hyperventilation severe, recurrent, and refractory to therapy. The associated problems
observed after the 1st few mo of life. The most common pattern of of intraventricular hemorrhage (IVH), BPD, and retinopathy of pre-
idiopathic apnea in preterm neonates is mixed apnea (50-75% of maturity are critical in determining the prognosis for apneic infants.
cases), with obstructive apnea preceding (usually) or following central Apnea of prematurity usually resolves by 37 wk of postconceptional
apnea. Short episodes of apnea are usually central, whereas prolonged age, although it may persist beyond term gestation, particularly in
ones are often mixed. Apnea depends on the sleep state; its frequency extremely preterm infants born at <28 wk of gestation, and does not
increases during active (rapid eye movement) sleep. predict future episodes of sudden infant death syndrome (SIDS). Some
infants with persistent apnea are discharged with cardiorespiratory
CLINICAL MANIFESTATIONS monitoring performed at home. In the absence of significant events,
The incidence of idiopathic apnea of prematurity varies inversely with home monitoring can be safely discontinued after 44 wk postconcep-
gestational age. The onset of idiopathic apnea can be during the 1st tional age.
1-2 wk after birth but is often delayed if there is RDS or other causes
of respiratory distress. Apneic episodes have been noted to be as fre- APNEA AND SUDDEN INFANT
quent on day 1 as throughout the 1st wk in premature infants without DEATH SYNDROME
respiratory disease. In preterm infants, serious apnea is defined as Although preterm infants are at higher risk for SIDS, apnea of prema-
cessation of breathing for longer than 20 sec or for any duration if turity is not a risk factor for SIDS. The epidemiologic evidence that
accompanied by cyanosis and bradycardia. The incidence of associated positioning the babies to sleep on their backs reduces the rate of SIDS
bradycardia increases with the length of the preceding apnea and cor- deaths by more than 50% suggests that position, and not prematurity,
relates with the severity of hypoxia. Short apnea episodes (10 sec) are has been the primary cause of SIDS. Avoidance of cigarette smoke
rarely associated with bradycardia, whereas longer episodes (>20 sec) exposure and of overheating the infant are also important in the pre-
have a higher incidence of bradycardia. Bradycardia follows the apnea vention of SIDS.
by 1-2 sec in more than 95% of cases and is most often sinus, but on
occasion it can be nodal. Vagal responses and, rarely, heart block are Bibliography is available at Expert Consult.
causes of bradycardia without apnea. Short oxygen desaturation epi-
sodes noted with oxygen saturation monitoring are normal in neo-
nates, and treatment is not necessary. 101.3  Respiratory Distress Syndrome
TREATMENT (Hyaline Membrane Disease)
Infants at risk for apnea should get cardiorespiratory monitoring. Waldemar A. Carlo and Namasivayam Ambalavanan
Gentle tactile stimulation is often adequate therapy for mild and inter-
mittent episodes. The onset of apnea in a previously well preterm INCIDENCE
neonate after the 2nd wk of life or in a term infant at any time is a Respiratory distress syndrome occurs primarily in premature infants;
critical event that warrants prompt investigation. Recurrent apnea of its incidence is inversely related to gestational age and birthweight. It
prematurity may be treated with caffeine or theophylline. Methyl­ occurs in 60-80% of infants <28 wk of gestational age, in 15-30% of
xanthines increase central respiratory drive by lowering the threshold those between 32 and 36 wk of gestational age, and rarely in those
of response to hypercapnia as well as enhancing contractility of >37 wk of gestational age. The risk for development of RDS increases
the diaphragm and preventing diaphragmatic fatigue. Caffeine and with maternal diabetes, multiple births, cesarean delivery, precipitous
theophylline are as effective, but caffeine has fewer side effects (less delivery, asphyxia, cold stress, and a maternal history of previously
tachycardia and feeding intolerance). Loading doses of 5-7 mg/kg of affected infants. The incidence is highest in preterm male or white
theophylline (orally) or aminophylline (intravenously) should be fol- infants. The risk of RDS is reduced in pregnancies with chronic or
lowed by doses of 1-2 mg/kg given every 6-12 hr by the oral or intra- pregnancy-associated hypertension, maternal heroin use, prolonged
venous route. Loading doses of 20 mg/kg of caffeine citrate are rupture of membranes, and antenatal corticosteroid prophylaxis.
followed 24 hr later by maintenance doses of 5 mg/kg/24 hr qd, either
orally or intravenously. These doses should be monitored through ETIOLOGY AND PATHOPHYSIOLOGY
observation of vital signs and clinical response. Serum drug determi- Surfactant deficiency (decreased production and secretion) is the
nations (therapeutic levels: theophylline, 6-10 µg/mL; caffeine, primary cause of RDS. The failure to attain an adequate FRC and the
8-20 µg/mL) are optional because important side effects of these medi- tendency of affected lungs to become atelectatic correlate with high
cations are rare. Higher doses of methylxanthines may be more effec- surface tension and the absence of pulmonary surfactant. The major
tive, do not necessarily result in more frequent side effects, and may constituents of surfactant are dipalmitoyl phosphatidylcholine (leci-
reduce major neurodevelopmental disabilities. Withholding respira- thin), phosphatidylglycerol, apoproteins (surfactant proteins SP-A,
tory stimulants in infants with RDS may result in ventilator depen- SP-B, SP-C, and SP-D), and cholesterol (Fig. 101-2). With advancing
dency, increased bronchopulmonary dysplasia (BPD), and death. gestational age, increasing amounts of phospholipids are synthesized
Doxapram, known to be a potent respiratory stimulant, acts predomi- and stored in type II alveolar cells (Fig. 101-3). These surface-active
nantly on peripheral chemoreceptors and is effective in neonates with agents are released into the alveoli, where they reduce surface tension
apnea of prematurity that is unresponsive to methylxanthines. Transfu- and help maintain alveolar stability by preventing the collapse of small
sion of packed red blood cells to reduce the incidence of idiopathic air spaces at end-expiration. Because of immaturity, the amounts pro-
apnea is reserved for severely anemic infants. Gastroesophageal reflux duced or released may be insufficient to meet postnatal demands.
is common in neonates, but data do not support a causal relationship Surfactant is present in high concentrations in fetal lung homogenates
between gastroesophageal reflux and apneic events or the use of anti- by 20 wk of gestation, but it does not reach the surface of the lungs
reflux medications to reduce the frequency of apnea in preterm infants. until later. It appears in amniotic fluid between 28 and 32 wk of gesta-
Nasal continuous positive airway pressure (continuous positive tion. Mature levels of pulmonary surfactant are present usually after
airway pressure [CPAP], 3-5 cm H2O) and high-flow humidification 35 wk of gestation.

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Chapter 101  ◆  Respiratory Tract Disorders  850.e1

Bibliography Schmidt B, Anderson PJ, Doyle LW, et al: Survival without disability to age 5 years
Arad-Cohen N, Cohen A, Tirosh E: The relationship between gastroesophageal after neonatal caffeine therapy for apnea of prematurity, JAMA 307:275–282,
reflux and apnea in infants, J Pediatr 137:321–326, 2000. 2012.
Committee on Fetus and Newborn, American Academy of Pediatrics: Apnea, Schmidt B, Roberts RS, Davis P, et al: Long term effects of caffeine for apnea of
sudden infant death syndrome, and home monitoring, Pediatrics 111:914–917, prematurity, N Engl J Med 357:1893–1902, 2007.
2003. Sreenan C, Lemke RP, Hudson-Mason A, et al: High-flow nasal cannulae in the
Kimball AL, Carlton DP: Gastroesophageal reflux medications in the treatment of management of apnea of prematurity: a comparison with conventional nasal
apnea in premature infants, J Pediatr 138:355–360, 2001. continuous positive airway pressure, Pediatrics 107:1081–1083, 2001.
Ramanathan R, Corwin MJ, Hunt CE, et al: Cardiorespiratory events recorded on Steer P, Flenady V, Shearman A, et al: High dose caffeine citrate for extubation of
home monitors: comparison of healthy infants with those at increased risk for preterm infants: a randomized controlled trial, Arch Dis Child Fetal Neonatal Ed
SIDS, JAMA 285:2199–2207, 2001. 89:F499–F503, 2004.

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Chapter 101  ◆  Respiratory Tract Disorders  851

Although rare, genetic disorders may contribute to respiratory dis- Deficient synthesis or release of surfactant, together with small
tress. Abnormalities in surfactant protein B and C genes as well as a respiratory units and a compliant chest wall, produces atelectasis and
gene responsible for transporting surfactant across membranes (ABC results in perfused but not ventilated alveoli, causing hypoxia.
transporter 3 [ABCA3]) are associated with severe and often lethal Decreased lung compliance, small tidal volumes, increased physiologic
familial respiratory disease. Other familial causes of neonatal respira- dead space, and insufficient alveolar ventilation eventually result in
tory distress (not RDS) include alveolar capillary dysplasia, acinar dys- hypercapnia. The combination of hypercapnia, hypoxia, and acidosis
plasia, pulmonary lymphangiectasia, and mucopolysaccharidosis. produces pulmonary arterial vasoconstriction with increased right-to-
Synthesis of surfactant depends in part on normal pH, temperature, left shunting through the foramen ovale and ductus arteriosus and
and perfusion. Asphyxia, hypoxemia, and pulmonary ischemia, par- within the lung itself. Progressive injury to epithelial and endothelial
ticularly in association with hypovolemia, hypotension, and cold stress, cells from atelectasis (atelectrauma), volutrauma, ischemic injury, and
may suppress surfactant synthesis. The epithelial lining of the lungs oxygen toxicity results in effusion of proteinaceous material into the
may also be injured by high oxygen concentrations and the effects of alveolar spaces (Fig. 101-4).
respirator management, thereby resulting in a further reduction in
surfactant. CLINICAL MANIFESTATIONS
Alveolar atelectasis, hyaline membrane formation, and interstitial Signs of RDS usually appear within minutes of birth, although they
edema make the lungs less compliant in RDS, so greater pressure is may not be recognized for several hours in larger premature infants
required to expand the alveoli and small airways. The chest wall of the until rapid, shallow respirations become more obvious. A later onset
preterm infant, which is highly compliant, offers less resistance than of tachypnea should suggest other conditions. Some patients require
that of the mature infant to the natural tendency of the lungs to col- resuscitation at birth because of intrapartum asphyxia or initial severe
lapse. Thus, at end-expiration, the volume of the thorax and lungs respiratory distress (especially with a birthweight <1,000 g). Charac-
tends to approach residual volume, and atelectasis may develop. teristically, tachypnea, prominent (often audible) grunting, intercostal
and subcostal retractions, nasal flaring, and cyanosis are noted. Breath
sounds may be normal or diminished with a harsh tubular quality, and
Neutral lipids on deep inspiration, fine crackles may be heard. The natural course of
untreated RDS is characterized by progressive worsening of cyanosis
SP-A and dyspnea. If the condition is inadequately treated, blood pressure
SP-B may fall; cyanosis and pallor increase, and grunting decreases or disap-
SP-C pears, as the condition worsens. Apnea and irregular respirations are
65% SP-D ominous signs requiring immediate intervention. Untreated patients
Other protein may also have a mixed respiratory-metabolic acidosis, edema, ileus,
Phosphatidylinositol and oliguria. Respiratory failure may occur in infants with rapid pro-
gression of the disease. In most cases, the signs reach a peak within 3
Phosphatidylethanolamine
days, after which improvement is gradual. Improvement is often her-
Phosphatidylcholine alded by spontaneous diuresis and improved blood gas values at lower
Phosphatidylglycerol inspired oxygen levels and/or lower ventilator support. Death can
result from severe impairment of gas exchange, alveolar air leaks (inter-
stitial emphysema, pneumothorax), pulmonary hemorrhage, or IVH.
BPD is a form of chronic lung disease that often develops in infants
Figure 101-2 Composition of surfactant recovered by alveolar wash. with severe RDS.
The quantities of the different components are similar for surfactant
from the mature lungs of mammals. SP, surfactant protein. (From Jobe
AH: Fetal lung development, tests for maturation, induction of matura- DIAGNOSIS
tion, and treatment. In Creasy RK, Resnick R, editors: Maternal-fetal The clinical course, chest x-ray findings, and blood gas and acid–base
medicine: principles and practice, ed 3, Philadelphia, 1994, WB values help establish the clinical diagnosis. On x-ray, the lungs may
Saunders.) have a characteristic but not pathognomonic appearance that includes

Air

Water
MLB LMF

MLB
MVB

SLB

GZ

N
ER

A B
Figure 101-3 A, Fetal rat lung (low magnification), day 20 (term: day 22) showing developing type II cells, stored glycogen (pale areas), secreted
lamellar bodies, and tubular myelin. B, Possible pathway for transport, secretion, and reuptake of surfactant. ER, endoplasmic reticulum; GZ, Golgi
zone; LMF, lattice (tubular) myelin figure; MLB, mature lamellar body; MVB, multivesicular body; N, nucleus; SLB, small lamellar body. (A courtesy
of Mary Williams, MD, University of California, San Francisco; B from Hansen T, Corbet A: Lung development and function. In Taeusch HW, Ballard
RA, Avery MA, editors: Schaffer and Avery’s diseases of the newborn, ed 6, Philadelphia, 1991, WB Saunders.)

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852  Part XII  ◆  The Fetus and the Neonatal Infant

Prematurity
C-section Familial predisposition
Intrapartum asphyxia Acidosis

Diminished
surfactant

Impaired
cellular Progressive
metabolism atelectasis

Alveolar Hypoventilation
hypoperfusion (disturbed V/Q)

Transient tachypnea
Pulmonary Neonatal asphyxia
pCO2’ pO2’ pH
vasoconstriction Hypothermia
Apnea

Hypotension
“shock”

Hypovolemia
Figure 101-4 Contributing factors in the pathogenesis of hyaline membrane disease. The potential “vicious circle” perpetuates hypoxia and
pulmonary insufficiency. (From Farrell P, Zachman R: Pulmonary surfactant and the respiratory distress syndrome. In Quilligan EJ, Kretchmer N,
editors: Fetal and maternal medicine, New York, 1980, Wiley. Reprinted by permission of John Wiley and Sons, Inc.)

a fine reticular granularity of the parenchyma and air bronchograms, PREVENTION


which are often more prominent early in the left lower lobe because of Avoidance of unnecessary or poorly timed early cesarean section
superimposition of the cardiac shadow (Fig. 101-5). The initial x-ray (<39 wk) or induction of labor, appropriate management of high-risk
appearance is occasionally normal, with the typical pattern developing pregnancy and labor (including administration of antenatal corticoste-
during the first day. Considerable variation in radiographic findings roids), and prediction of pulmonary immaturity with possible in utero
may be seen, depending on the phase of respiration (inspiratory vs. acceleration of maturation (see Chapter 98) are important preventive
expiratory radiograph) and the use of CPAP or positive end-expiratory strategies. Antenatal and intrapartum fetal monitoring may decrease
pressure (PEEP); this variation often results in poor correlation the risk of fetal asphyxia; asphyxia is associated with an increased
between radiographic findings and the clinical course. Laboratory incidence and severity of RDS.
findings are characterized initially by hypoxemia and later by progres- Administration of antenatal corticosteroids to women before 34 wk
sive hypoxemia, hypercapnia, and variable metabolic acidosis. of gestation significantly reduces the incidence and mortality of RDS
In the differential diagnosis, early-onset sepsis may be indistin- as well as overall neonatal mortality. Antenatal steroids also reduce
guishable from RDS. In neonates with pneumonia, the chest radio- (1) overall mortality, (2) the need for and duration of ventilatory
graph may be identical to that for RDS. Maternal group B streptococcal support and admission to a neonatal ICU, and (3) the incidence of
colonization, identification of organisms on Gram staining of gastric severe IVH, necrotizing enterocolitis, and neurodevelopmental impair-
or tracheal aspirates or a buffy coat smear, and/or the presence of ment. Postnatal growth is not adversely affected. Antenatal steroids do
marked neutropenia may suggest the diagnosis of early-onset sepsis. not increase the risk of maternal death, chorioamnionitis, or puerperal
Cyanotic heart disease (in particular, total anomalous pulmonary sepsis. Steroid administration is recommended for all women in
venous return) can also mimic RDS both clinically and radiographi- preterm labor who are likely to deliver a fetus within 1 wk. Antenatal
cally. Echocardiography with color-flow imaging should be performed steroids act synergistically with postnatal exogenous surfactant therapy
in infants who show no response to surfactant replacement to rule out so they should be given even though surfactant therapy is effective.
cyanotic congenital heart disease as well as ascertain patency of the Betamethasone and dexamethasone have both been used antenatally.
ductus arteriosus and assess pulmonary vascular resistance (PVR). Betamethasone may reduce neonatal death to a greater extent as com-
Persistent pulmonary hypertension, aspiration (meconium, amni- pared to dexamethasone.
otic fluid) syndromes, spontaneous pneumothorax, pleural effu- In the past administration of surfactant into the trachea of symp-
sions, and congenital anomalies, such as cystic adenomatoid tomatic premature infants immediately after birth (prophylactic) or
malformation, pulmonary lymphangiectasia, diaphragmatic hernia, during the 1st few hr of life (early rescue) showed reduced air leak and
and lobar emphysema, must be considered in patients with an atypical mortality from RDS. CPAP started at birth is as effective as prophylactic
clinical course, but can generally be differentiated from RDS through or early surfactant and is the approach of choice for the delivery room
radiographic and other evaluations. Transient tachypnea may be dis- management of a preterm neonate at risk for RDS.
tinguished by its shorter and milder clinical course and is characterized
by low or no need for oxygen supplementation. Congenital alveolar TREATMENT
proteinosis (congenital surfactant protein B deficiency) is a rare famil- The basic defect requiring treatment in RDS is inadequate pulmonary
ial disease that manifests as severe and lethal RDS in predominantly exchange of oxygen and carbon dioxide; metabolic acidosis and circu-
term and near-term infants (see Chapter 405). In atypical cases of RDS, latory insufficiency are secondary manifestations. Early supportive
a lung profile (lecithin : sphingomyelin ratio and phosphatidylglycerol care of premature infants, especially in the treatment of acidosis,
determination) performed on a tracheal aspirate can be helpful in hypoxia, hypotension (see Chapter 98), and hypothermia, may lessen
establishing a diagnosis of surfactant deficiency. the severity of RDS. Therapy requires careful and frequent monitoring

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Chapter 101  ◆  Respiratory Tract Disorders  853

A
A

B
B
C
C

A B
Figure 101-5 Infant with respiratory distress syndrome. Note the granular lungs, air bronchogram, and air-filled esophagus. Anteroposterior (A)
and lateral (B) roentgenograms are needed to distinguish the umbilical artery from the vein catheter and to determine the appropriate level of
insertion. The lateral view clearly shows that the catheter has been inserted into an umbilical vein and is lying in the portal system of the liver.
A indicates endotracheal tube; B indicates the umbilical venous catheter at the junction of the umbilical vein, ductus venosus, and portal vein;
C indicates the umbilical artery catheter passed up the aorta to T12. (Courtesy of Walter E. Berdon, Babies Hospital, New York City.)

of heart and respiratory rates, oxygen saturation, Pao2, Paco2, pH, of CPAP for stabilization of at-risk preterm infants beginning as early as
serum bicarbonate, electrolytes, glucose, hematocrit, blood pressure, in the delivery room reduces ventilatory needs. Another approach is to
and temperature. Arterial catheterization is frequently necessary. intubate the preterm infant, administer intratracheal surfactant and
Because most cases of RDS are self-limited, the goal of treatment is to then extubate the infant and begin CPAP. The amount of CPAP
minimize abnormal physiologic variations and superimposed iatro- required usually decreases after approximately 72 hr of age, and most
genic problems. Treatment of infants with RDS is best carried out in infants can be weaned from CPAP shortly thereafter. If an infant with
the neonatal ICU. RDS undergoing CPAP cannot keep oxygen saturation >90% while
The general principles for supportive care of any premature infant breathing 40-70% oxygen, assisted ventilation and surfactant are
should be adhered to, including developmental care and scheduled indicated.
“touch times.” To avoid hypothermia and minimize oxygen consump- Infants with respiratory failure or persistent apnea require assisted
tion, the infant should be placed in an incubator or radiant warmer, mechanical ventilation. Reasonable measures of respiratory failure are:
and core temperature maintained between 36.5 and 37°C (97.7 and (1) arterial blood pH <7.20, (2) arterial blood Pco2 of 60 mm Hg or
98.6°F) (see Chapters 97 and 98). Use of an incubator is preferable in higher, and (3) oxygen saturation <90% at oxygen concentrations of
very-low birthweight (VLBW) infants owing to the high insensible 40-70% and CPAP of 5-10 cm H2O. Infants with persistent apnea also
water losses associated with radiant heat. Calories and fluids should need mechanical ventilation. Intermittent positive pressure ventilation
initially be provided intravenously. For the 1st 24 hr, 10% glucose delivered by time-cycled, pressure-limited, continuous flow ventilators
solution with additional amino acids in extremely premature infants, is a common method of conventional ventilation for newborns. Other
should be infused through a peripheral vein at a rate of 65-75 mL/ methods of conventional ventilation are synchronized intermittent
kg/24 hr. Electrolytes should be added on day 2 in the most mature mandatory ventilation (the set rate and pressure synchronized with the
infants and on days 3-7 in the more immature ones. Fluid volume is patient’s own breaths), pressure support (the patient triggers each
increased gradually over the 1st wk. Excessive fluids (>140 mL/kg/ breath and a set pressure is delivered), and volume ventilation (a mode
day) contribute to the development of patent ductus arteriosus (PDA) in which a specific tidal volume is set and the delivered pressure
and BPD. varies), and combinations thereof. Assisted ventilation for infants with
Warm humidified oxygen should be provided at a concentration RDS should always include appropriate PEEP (see Chapter 71.1). High
initially sufficient to keep arterial oxygen pressure between 50 and ventilatory rates (≥60/min) with lower tidal volumes result in fewer air
70 mm Hg (91-95% saturation) in order to maintain normal tissue leaks. With use of high ventilatory rates, sufficient expiratory time
oxygenation while minimizing the risk of oxygen toxicity. If oxygen should be allowed to avoid the inadvertent PEEP.
saturation cannot be kept >90% at inspired oxygen concentrations of The goal of mechanical ventilation is to improve oxygenation and
40-70% or greater, applying CPAP at a pressure of 5-10 cm H2O via elimination of carbon dioxide without causing pulmonary injury or
nasal prongs is indicated and usually produces a rapid improvement oxygen toxicity. Acceptable ranges of blood gas values, after the risks
in oxygenation. CPAP reduces collapse of surfactant-deficient alveoli of hypoxia and acidosis are balanced against those of mechanical ven-
and improves both FRC and ventilation–perfusion matching. Early use tilation, vary among institutions: Pao2 50-70 mm Hg, Paco2 45-65 mm

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854  Part XII  ◆  The Fetus and the Neonatal Infant

Hg (and higher after the first few days when the risk of IVH is less), not offer advantages if used as the initial ventilation strategy to treat
and pH 7.20-7.35. During mechanical ventilation, oxygenation is infants with RDS.
improved by increasing either the fraction of inspired oxygen (Fio2) or Surfactant deficiency is the primary pathophysiology of RDS.
the mean airway pressure. The latter can be increased by raising the Immediate effects of surfactant replacement therapy include improved
peak inspiratory pressure, PEEP gas flow, or inspiratory-expiratory alveolar-arterial oxygen gradients, reduced ventilatory support,
ratio. Pressure changes are usually most effective. However, excessive increased pulmonary compliance, and improved chest radiograph
PEEP may impede venous return, thereby reducing cardiac output and appearance. In neonates with RDS who fail CPAP, treatment with
decreasing oxygen delivery despite improvement in Pao2. PEEP levels endotracheal surfactant should be initiated immediately after intuba-
of 4-6 cm H2O are usually safe and effective. Carbon dioxide elimina- tion. Repeated dosing is given every 6-12 hr for a total of 2 to 4 doses,
tion is achieved by increasing the peak inspiratory pressure (tidal depending on the preparation. Exogenous surfactant should be given
volume) or the rate of the ventilator. by a physician who is qualified in neonatal resuscitation and respira-
A strategy to minimize ventilator-associated lung injury is the use tory management. Additional onsite staff support required includes
of CPAP instead of endotracheal intubation. The decreased need for nurses and respiratory therapists experienced in the ventilatory man-
ventilator support with the use of CPAP may allow lung inflation to be agement of preterm infants. Appropriate monitoring equipment (radi-
maintained but may prevent volutrauma from overdistention and/or ology, blood gas laboratory, pulse oximetry) must also be available.
atelectasis. Early nasal CPAP is beneficial as compared to intubation Complications of surfactant therapy include transient hypoxia, hyper-
and prophylactic surfactant, including lower mortality or BPD with capnia, bradycardia and hypotension, blockage of the endotracheal
CPAP treatment. tube, and pulmonary hemorrhage (see Chapter 101.13).
An effective strategy with conventional mechanical ventilation is the A number of surfactant preparations are available, including syn-
use of high rates and presumably small tidal volumes as Paco2 levels thetic surfactants and natural surfactants derived from animal sources.
were kept in comparable ranges. Meta-analyses of the randomized The lack of reduction in BPD rates following surfactant replacement is
controlled trials comparing high (>60 breaths/min) and low (usually probably, in part, a result of the survival of infants with severe RDS
30-40 breaths/min) rates (and presumed low vs. high tidal volumes, who would have died without surfactant administration. Infants
respectively) revealed that the high ventilatory rate strategy led to requiring ventilator support after 1 wk of age may experience transient
fewer air leaks and a trend for increased survival. episodes of surfactant dysfunction associated with deficiencies of SP-B
If mechanical ventilation is needed, a ventilatory approach using and SP-C, which are temporally associated with episodes of infection
small tidal volumes and permissive hypercapnia can be employed. and respiratory deterioration. Surfactant treatment may be beneficial
Permissive hypercapnia is a strategy for the management of patients in these infants.
receiving ventilatory support in which priority is given to the preven- Strategies for weaning infants from ventilators vary widely and are
tion or limitation of lung injury from the ventilator by tolerating rela- influenced by lung mechanics as well as the availability of ventilatory
tively high levels of Paco2 rather than maintenance of normal blood modes (pressure support). Once extubated, many infants are transi-
gas values. Permissive hypercapnia can be implemented during CPAP tioned to nasal CPAP to avoid postextubation atelectasis and reduce
and mechanical ventilation. Volume-targeted ventilation allows the re-intubation. Synchronized nasal intermittent ventilation decreases
clinician to set a tidal volume that may prevent volutrauma. There are the need for re-intubation in premature infants. High flow (1-2 L/min)
limited data on volume-targeted ventilation, but this mode of ventila- or warmed, humidified high-flow (2-8 L/min) nasal cannula oxygen is
tion may decrease the rates of pneumothorax and BPD. commonly used to support term and near-term infants following extu-
Hyperoxia may also contribute to lung injury in preterm infants. bation and to wean premature infants from nasal CPAP. Preloading
However, a lower target range of oxygenation (85-89%), as compared with methylxanthines may enhance the success of extubation.
with a higher range (91-95%) increases mortality, and does not alter
rates of BPD, BPD/death, blindness, or neurodevelopmental impair- Pharmacologic Therapies
ment. Therefore, the currently recommended range of oxygen satu- Systemic corticosteroids have been used to treat infants with RDS, to
ration targets is 91-95%. selectively treat infants who continue to require respiratory support,
Many ventilated neonates receive sedation or pain relief with ben- and to treat those in whom BPD develops. Mortality and/or BPD at
zodiazepines or opiates (morphine, fentanyl), respectively. Midazolam 36 wk decrease with moderately early (7-14 days) administration of
is approved for use in neonates and has demonstrated sedative effects. corticosteroids. Early (<96 hr) and delayed (>2-3 wk) administration
Adverse hemodynamic effects and myoclonus have been associated of systemic steroids has also been assessed with meta-analyses, and the
with its use in neonates. If midazolam is used, a continuous infusion results are qualitatively similar. However, there are short-term adverse
or administration of individual doses over at least 10 min is recom- effects, including hyperglycemia, hypertension, gastrointestinal bleed-
mended to reduce these risks. Data are insufficient to assess the efficacy ing, gastrointestinal perforation, hypertrophic obstructive cardiomy-
and safety of lorazepam. Diazepam is not recommended owing to its opathy, poor weight gain, poor growth of the head, and a trend toward
long half-life, its long-acting metabolites, and concern about the benzyl a higher incidence of periventricular leukomalacia. Furthermore, data
alcohol content of diazepam injection. Continuous infusion of mor- showing an increased incidence of neurodevelopmental delay and
phine in VLBW neonates requiring mechanical ventilation does not cerebral palsy in infants randomly assigned to receive systemic corti-
reduce mortality rates, severe IVH, or periventricular leukomalacia. costeroids raise serious concerns about adverse long-term outcomes of
The need for additional doses of morphine is associated with poor this therapy. Thus, routine use of systemic corticosteroids for the pre-
outcome. vention or treatment of BPD is not recommended by the Consensus
High-frequency ventilation (HFV) achieves desired alveolar venti- Group of the American Academy of Pediatrics and the Canadian Pedi-
lation by using smaller tidal volumes and higher rates (300-1,200 atric Society. Administration of inhaled steroids to ventilated preterm
breaths/min or 5-20 Hz). HFV may improve elimination of carbon infants during the 1st 2 wk after birth reduced the need for systemic
dioxide and improve oxygenation in patients who show no response steroids and tended to decrease rates of death and/or BPD at 36 wk
to conventional ventilators and those who have severe RDS, interstitial without an increase in adverse effects.
emphysema, recurrent pneumothoraces, or meconium aspiration Inhaled nitric oxide has been evaluated in preterm infants follow-
pneumonia. High-frequency oscillatory ventilation (HFOV) and high- ing the observation of its effectiveness in term and near-term infants
frequency jet ventilation are the most frequently used methods of with hypoxemic respiratory failure. Inhaled nitric oxide (iNO)
HFV. HFOV reduces BPD but may raise the risk for intracranial hem- decreases the need for extracorporeal membrane oxygenation
orrhage. HFOV strategies that promote lung recruitment, combined (ECMO) in term and near-term infants with hypoxic respiratory
with surfactant therapy, may improve gas exchange. High-frequency failure or persistent pulmonary hypertension of the neonate. Trials in
jet ventilation facilitates resolution of air leaks. Elective use of either preterm infants report heterogeneous effects on BPD, mortality, and
method, in comparison with conventional ventilation, generally does other important outcomes. The most current data do not support the

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Chapter 101  ◆  Respiratory Tract Disorders  855

routine administration of iNO in preterm infants with hypoxemic Measures to reduce the incidence of these complications include
respiratory failure. skillful intubation, adequate securing of the tube, use of polyvinyl
Prevention of extubation failure has been attempted with use of endotracheal tubes, use of the smallest tube that will provide effective
various pharmacologic approaches. Methylxanthines appear to have a ventilation in order to reduce local pressure necrosis and ischemia,
large effect on reducing extubation failure. Similarly, use of systemic avoidance of frequent changes and motion of the tube in situ, avoid-
steroids before extubation reduces the need for reintubation (from 10% ance of too frequent or too vigorous suctioning, and prevention of
to 1%). In contrast, administration of racemic epinephrine after extu- infection through meticulous cleanliness and frequent sterilization of
bation does not improve pulmonary function or the rate of extubation all apparatus attached to or passed through the tube. The personnel
failure. inserting and caring for the endotracheal tube should be experienced
Metabolic acidosis in RDS may be a result of perinatal asphyxia and skilled in such care.
and hypotension and is often encountered when an infant has Risks associated with umbilical arterial catheterization include
required prolonged resuscitation (see Chapter 100). Sodium bicarbon- vascular embolization, thrombosis, spasm, and vascular perforation;
ate, 1-2 mEq/kg, may be administered over 15-20 min through a ischemic or chemical necrosis of abdominal viscera; infection; acciden-
peripheral or umbilical vein, followed by an acid–base determination tal hemorrhage; hypertension; and impairment of circulation to a leg
within 30 min, or it may be administered over several hours. Often, with subsequent gangrene. Aortography has demonstrated that clots
sodium bicarbonate is administered on an emergency basis through form in or about the tips of 95% of catheters placed in an umbilical
an umbilical venous catheter. Alkali therapy may result in skin slough- artery. Aortic ultrasonography can also be used to investigate for the
ing from infiltration, increased serum osmolarity, hypernatremia, presence of thrombosis. The risk of a serious clinical complication
hypocalcemia, hypokalemia, and liver injury when concentrated solu- resulting from umbilical catheterization is probably between 2%
tions are administered rapidly through an umbilical vein catheter and 5%.
wedged in the liver. Transient blanching of the leg may occur during catheterization of
Monitoring of aortic blood pressure through an umbilical or the umbilical artery. It is usually caused by reflex arterial spasm, the
peripheral arterial catheter or by oscillometric technique is useful in incidence of which is lessened by using the smallest available catheter,
managing the shock-like state that may occur during the 1st hr or so particularly in very small infants. The catheter should be removed
in premature infants who have been asphyxiated or have severe RDS immediately; catheterization of the other artery may then be attempted.
(see Fig. 100-2 in Chapter 100). The position of a radiopaque umbilical Persistent spasm after removal of the catheter may be relieved by a
catheter should be checked radiographically after insertion (see Fig. small amount of topical nitroglycerin paste applied to the affected area
101-5). The tip of an umbilical artery catheter should lie at L3-L5 just or by warming the other leg. Blood sampling from a radial artery may
above the bifurcation of the aorta or at T6-T10. Preferred sites for similarly result in spasm or thrombosis, and the same treatment is
peripheral catheters are the radial or posterior tibial arteries. The place- indicated. Intermittent severe spasm or unrelieved spasm may respond
ment and supervision should be carried out by skilled and experienced to the cautious use of topical nitroglycerin. Spasm or thrombosis unre-
personnel. Catheters should be removed as soon as patients no longer sponsive to treatment may result in gangrene of the organ or area
have any indication for their continued use—usually when an infant is supplied by the vessel.
stable and the Fio2 is <40%. Hypotension and low flow in the superior Serious hemorrhage upon removal of the catheter is rare. Thrombi
vena cava have been associated with higher rates of CNS morbidity and may form in the artery or in the catheter, the incidence of which can
mortality and should be treated with cautious administration of be lowered by using a smooth-tipped catheter with a hole only at its
volume (crystalloid) and early use of vasopressors. Dopamine is more end, by rinsing the catheter with a small amount of saline solution
effective in raising blood pressure than dobutamine. Hypotension may containing heparin, or by continuously infusing a solution containing
be refractory to pressors, but responsive to glucocorticoids, especially 1-2 units/mL of heparin. The risk of thrombus formation with poten-
in neonates <1,000 g. This hypotension may result from transient tial vascular occlusion can also be reduced by removing the catheter
adrenal insufficiency in the ill premature infant, which may be treated when early signs of thrombosis, such as narrowing of pulse pressure
with intravenous hydrocortisone at 1-2 mg/kg/dose q 6-12 hr (see and disappearance of the dicrotic notch, are noted. Some authorities
Chapter 98). prefer to use the umbilical artery for blood sampling only and to leave
Periodic monitoring of Pao2, Paco2, and pH is an important part the catheter filled with heparinized saline between samplings. Reno-
of the management; if assisted ventilation is being used, such monitor- vascular hypertension may occur days to weeks after umbilical arterial
ing is essential. Oxygenation may be assessed continuously from trans- catheterization in a small proportion of neonates.
cutaneous electrodes or pulse oximetry (oxygen saturation). Capillary Umbilical vein catheterization is associated with many of the same
blood samples are of limited value for determining Po2 but may be risks as umbilical artery catheterization. Additional risks are cardiac
useful for evaluating Pco2 and pH. perforation and pericardial tamponade; portal hypertension can
Because of the difficulty of distinguishing group B streptococcal or develop from portal vein thrombosis, especially in the presence of
other bacterial infections from RDS, empirical antibiotic therapy is omphalitis.
indicated until the results of blood cultures are available. Penicillin or Air leaks are a common complication of the management of infants
ampicillin with an aminoglycoside is suggested, although the choice of with RDS (see Chapter 101.12).
antibiotics should be based on the recent pattern of bacterial sensitivity Some neonates with RDS may have clinically significant shunting
in the hospital where the infant is being treated (see Chapter 109). through a PDA. Delayed closure of the PDA is associated with hypoxia,
acidosis, increased pulmonary pressure secondary to vasoconstriction,
COMPLICATIONS OF RESPIRATORY DISTRESS systemic hypotension, immaturity, and local release of prostaglandins,
SYNDROME AND INTENSIVE CARE which dilate the ductus. Shunting through the PDA may initially be
The most serious complications of tracheal intubation are pneumo- bidirectional or right-to-left. As RDS resolves, PVR decreases, and
thorax and other air leaks, asphyxia from obstruction or dislodgment left-to-right shunting may occur, leading to left ventricular volume
of the tube, bradycardia during intubation or suctioning, and the overload and pulmonary edema. Manifestations of PDA may include
subsequent development of subglottic stenosis. Other complications (1) a hyperdynamic precordium, bounding peripheral pulses, wide
include bleeding from trauma during intubation, posterior pharyngeal pulse pressure, and a continuous or systolic murmur with or without
pseudodiverticula, need for tracheostomy, ulceration of the nares extension into diastole or an apical diastolic murmur, or multiple clicks
caused by pressure from the tube, permanent narrowing of the nostril resembling the shaking of dice; (2) radiographic evidence of cardio-
as a result of tissue damage and scarring from irritation or infection megaly and increased pulmonary vascular markings; (3) hepatomegaly;
around the tube, erosion of the palate, avulsion of a vocal cord, laryn- (4) increasing oxygen dependence; and (5) carbon dioxide retention.
geal ulcer, papilloma of a vocal cord, and persistent hoarseness, stridor, The diagnosis is confirmed by echocardiographic visualization of a
or edema of the larynx. PDA with Doppler flow imaging that demonstrates left-to-right or

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856  Part XII  ◆  The Fetus and the Neonatal Infant

bidirectional shunting. Prophylactic “closure” before signs of a PDA, increased pulmonary artery pressure, and, possibly, a family history of
closure of the asymptomatic but clinically detected PDA, and closure atopy or asthma. Genetic polymorphisms may increase the risk for
of the symptomatic PDA are 3 strategies to manage a PDA. Interven- development of BPD. In some VLBW infants without RDS who require
tions include fluid restriction, the use of cyclooxygenase inhibitors mechanical ventilation for apnea or respiratory insufficiency, BPD that
(indomethacin or ibuprofen) to close the ductus, and surgical closure. does not follow the classic pattern may develop. Overhydration during
Short-term benefits have to be balanced against adverse effects such as the 1st days of life may also contribute to the development of BPD.
transient renal dysfunction and a possible increase in the risk of intes- Vitamin A supplementation (5,000 IU intramuscularly 3 times/wk for
tinal perforation with indomethacin. Much uncertainty about “best 4 wk) in VLBW infants reduces the risk of BPD (1 case prevented for
practice” in the management of a PDA remains. Many cases respond every 14-15 infants treated). Early use of nasal CPAP and rapid extuba-
to general supportive measures, including fluid restriction. Medical tion with transition to nasal CPAP are associated with a decreased risk
and/or surgical ductal closure is indicated in the premature infant with of BPD.
a large PDA when there is a delay in clinical improvement or deteriora- Instead of showing improvement on the 3rd or 4th day, which would
tion after initial clinical improvement of RDS. Intravenous indometha- be consistent with the natural course of RDS, some infants demonstrate
cin (0.1-0.2 mg/kg/dose) is given in 3 doses every 12-24 hr; treatment an increased need for oxygen and ventilatory support. Respiratory
may be repeated once. A second course may be needed in a few symp- distress persists or worsens and is characterized by hypoxia, hyper-
tomatic patients. If closure does not occur in a symptomatic patient, capnia, oxygen dependence, and, in severe cases, the development of
surgical ligation is usually the next step. Prophylactic low-dose indo- right-sided heart failure. The chest radiograph may reveal pulmonary
methacin given soon after birth reduces the incidence of both IVH and interstitial emphysema, wandering atelectasis with concomitant hyper-
PDA and improves the rate of permanent ductus closure even in the inflation, and cyst formation (Fig. 101-6). Four distinct pathologic
most immature infants. Contraindications to indomethacin include stages of classic BPD have been identified: acute lung injury, exudative
thrombocytopenia (<50,000 platelets/mm3), bleeding disorders, oligu- bronchiolitis, proliferative bronchiolitis, and obliterative fibroprolifera-
ria (urine output <1 mL/kg/hr), necrotizing enterocolitis, isolated tive bronchiolitis. Histologic study at this stage (10-20 days) shows
intestinal perforation, and an elevated plasma creatinine value residual hyaline membrane formation, progressive alveolar coales-
(>1.8 mg/dL). The infant whose symptomatic PDA fails to close with cence with atelectasis of the surrounding alveoli, interstitial edema,
indomethacin or who has contraindications to indomethacin is a can- coarse focal thickening of the basement membrane, and widespread
didate for surgical closure. Surgical mortality is very low even in the bronchial and bronchiolar mucosal metaplasia and hyperplasia. These
extremely low-birthweight infants. Complications of surgery include findings correspond to a severe maldistribution of ventilation. Patho-
Horner syndrome, injury to the recurrent laryngeal nerve, chylothorax, logic examination of infants who die later in the course of BPD reveals
transient hypertension, pneumothorax, and bleeding from the surgical cardiac enlargement and pulmonary changes consisting of focal areas
site. Inadvertent ligation of the left pulmonary artery or the transverse of emphysema with hypertrophy of the peribronchial smooth muscle
aortic arch has rarely been reported. of the tributary bronchioles, perimucosal fibrosis, widespread metapla-
Intravenous ibuprofen may be an alternative to indomethacin; it can sia of the bronchiolar mucosa, thickening of basement membranes,
be as effective in closing a PDA without reducing cerebral, mesenteric, and separation of the capillaries from the alveolar epithelial cells.
or renal blood flow velocity. Compared with indomethacin, therapeu- BPD can be classified according to the need for oxygen supplemen-
tic ibuprofen has a lower risk of oliguria. tation (Table 101-2). Neonates receiving positive pressure support or
BPD is a result of lung injury in infants requiring mechanical ven- ≥30% supplemental oxygen at 36 wk or at discharge (whichever occurs
tilation and supplemental oxygen. The clinical, radiographic, and lung first) are diagnosed as having severe BPD. Those needing supplementa-
histology of classic BPD described in 1967, in an era before the wide- tion with 22-29% oxygen at this age are diagnosed as having moderate
spread use of antenatal steroids and postnatal surfactant, was that of a BPD. Those who need oxygen supplementation for >28 days but are
disease of more mature preterm infants with RDS who were treated breathing room air at 36 wk or at discharge are diagnosed as having
with positive-pressure ventilation and oxygen. The new BPD is a mild BPD. Those receiving <30% oxygen should undergo a stepwise
disease primarily of infants with birthweight <1,000 g who were born 2% reduction in supplemental oxygen to room air while under con-
at <28 wk of gestation, some of whom have little or no lung disease at tinuous observation and with oxygen saturation monitoring to deter-
birth but experience progressive respiratory failure over the 1st few wk mine whether they can be weaned off oxygen (physiologic definition
of life. of BPD). This test is highly reliable and correlated with discharge home
The lung histology currently found in infants with the new BPD on oxygen, length of hospital stay, and hospital readmissions in the 1st
include alveolar hypoplasia, variable saccular wall fibrosis, and yr of life.
minimal airway disease. Some specimens also have decreased pulmo- Severe BPD requires prolonged mechanical ventilation. Gradual
nary microvasculature development. The histopathology of BPD indi- weaning should be attempted despite elevations in Paco2, because
cates interference with normal alveolar septation and microvascular hypercapnia may be the result of gas trapping rather than inadequate
maturation, which may prevent subsequent lung growth and develop- minute ventilation. Acceptable blood gas concentrations include
ment. The pathogenesis of BPD is multifactorial and affects both the hypercapnia with pH >7.20 and a Pao2 of 50-70 mm Hg with an
lungs and the heart. RDS is a disease of progressive alveolar collapse. oxygen saturation of 91-95%. Lower levels of Pao2 may exacerbate
Alveolar collapse (atelectrauma) as a consequence of surfactant defi- pulmonary hypertension with resultant cor pulmonale, so the lower
ciency, together with ventilator-induced phasic overdistention of the limit of oxygenation targets in neonates with BPD are higher than
lung (volutrauma), promotes injury. Oxygen induces injury by pro- those in neonates with RDS. Airway obstruction in BPD may be due
ducing free radicals that cannot be metabolized by the immature anti- to mucus and edema production, bronchospasm, and airway collapse
oxidant systems of VLBW neonates. Mechanical ventilation and from acquired tracheobronchomalacia. These events may contribute to
oxygen injure the lung through their effect on alveolar and vascular “blue spells.” Alternatively, blue spells may be the result of acute pul-
development. Inflammation (detected with measurement of circulat- monary vasospasm or right ventricular dysfunction.
ing neutrophils, neutrophils and macrophages in alveolar fluid, and Treatment of BPD includes nutritional support, fluid restriction,
proinflammatory cytokines) contributes to the progression of lung drug therapy, maintenance of adequate oxygenation, and prompt treat-
injury. Several clinical factors, including immaturity, chorioamnion- ment of infection. Growth must be monitored because recovery
itis, infection, symptomatic PDA, and malnutrition, contribute to the depends on the growth of lung tissue and remodeling of the pulmonary
development of BPD. vascular bed. Nutritional supplementation to provide added calories
The occurrence of BPD is inversely related to gestational age. Addi- (24-30 calories/30 mL formula), protein (3-3.5 g/kg/24 hr), and fat
tional associations include the presence of interstitial emphysema, (3 g/kg/24 hr) is needed for growth. Diuretic therapy results in a short-
male sex, low Paco2 during the treatment of RDS, PDA, high peak term improvement in lung mechanics and may lead to decreased
inspiratory pressure, increased airway resistance in the 1st wk of life, oxygen and ventilatory requirements. Furosemide (1 mg/kg/dose

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Chapter 101  ◆  Respiratory Tract Disorders  857

A B

C D
Figure 101-6 Pulmonary changes in infants treated with prolonged, intermittent positive-pressure breathing with air containing 80-100% oxygen
in the immediate postnatal period for the clinical syndrome of hyaline membrane disease. A, A 5 day old infant with nearly complete opacifica-
tion of the lungs. B, A 13 day old infant with “bubbly lungs” simulating the roentgenographic appearance of the Wilson-Mikity syndrome. C, A
7 mo old infant with irregular, dense strands in both lungs, hyperinflation, and cardiomegaly suggestive of chronic lung disease. D, Large right
ventricle and a cobbly, irregular aerated lung of an infant who died at 11 mo of age. This infant also had a PDA. (From Northway WH Jr, Rosan
RC, Porter DY: Pulmonary disease following respirator therapy of hyaline-membrane disease, N Engl J Med 276:357–368, 1967.)

Table 101-2 Definition of BPD: Diagnostic Criteria*


GESTATIONAL AGE
<32 Wk ≥32 Wk
Time point of 36 wk postmenstrual age or discharge home, whichever >28 days but <56 days postnatal age or discharge home,
assessment comes first whichever comes first
Treatment with >21% oxygen for at least 28 days plus Treatment with >21% oxygen for at least 28 days plus
Mild BPD Breathing room air at 36 wk postmenstrual age or discharge Breathing room air by 56 days postnatal age or discharge
home, whichever comes first home, whichever comes first
Moderate BPD Need† for <30% oxygen at 36 wk postmenstrual age or Need† for <30% oxygen at 56 days postnatal age or discharge
discharge home, whichever comes first home, whichever comes first
Severe BPD Need† for ≥30% oxygen and/or positive pressure (PPV or Need† for ≥30% oxygen and/or positive pressure (PPV or
NCPAP) at 36 wk postmenstrual age or discharge home, NCPAP) at 56 days postnatal age or discharge home,
whichever comes first whichever comes first
*BPD usually develops in neonates being treated with oxygen and PPV for respiratory failure, most commonly respiratory distress syndrome. Persistence of the clinical
features of respiratory disease (tachypnea, retractions, crackles) is considered common to the broad description of BPD and has not been included in the diagnostic
criteria describing the severity of BPD. Infants treated with >21% oxygen and/or PPV for nonrespiratory disease (e.g., central apnea or diaphragmatic paralysis) do not
have BPD unless parenchymal lung disease also develops and they have clinical features of respiratory distress. A day of treatment with >21% oxygen means that the
infant received >21% oxygen for more than 12 hr on that day. Treatment with >21% oxygen and/or PPV at 36 wk postmenstrual age or at 56 days postnatal age or
discharge should not reflect an “acute” event, but should rather reflect the infant’s usual daily therapy for several days preceding and after 36 wk postmenstrual age,
56 days postnatal age, or discharge.

A physiologic test confirming that the oxygen requirement at the assessment time point remains to be defined. This assessment may include a pulse oximetry
saturation range.
BPD, bronchopulmonary dysplasia; NCPAP, nasal continuous positive airway pressure; PPV, positive-pressure ventilation.
From Jobe AH, Bancalari E: Bronchopulmonary dysplasia, Am J Respir Crit Care Med 163:1723–1729, 2001.

intravenously twice daily [bid] or 2 mg/kg/dose orally bid) is the treat- hypokalemia, alkalosis, azotemia, hypocalcemia, hypercalciuria, cho-
ment of choice for acute fluid overload in infants with BPD. This loop lelithiasis, renal stones, nephrocalcinosis, and ototoxicity. Potassium
diuretic has been demonstrated to decrease pulmonary interstitial chloride supplementation is often necessary. Hyponatremia should be
emphysema and PVR, improve pulmonary function, and facilitate treated with fluid restriction and a decrease in the dose or frequency
weaning from mechanical ventilation and oxygen. Adverse effects of of furosemide. Thiazide diuretics have been used in infants with BPD.
long-term diuretic therapy are common and include hyponatremia, Several trials of thiazide diuretics combined with spironolactone have

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858  Part XII  ◆  The Fetus and the Neonatal Infant

shown increased urine output with or without improvement in pulmo- RDS by approximately 40%, but the incidence of BPD has not been
nary mechanics in infants with BPD. Adverse effects include electrolyte measurably affected.
imbalance. Although 85-90% of all infants surviving RDS after requiring venti-
Inhaled bronchodilators improve lung mechanics by decreasing latory support with respirators are normal, the outlook is much better
airway resistance. Albuterol is a specific β2-agonist used to treat for those weighing >1,500 g. The long-term prognosis for normal pul-
bronchospasm in infants with BPD. Albuterol may improve lung com- monary function in most infants surviving RDS is excellent. Survivors
pliance by decreasing airway resistance secondary to smooth muscle of severe neonatal respiratory failure may have significant pulmonary
cell relaxation. Changes in pulmonary mechanics may last as long as and neurodevelopmental impairment.
4-6 hr. Adverse effects include hypertension and tachycardia. Ipratro- Prolonged ventilation, IVH, pulmonary hypertension, cor pulmo-
pium bromide is a muscarinic antagonist related to atropine, but with nale, and oxygen dependence beyond 1 yr of life are poor prognostic
more potent bronchodilator effects. Improvements in pulmonary signs. Mortality in infants with BPD ranges from 10-25% and is highest
mechanics have been demonstrated in BPD after ipratropium bromide in infants who remain ventilator dependent for longer than 6 mo.
inhalation. Combination therapy using albuterol and ipratropium Cardiorespiratory failure associated with cor pulmonale and acquired
bromide may be more effective than either agent alone. Few adverse infection (respiratory syncytial virus) are common causes of death.
effects have been noted. With current aerosol administration strategies, Survivors with BPD often go home on a regimen of oxygen, diuretics,
exactly how much medication is delivered to the airways and lungs of and bronchodilator therapy.
infants with BPD, especially if they are ventilator dependent, is unclear. Pulmonary function slowly improves in most survivors owing to
Because significant smooth muscle relaxation does not appear to occur continued lung and airway growth and healing. Rehospitalization for
within the 1st few wk of life, aerosol therapy in the early stages of BPD impaired pulmonary function is most common during the 1st 2 yr of
is not indicated. Methylxanthines are used to increase respiratory life. There is a gradual decrease in symptom frequency in children ages
drive, decrease apnea, and improve diaphragmatic contractility. Meth- 6-9 yr from the frequency during the 1st 2 yr of life. Persistence of
ylxanthines may also decrease PVR and increase lung compliance in respiratory symptoms and abnormal pulmonary function test results
infants with BPD, probably through direct smooth muscle relaxation. are present in children ages 7-10 yr. Pulmonary function testing in
They also exhibit diuretic effects. These effects may accelerate weaning children with a history of BPD shows persistent abnormalities in clini-
from mechanical ventilation. Synergy between theophylline and cal moderate expiratory flow obstruction. Approximately 25-50% of
diuretics has been demonstrated. Theophylline has a half-life of very-low birthweight infants and more than 50% of children born at
30-40 hr, is metabolized primarily to caffeine in the liver and may have less than 26 wk of gestation continue to have abnormal spirometry as
adverse effects, such as tachycardia, gastroesophageal reflux, agitation, preadolescents. Many have asthma and respond to bronchodilators.
and seizures. Caffeine has a longer half-life than theophylline. Both are Infants are at risk for severe respiratory syncytial virus infections and
available in intravenous and enteral formulations. must receive prophylactic therapy (see Chapter 260). Airway obstruc-
Preventive therapy of BPD with postnatal dexamethasone may tion and hyperactivity and hyperinflation are noted in some adolescent
reduce the time to extubation and may decrease the risk of BPD but is and adult survivors of BPD. High-resolution chest CT scanning or MRI
associated with substantial short- and long-term risks, including studies in children and adults with a history of BPD reveal lung abnor-
hypertension, hyperglycemia, gastrointestinal bleeding and perfora- malities that correlate directly with the degree of pulmonary function
tion, hypertrophic cardiomyopathy, sepsis, and poor weight gain and abnormality.
head growth. Survival is not improved, and infants who have been Noncardiorespiratory complications of BPD include growth failure,
treated with dexamethasone have an increased risk of neurodevelop- psychomotor retardation, and parental stress, as well as sequelae of
mental delay and cerebral palsy. The use of dexamethasone for the therapy, such as nephrolithiasis, osteopenia, and electrolyte imbalance.
prevention of BPD is not recommended unless an infant has severe Airway problems, such as tonsillar and adenoidal hypertrophy, vocal
pulmonary disease, for example is ventilator dependent for at least 1 cord paralysis, subglottic stenosis, and tracheomalacia, are common
to 2 wk after birth. A rapid tapering course of therapy, starting at and may aggravate or cause pulmonary hypertension. Subglottic ste-
0.25 mg/kg/day and lasting for 5-7 days, may be adequate. Inhaled nosis may require tracheotomy or an anterior cricoid split procedure
beclomethasone does not prevent BPD but does decrease the need for to relieve upper airway obstruction. Cardiac complications of BPD
systemic steroids. Inhaled corticosteroids facilitate earlier extubation include pulmonary hypertension, cor pulmonale, systemic hyperten-
of ventilated infants with BPD. sion, left ventricular hypertrophy, and the development of aortopul-
Physiologic abnormalities of the pulmonary circulation in BPD monary collateral vessels, which, if large, may cause heart failure.
include elevated PVR and abnormal vasoreactivity. Acute exposure to
even modest levels of hypoxemia causes large elevations in pulmonary Bibliography is available at Expert Consult.
artery pressure in infants with BPD with pulmonary hypertension.
Higher oxygen saturations are effective in lowering pulmonary artery
pressure. The current recommendation for treatment of patients with
BPD and pulmonary hypertension is to maintain oxygen saturation 101.4  Transient Tachypnea of the Newborn
values in the 91-95% range. Namasivayam Ambalavanan and Waldemar A. Carlo
Low-dose iNO has no acute effects on lung function, cardiac func-
tion, or oxygenation in evolving BPD. The use of low-dose iNO may Transient tachypnea is most common after term cesarean delivery. It
improve oxygenation in some infants with severe BPD, allowing is characterized by the early onset of tachypnea, sometimes with retrac-
decreased Fio2 and ventilator support. tions, or expiratory grunting and, occasionally, cyanosis that is relieved
by minimal oxygen supplementation (<40%). Most infants recover
PROGNOSIS rapidly, usually within 3 days. The chest generally sounds clear without
Early provision of intensive observation and care of high-risk newborn crackles or wheeze, and the chest radiograph shows prominent pulmo-
infants can significantly reduce the morbidity and mortality associated nary vascular markings, fluid in the intralobar fissures, overaeration,
with RDS and other acute neonatal illnesses. Antenatal steroids, post- flat diaphragms, and, rarely, small pleural effusions. Hypercapnia
natal surfactant use, and improved modes of ventilation have resulted and acidosis are uncommon. Distinguishing the disease from RDS and
in low mortality from RDS (≈10%). Mortality increases with decreas- other respiratory disorders (e.g., pneumonia) may be difficult, and
ing gestational age. Optimal results depend on the availability of expe- transient tachypnea is frequently a diagnosis of exclusion; the distinc-
rienced and skilled personnel, care in specially designed and organized tive features of transient tachypnea are rapid recovery of the infant and
regional hospital units, proper equipment, and lack of complications the absence of radiographic findings for RDS (hypoaeration, diffuse
such as severe asphyxia, intracranial hemorrhage, or irremediable con- reticulogranular pattern, air bronchograms) and other lung disorders.
genital malformation. Surfactant therapy has reduced mortality from The syndrome is believed to be secondary to slow absorption of fetal

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Chapter 101  ◆  Respiratory Tract Disorders  858.e1

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in preterm infants with significant patent ductus arteriosus, J Pediatr in preterm infants in the delivery room; systematic review and meta-analysis,
161:404–408, 2012. BMJ 342:d1696, 2011.
Dunn MS, Kaempf J, deKlerk A, et al: Randomized trial comparing three Schmölzer GM, Te Pas AB, Davis PG, et al: Reducing lung injury during neonatal
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Pediatrics 128:1069–1076, 2011. Shah SS, Ohlsson A, Halliday H, et al: Inhaled versus systemic corticosteroids for
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Göpel W, Kribs A, Ziegler A, et al: Avoidance of mechanical ventilation by treatment and respiratory outcome in premature infants: a double-blind
surfactant treatment of spontaneously breathing preterm infants (AMV): an randomized controlled trial, J Pediatr 160:929–935, 2012.
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Greenough A, Dimitriou G, Prendergast M: Synchronized mechanical ventilation young adults after repeat courses of antenatal corticosteroids, J Pediatr
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(1):CD000456, 2008. Stark AR, Carlo WA, Tyson JE, et al: Adverse effects of early dexamethasone
Hammerman C, Shchors I, Jacobson S, et al: Ibuprofen versus continuous treatment in extremely-low-birth-weight infants, N Engl J Med 344:95–101,
indomethacin in premature neonates with patent ductus arteriosus: is the 2001.
difference in the mode of administration?, Pediatr Res 64:291–297, 2008. Stevens TP, Blennow M, Myers EH, et al: Early surfactant administration with brief
Hamvas A, Cole FS, Nogee LM: Genetic disorders of surfactant proteins, ventilation vs. selective surfactant and continued mechanical ventilation for
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For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
858.e2  Chapter 101  ◆  Respiratory Tract Disorders

for preterm infants with or at risk for respiratory distress syndrome (review), Vellanki H, Antunes M, Locke RG, et al: Decreased incidence of pneumothorax in
Cochrane Database Syst Rev (4):CD003063, 2007. VLBW infants after increased monitoring of tidal volumes, Pediatrics
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preterm infants, Cochrane Database Syst Rev (3):CD001243, 2005. limited ventilation in the neonate, Cochrane Database Syst Rev (3):CD003666,
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Med 362:1970–1978, 2010. following two different treatment approaches (early ligation and selective
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Network, Carlo WA, Finer NN, et al: Target ranges of oxygen saturation in Yeh TF, Ling HC, Chang CH, et al: Early intratracheal instillation of budesonide
extremely preterm infants, N Engl J Med 362:1959–1969, 2010. using surfactant as a vehicle to prevent chronic lung disease in preterm infants:
Tan A, Schulze AA, O’Donnell CPF, et al: Air versus oxygen for resuscitation of a pilot study, Pediatrics 121:e1310–e1318, 2008.
infants at birth, Cochrane Database Syst Rev (2):CD002273, 2005. Yoder BA, Stoddard RA, Li M, et al: Heated, humidified high-flow nasal cannula
Trembath A, Hornik CP, Clark R, et al: Comparative effectiveness of surfactant versus nasal CPAP for respiratory support in neonates, Pediatrics 131:e1482–
preparations in premature infants, J Pediatr 163:955–960, 2013. e1490, 2013.
Vaucher YE, Peralta-Carcelen M, Finer NN, et al: Neurodevelopmental outcomes
in the early CPAP and pulse oximetry trial, N Engl J Med 367:2495–2504, 2012.

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Chapter 101  ◆  Respiratory Tract Disorders  859

lung fluid, resulting in decreased pulmonary compliance and tidal


volume and increased dead space. In severe cases, retained fetal lung
fluid may interfere with the normal postnatal fall in PVR, resulting in
persistent pulmonary hypertension; a mild surfactant deficiency may
be present. Treatment is supportive. There is no evidence supporting
the use of oral furosemide or racemic epinephrine in this disorder. One
study demonstrated efficacy of inhaled salbutamol in enhancing reso-
lution of transient tachypnea of the newborn.
Severe respiratory morbidity and mortality have been reported in
infants born by elective cesarean section before full term (late preterm
infants) who initially present with signs and symptoms of transient
tachypnea. These infants often demonstrate refractory hypoxemia as a
result of pulmonary hypertension and require ECMO support. The
term “malignant transient tachypnea of the newborn” has been used
to describe this condition. The initial approach to these infants is
similar to that of RDS plus the concern for pulmonary hypertension.

Bibliography is available at Expert Consult.

101.5  Aspiration of Foreign Material


(Fetal Aspiration Syndrome,
Aspiration Pneumonia)
Waldemar A. Carlo

With fetal distress, infants often initiate vigorous respiratory move-


ments in utero because of interference with the supply of oxygen
through the placenta. Under such circumstances, the infant may aspi-
rate amniotic fluid containing vernix caseosa, epithelial cells, meco-
nium, blood, or material from the birth canal, which may block the
Figure 101-7 Fetal aspiration syndrome (aspiration pneumonia).
smallest airways and interfere with alveolar exchange of oxygen and Note the coarse granular pattern with irregular aeration typical of fetal
carbon dioxide. Pathogenic bacteria may accompany the aspirated distress from the aspiration of material contained in amniotic fluid, such
material, and pneumonia may ensue, but even in noninfected cases, as vernix caseosa, epithelial cells, and meconium. (From Goodwin SR,
respiratory distress accompanied by radiographic evidence of aspira- Grave SA, Haberkern CM: Aspiration in intubated premature infants,
tion is seen (Fig. 101-7). Pediatrics 75:85–88, 1985.)
Postnatal pulmonary aspiration may also occur in newborn infants
as a result of prematurity, tracheoesophageal fistula, esophageal and
duodenal obstruction, gastroesophageal reflux, improper feeding prac-
tices, and administration of depressant medicines. To avoid aspiration be prominent. The condition usually improves within 72 hr, but when
of gastric contents, the stomach should be aspirated using a soft cath- its course requires assisted ventilation, it may be severe with a high risk
eter just before surgery or other major procedures that require anes- for mortality. Tachypnea may persist for many days or even several
thesia or conscious sedation. The treatment of aspiration pneumonia weeks. The typical chest radiograph is characterized by patchy infil-
is symptomatic and may include respiratory support and systemic anti- trates, coarse streaking of both lung fields, increased anteroposterior
biotics (see Chapters 109.8 and 397). Gradual improvement generally diameter, and flattening of the diaphragm. A normal chest roentgeno-
occurs over 3-4 days. gram in an infant with severe hypoxemia and no cardiac malformation
suggests the diagnosis of pulmonary hypertension (see Chapter 101.7).

PREVENTION
101.6  Meconium Aspiration The risk of meconium aspiration may be decreased by rapid identifica-
Namasivayam Ambalavanan and Waldemar A. Carlo tion of fetal distress and initiation of prompt delivery in the presence
of late fetal heart rate deceleration or poor beat-to-beat fetal heart rate
Meconium-stained amniotic fluid is found in 10-15% of births and variability. Despite initial enthusiasm for amnioinfusion, it does not
usually occurs in term or postterm infants. Meconium aspiration syn- reduce the risk of MAS, cesarean delivery, or other major indicators of
drome (MAS) develops in 5% of such infants; 30% require mechanical maternal or neonatal morbidity. Intrapartum nasopharyngeal suction-
ventilation and 3-5% die. Usually, but not invariably, fetal distress and ing in infants with meconium-stained amniotic fluid does not reduce
hypoxia occur before the passage of meconium into amniotic fluid. The the risk for MAS.
infants are meconium stained and may be depressed and require resus-
citation at birth. Figure 101-8 shows the pathophysiology of the MAS. TREATMENT
Infants with MAS are at increased risk of persistent pulmonary hyper- Routine intubation to aspirate the lungs of vigorous infants born
tension (see Chapter 101.7). through meconium-stained fluid is not effective in reducing the MAS
or other major adverse outcomes. Depressed infants (those with hypo-
CLINICAL MANIFESTATIONS tonia, bradycardia, or decreased respiratory effort) are at higher risk of
Either in utero or with the first breath, thick, particulate meconium is MAS and may benefit from endotracheal intubation and suction to
aspirated into the lungs. The resulting small airway obstruction may remove meconium from the airway before the first breath in the deliv-
produce respiratory distress within the first hours, with tachypnea, ery room, but the data are inconclusive.
retractions, grunting, and cyanosis observed in severely affected Treatment of the MAS includes supportive care and standard man-
infants. Partial obstruction of some airways may lead to pneumome- agement for respiratory distress. The beneficial effect of mean airway
diastinum, pneumothorax, or both. Overdistention of the chest may pressure on oxygenation must be weighed against the risk of

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Chapter 101  ◆  Respiratory Tract Disorders  859.e1

Bibliography Liem JJ, Huq SI, Ekuma O, et al: Transient tachypnea of the newborn may be an
Armangil D, Yurdakök M, Korkmaz A, et al: Inhaled beta-2 agonist salbutamol for early clinical manifestation of wheezing symptoms, J Pediatr 151:29–33, 2007.
the treatment of transient tachypnea of the newborn, J Pediatr 159:398–403, Machado LU, Holmer H, Baldisserotto M, et al: Surfactant deficiency in transient
2011. tachypnea of the newborn, J Pediatr 159:750–754, 2011.

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For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
860  Part XII  ◆  The Fetus and the Neonatal Infant

Physiologic meconium passage


↑ PVR
(particularly if postdates)
SVR ↓
Fetal compromise (hypoxia, cord
compression, etc.) meconium passage

Meconium-stained amniotic fluid Pulmonay Vascular Heart


(structural changes; ↑ right to left shunting (RV pressure
altered reactivity to at PDA and FO overload,
Post-partum In-utero Continued dilator and constrictor hypotension, and
aspiration gasping compromise stimuli) LV dysfunction)

Meconium aspiration
Hypoxia,
hypercarbia,
Peripheral Proximal Inflammatory acidosis
airway airway and chemical
obstruction obstruction pneumonitis Remodeling of
pulmonary Lung
vasculature ↓ lung volume
Partial ↓ compliance
Complete ↑ intrapulmonary shunt
Acidosis
Ball-valve effect Hypoxemia
Hypercapnea Persistent Figure 101-9 Cardiopulmonary interactions in PPHN. FO, foramen
Atelectasis pulmonary ovale; LV, left ventricular; PDA, patent ductus arteriosus; PVR, pulmo-
hypertension nary vascular resistance; RV, right ventricular; SVR, systemic vascular
Air-trapping resistance. (From Kinsella JP, Abman SH: Recent developments in the
pathophysiology and treatment of persistent pulmonary hypertension
• of the newborn, J Pediatr 126:853–864, 1995.)
V/Q mismatch

Air leaks

utero constriction of the ductus arteriosus, maternal late trimester use


Figure 101-8 Pathophysiology of meconium passage and the of selective serotonin reuptake inhibitors, and pulmonary hypoplasia
meconium aspiration syndrome. V/Q,   ventilation-perfusion ratio.
(From Wiswell TE, Bent RC: Meconium staining and the meconium
caused by diaphragmatic hernia, amniotic fluid leak, oligohydramnios,
aspiration syndrome: unresolved issues, Pediatr Clin North Am 40:955– or pleural effusions. PPHN is often idiopathic. Some patients with
981, 1993.) PPHN have low plasma arginine and NO metabolite concentrations
and polymorphisms of the carbamoyl phosphate synthase gene, find-
ings suggestive of a possible subtle defect in NO production. The inci-
pneumothorax. Administration of exogenous surfactant and/or iNO to dence is 1/500-1,500 live births with a wide variation among clinical
infants with MAS and hypoxemic respiratory failure, or pulmonary centers.
hypertension requiring mechanical ventilation, decreases the need for
ECMO, which is needed by the most severely affected infants who PATHOPHYSIOLOGY
show no response to therapy. Severe meconium aspiration may be Persistence of the fetal circulatory pattern of right-to-left shunting
complicated by persistent pulmonary hypertension. Patients with MAS through the PDA and foramen ovale after birth is a result of excessively
that is refractory to conventional mechanical ventilation may benefit high PVR. Fetal PVR is usually elevated relative to fetal systemic or
from HFV or ECMO (see Chapter 101.7). postnatal pulmonary pressure. This fetal state normally permits shunt-
ing of oxygenated umbilical venous blood to the left atrium (and brain)
PROGNOSIS through the foramen ovale, from which it bypasses the lungs through
The mortality rate of meconium-stained infants is considerably higher the ductus arteriosus and passes to the descending aorta. After birth,
than that of nonstained infants. The decline in neonatal deaths caused PVR normally declines rapidly as a consequence of vasodilation sec-
by MAS during the last decades is related to improvements in obstetric ondary to lung inflation, a rise in postnatal Pao2, a reduction in Paco2,
and neonatal care. Residual lung problems are rare, but include symp- increased pH, and release of vasoactive substances. Increased neonatal
tomatic cough, wheezing, and persistent hyperinflation for up to PVR may be (1) maladaptive from an acute injury (not demonstrating
5-10 yr. The ultimate prognosis depends on the extent of CNS injury normal vasodilation in response to increased oxygen and other changes
from asphyxia and the presence of associated problems such as pulmo- after birth); (2) the result of increased pulmonary artery medial muscle
nary hypertension. thickness and extension of smooth muscle layers into the usually non-
muscular, more peripheral pulmonary arterioles in response to chronic
Bibliography is available at Expert Consult. fetal hypoxia; (3) a consequence of pulmonary hypoplasia (diaphrag-
matic hernia, Potter syndrome); or (4) obstructive as a result of poly-
cythemia or total anomalous pulmonary venous return, or of alveolar
101.7  Persistent Pulmonary Hypertension capillary dysplasia, which is a lethal autosomal recessive disorder char-
of the Newborn (Persistent Fetal acterized by thickened alveolar septa, increased muscularization of the
pulmonary arterioles, a reduced number of capillaries, and misalign-
Circulation) ment of the intrapulmonary veins. Regardless of etiology, profound
Namasivayam Ambalavanan and Waldemar A. Carlo hypoxemia from right-to-left shunting and normal or elevated Paco2
are present (Fig. 101-9).
Persistent pulmonary hypertension of the newborn (PPHN) occurs
mostly in in term and postterm infants. Predisposing factors include CLINICAL MANIFESTATIONS
birth asphyxia, MAS, early-onset sepsis, RDS, hypoglycemia, polycy- Infants with PPHN usually become ill in the delivery room or within
themia, maternal use of nonsteroidal antiinflammatory drugs with in the 1st 12 hr after birth. PPHN related to polycythemia, idiopathic

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Chapter 101  ◆  Respiratory Tract Disorders  860.e1

Bibliography Wiswell TE, Gannon CM, Jacob J, et al: Delivery room management of the
Vain NE, Szyld EG, Prudent LM: Oropharyngeal and nasopharyngeal suctioning of apparently vigorous meconium-stained neonate: results of the multicenter,
meconium-stained neonates before delivery of their shoulders: multicentre, international collaborative trial, Pediatrics 105:1–7, 2000.
randomized controlled trial, Lancet 364:597–602, 2004.

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Chapter 101  ◆  Respiratory Tract Disorders  861

causes, hypoglycemia, hypothermia, or asphyxia may result in severe is controversial and reserved for the newborn that cannot be treated
cyanosis with tachypnea, although initial signs of respiratory distress with sedatives alone. Muscle relaxants may promote atelectasis of
may be minimal. Infants who have PPHN associated with meconium dependent lung regions and ventilation–perfusion mismatch and may
aspiration, group B streptococcal pneumonia, diaphragmatic hernia, be associated with an increased risk of death.
or pulmonary hypoplasia usually exhibit cyanosis, grunting, flaring, Inotropic therapy is frequently needed to support blood pressure
retractions, tachycardia, and shock. Multiorgan involvement may be and perfusion. Whereas dopamine is frequently used as a first-line
present (see Table 98-1 in Chapter 98). Myocardial ischemia, papillary agent, other agents, such as dobutamine, epinephrine, and milrinone
muscle dysfunction with mitral and tricuspid regurgitation, and biven- may be helpful when myocardial contractility is poor. Some of the
tricular dysfunction produce cardiogenic shock with decreases in sickest newborns with PPHN demonstrate hypotension refractory to
pulmonary blood flow, tissue perfusion, and oxygen delivery. The vasopressor administration. This results from desensitization of the
hypoxemia is often labile and out of proportion to the findings on chest cardiovascular system to catecholamines by overwhelming illness and
radiographs. relative adrenal insufficiency. Hydrocortisone rapidly upregulates car-
diovascular adrenergic receptor expression and serves as a hormone
DIAGNOSIS substitute in cases of adrenal insufficiency.
PPHN should be suspected in all term infants who have cyanosis NO is an endothelium-derived signaling molecule that relaxes vas-
independent of a history of fetal distress, intrauterine growth restric- cular smooth muscle and can be delivered to the lung by inhalation.
tion, meconium-stained amniotic fluid, hypoglycemia, polycythemia, Use of iNO reduces the need for ECMO support by approximately 40%.
diaphragmatic hernia, pleural effusions, or birth asphyxia. Hypoxemia The optimal starting dose is 20 ppm. Higher doses have not been
is universal and is at least intermittently unresponsive to 100% oxygen shown to be more effective and are associated with side effects includ-
given by oxygen hood, but it may respond transiently to hyperoxic ing methemoglobinemia and increased levels of nitrogen dioxide, a
hyperventilation administered after endotracheal intubation or to the pulmonary irritant. Most newborns require iNO for <5 days. Although
application of a bag and mask. A Pao2 or oxygen saturation gradient NO has been used as long-term therapy in children and adults with
between a preductal (right radial artery) and a postductal (umbilical primary pulmonary hypertension, prolonged dependency is rare in
artery) site of blood sampling suggests right-to-left shunting through neonates and suggests the presence of lung hypoplasia, congenital
the ductus arteriosus. Foramen ovale shunting does not lead to a Pao2 heart disease, or alveolar capillary dysplasia. The maximal safe dura-
or oxygen saturation gradient. tion of iNO therapy is unknown. The dose can be weaned to 5 ppm
Real-time echocardiography combined with Doppler flow imaging after 6-24 hr of therapy. The dose can then be weaned slowly and dis-
is very helpful in evaluating PPHN. Systolic flattening of the interven- continued when the Fio2 is <0.6 and the iNO dose is 1 ppm. Abrupt
tricular septum as the right ventricular systolic pressure approaches discontinuation should be avoided as it may cause rebound pulmonary
the left ventricular systolic pressure can be used to estimate the degree hypertension. iNO should be used only at institutions that offer ECMO
of pulmonary hypertension. The peak velocity of the tricuspid valve support or have the capability of transporting an infant on iNO therapy
regurgitation jet, when present, yields a quantitative estimate of the if a referral for ECMO is necessary. Some infants with PPHN do not
right ventricular systolic pressure. Likewise, the direction and velocity respond adequately to iNO. Therapy with continuous inhaled or intra-
of a shunt across the PDA provides a quantitative comparison between venous prostacyclin (prostaglandin I2) has improved oxygenation and
the aortic and pulmonary artery pressures. In advanced cases, right- outcome in infants with PPHN. The safety and efficacy of sildenafil (a
to-left or bidirectional shunting across a PDA and/or a patent foramen type 5 phosphodiesterase inhibitor) in newborns with PPHN is under
ovale can be observed. investigation; initial results are promising.
In asphyxia-associated and idiopathic PPHN, chest x-ray findings
are normal, whereas in PPHN associated with pneumonia and Extracorporeal Membrane Oxygenation
diaphragmatic hernia, parenchymal opacification and bowel and/or In 5-10% of patients with PPHN, the response to 100% oxygen,
liver in the chest, respectively, are seen. The differential diagnosis of mechanical ventilation, and drugs is poor. In such patients, two param-
PPHN includes cyanotic heart disease (especially obstructed total eters have been used to predict mortality, the alveolar-arterial oxygen
anomalous pulmonary venous return) congenital surfactant deficiency gradient (Pao2−Pao2), and the oxygenation index, which is calculated
syndromes, alveolar-capillary dysplasia, and the associated etiologic as follows: Fio2 (as %) × MAP/Pao2.
entities that predispose to PPHN (hypoglycemia, polycythemia, sepsis, An alveolar–arterial gradient >620 for 8-12 hr and an oxygenation
hypothermia). index >40 that is unresponsive to iNO predict a high mortality rate
(>80%) and are indications for ECMO. ECMO is used to treat carefully
TREATMENT selected, severely ill infants with hypoxemic respiratory failure caused
Therapy is directed toward correcting any predisposing condition by RDS, meconium aspiration pneumonia, congenital diaphragmatic
(hypoglycemia, polycythemia, others) and improving poor tissue oxy- hernia, PPHN, or sepsis.
genation. The response to therapy is often unpredictable, transient, and ECMO is a form of cardiopulmonary bypass that augments systemic
complicated by the adverse effects of drugs or mechanical ventilation. perfusion and provides gas exchange. Most experience has been with
Initial management includes oxygen administration and correction of venoarterial bypass, which requires carotid artery ligation and the
acidosis, hypotension, and hypercapnia. Persistent hypoxemia should placement of large catheters in the right internal jugular vein and
be managed with intubation and mechanical ventilation. carotid artery. Venovenous bypass avoids carotid artery ligation and
The optimal approach to mechanical ventilation has evolved. In the provides gas exchange, but it does not support cardiac output. Blood
pre-iNO era, treatment of severe PPHN consisted of instituting is initially pumped through the ECMO circuit at a rate that approxi-
mechanical ventilation with 1 or more of the following: muscle relax- mates 80% of the estimated cardiac output, 150-200 mL/kg/min.
ants, hyperventilation, and alkalinization with sodium bicarbonate. Venous return passes through a membrane oxygenator, is rewarmed,
These therapies may lead to complications associated with hypocarbia and returns to the aortic arch in venoarterial ECMO and to the right
including reduced cerebral blood flow, cerebral palsy, and deafness; atrium in venovenous ECMO. Venous oxygen saturation values are
volutrauma; and impaired cardiac function which have resulted in less used to monitor tissue oxygen delivery and subsequent extraction for
use of these practices. Currently, infants with PPHN are usually infants undergoing venoarterial ECMO, whereas arterial oxygen satu-
managed without hyperventilation and/or alkalinization. In skilled ration values are used to monitor oxygenation for infants receiving
hands, “gentle ventilation” with normocarbia or permissive hypercar- venovenous ECMO.
bia and avoidance of hypoxemia result in excellent outcomes and a low Because ECMO requires complete heparinization to prevent clot-
incidence of chronic lung disease and ECMO use. ting in the circuit, it cannot be used in patients with or at high risk
Because of their instability and ability to fight the ventilator, new- for IVH (weight <2 kg, gestational age <34 wk). In addition, infants
borns with PPHN usually require sedation. The use of paralytic agents for whom ECMO is being considered should have reversible lung

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862  Part XII  ◆  The Fetus and the Neonatal Infant

disease, no signs of systemic bleeding, an absence of severe asphyxia highly variable, ranging from a small hole to complete agenesis of this
or lethal malformations, and they should have been ventilated for area of the diaphragm.
less than 10 days. Complications of ECMO include thromboembo-
lism, air embolization, bleeding, stroke, seizures, atelectasis, choles- CONGENITAL DIAPHRAGMATIC HERNIA
tatic jaundice, thrombocytopenia, neutropenia, hemolysis, infectious (BOCHDALEK)
complications of blood transfusions, edema formation, and systemic Pathology and Etiology
hypertension. Although CDH is characterized by a structural diaphragmatic defect,
a major limiting factor for survival is the associated pulmonary hypo-
PROGNOSIS plasia. Lung hypoplasia was initially thought to be solely caused by the
Survival in patients with PPHN varies with the underlying diagnosis. compression of the lung from the herniated abdominal contents, which
The long-term outcome for infants with PPHN is related to the associ- impaired lung growth. However, emerging evidence indicates that pul-
ated hypoxic-ischemic encephalopathy and the ability to reduce PVR. monary hypoplasia, at least in some cases, may precede the develop-
The long-term prognosis for infants who have PPHN and who survive ment of the diaphragmatic defect.
after treatment with hyperventilation is comparable to that for infants Pulmonary hypoplasia is characterized by a reduction in pulmonary
who have underlying illnesses of equivalent severity (birth asphyxia, mass and the number of bronchial divisions, respiratory bronchioles,
hypoglycemia, polycythemia). The outcome for infants with PPHN and alveoli. The pathology of pulmonary hypoplasia and CDH includes
who are treated with ECMO is also favorable; >80-90% survive, and abnormal septa in the terminal saccules, thickened alveoli, and thick-
60-75% of survivors appear normal at 1-3.5 yr of age. Survival of ened pulmonary arterioles. Biochemical abnormalities include relative
infants born with congenital diaphragmatic hernia (CDH) has surfactant deficiencies, increased glycogen in the alveoli, and decreased
increased over the past 10 yr to 67%; benchmark institutions are levels of phosphatidylcholine, total DNA, and total lung protein, all of
reporting survival rates >80%. Those infants with CDH who require which contribute to limited gas exchange.
ECMO continue to have a lower survival than the general neonatal
population undergoing ECMO (~50%). Epidemiology
The incidence of CDH is between 1/2,000 and 1/5,000 live births, with
Bibliography is available at Expert Consult. females affected twice as often as males. Defects are more common on
the left (85%) and are occasionally (<5%) bilateral. Pulmonary hypo-
plasia and malrotation of the intestine are part of the lesion, not associ-
ated anomalies. Most cases of CDH are sporadic, but familial cases
101.8  Diaphragmatic Hernia have been reported. Associated anomalies have been reported in up to
Akhil Maheshwari and Waldemar A. Carlo 30% of cases; these include CNS lesions, esophageal atresia, omphalo-
cele, and cardiovascular lesions. CDH is recognized as part of several
A diaphragmatic hernia is defined as a communication between the chromosomal syndromes: trisomy 21, trisomy 13, trisomy 18, Fryns,
abdominal and thoracic cavities with or without abdominal contents Brachmann-de Lange, Pallister-Killian, and Turner.
in the thorax (Fig. 101-10). The etiology is usually congenital but may
be traumatic. The symptoms and prognosis depend on the location of Diagnosis and Clinical Presentation
the defect and associated anomalies. The defect may be at the esopha- CDH can be diagnosed on prenatal ultrasonography (between 16 and
geal hiatus (hiatal), paraesophageal (adjacent to the hiatus), retroster- 24 wk of gestation) in >50% of cases. High-speed fetal MRI can further
nal (Morgagni), or at the posterolateral (Bochdalek) portion of the define the lesion. Findings on ultrasonography may include polyhy-
diaphragm. The term congenital diaphragmatic hernia typically refers dramnios, chest mass, mediastinal shift, gastric bubble or a liver in the
to the Bochdalek form. These lesions may cause significant respiratory thoracic cavity, and fetal hydrops. Certain imaging features may predict
distress at birth, can be associated with other congenital anomalies, outcome; these include lung : head size ratio. Nonetheless, no definitive
and have significant mortality and long-term morbidity. The overall characteristic reliably predicts outcome. After delivery, a chest radio-
survival from the CDH Study Group is 67%. The Bochdalek hernia graph is needed to confirm the diagnosis (Fig. 101-11). In some infants
accounts for up to 90% of the hernias seen in the newborn period, with with an echogenic chest mass, further imaging is required. The dif-
80-90% occurring on the left side. The Morgagni hernia accounts for ferential diagnosis may include other diaphragm disorders such as
2-6% of congenital diaphragmatic defects. The size of the defect is eventration, a cystic lung lesion (pulmonary sequestration, cystic ade-
nomatoid malformation), and others.
Arriving at the diagnosis early in pregnancy allows for prenatal
counseling, possible fetal interventions, and planning for postnatal
care. A referral to a center providing high-risk obstetrics, pediatric
surgery, and tertiary care neonatology is advised. Careful evaluation
for other anomalies should include echocardiography and amniocen-
tesis. To avoid unnecessary pregnancy termination and unrealistic
expectations, an experienced multidisciplinary group must carefully
counsel the parents of a child diagnosed with a diaphragmatic hernia.
Respiratory distress is a cardinal sign in babies with CDH. It may
occur immediately after birth or there may be a “honeymoon” period
of up to 48 hr during which the baby is relatively stable. Early respira-
tory distress, within 6 hr after birth, is thought to be a poor prognostic
sign. Respiratory distress is characterized clinically by tachypnea,
grunting, use of accessory muscles, and cyanosis. Children with CDH
may also have a scaphoid abdomen and increased chest wall diameter.
Bowel sounds may also be heard in the chest with decreased breath
Normal diaphragm Bochdalek diaphragmatic defect sounds bilaterally. The point of maximal cardiac impulse may be dis-
with herniation of small lung
placed away from the side of the hernia if mediastinal shift has
A B occurred. A chest x-ray and passage of a nasal gastric tube are all that
Figure 101-10 A, A normal diaphragm separating the abdominal and is usually required to confirm the diagnosis.
thoracic cavity. B, Diaphragmatic hernia with a small lung and abdomi- A small group of infants with CDH present beyond the neonatal
nal contents in the thoracic cavity. period. Patients with a delayed presentation may experience vomiting

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Chapter 101  ◆  Respiratory Tract Disorders  862.e1

Bibliography newborn: population based cohort study from the five Nordic countries, BMJ
Baquero H, Soliz A, Neira F, et al: Oral sildenafil in infants with persistent 344:d8012, 2012.
pulmonary hypertension of the newborn: a pilot randomized blinded study, Kulik TJ, Rhein LM, Mullen MP: Pulmonary arterial hypertension in infants with
Pediatrics 117:1077–1083, 2006. chronic lung disease: will we ever understand it?, J Pediatr 157(2):186–190,
Barrington KJ, Finer N: Inhaled nitric oxide for respiratory failure in preterm 2010.
infants, Cochrane Database Syst Rev (3):CD000509, 2007. Mugford M, Elbourne D, Field D: Extracorporeal membrane oxygenation for
Finer N, Barrington KJ: Nitric oxide for respiratory failure in infants born at or severe respiratory failure in newborn infants, Cochrane Database Syst Rev
near term, Cochrane Database Syst Rev (4):CD000399, 2006. (16):CD001340, 2008.
Ibrahim YI, Ninnis JR, Hopper AO, et al: Inhaled nitric oxide therapy increases Sen P, Thakur N, Stockton DW, et al: Expanding the phenotype of alveolar
blood nitrite, nitrate, and S-nitrosohemoglobin concentrations in infants with capillary dysplasia (ACD), J Pediatr 145:646–651, 2004.
pulmonary hypertension, J Pediatr 160:245–251, 2012. Steinhorn RH, Kinsella JP, Pierce C, et al: Intravenous sildenafil in the treatment
Kieler H, Artama M, Engeland A, et al: Selective serotonin reuptake inhibitors of neonates with persistent pulmonary hypertension, J Pediatr 155:841–847,
during pregnancy and risk of persistent pulmonary hypertension in the 2009.

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Chapter 101  ◆  Respiratory Tract Disorders  863

NO is a selective pulmonary vasodilator. Its use reduces ductal


shunting and pulmonary pressures and results in improved oxygen-
ation. Although it has been helpful in PPHN, randomized trials have
not demonstrated improved survival or reduced need for ECMO when
NO is used in newborns with CDH. Nonetheless, it is used in patients
with CDH before ECMO is started (see Chapter 101.7).

Extracorporeal Membrane Oxygenation


The availability of ECMO and the utility of preoperative stabilization
have improved survival of babies with CDH. ECMO is the therapeutic
option in children in whom conventional ventilation or conventional
ventilation and HFOV fail. ECMO is most commonly used before
repair of the defect. Several objective criteria for ECMO have been
developed (see Chapter 101.7).
Birthweight and the 5-min Apgar score may be the best predictors
of outcome in patients treated with ECMO. The lower limit of weight
for ECMO is 2,000 g.
The duration of ECMO for neonates with diaphragmatic hernia is
longer (7-14 days) than for those with persistent fetal circulation or
meconium aspiration, and may last up to 2-4 wk. Timing of repair of
the diaphragm while the infant receives ECMO is controversial; some
experts prefer early repair to allow a greater duration of ECMO after
the repair, whereas many defer repair until the infant has demonstrated
the ability to tolerate weaning from ECMO. The recurrence of pulmo-
nary hypertension is associated with a high mortality, and weaning
from ECMO support should be cautious. If the patient cannot be
Figure 101-11 This chest radiograph shows a stomach, nasogastric weaned from ECMO after repair of CDH, options include discontinu-
tube, and small bowel contents in the thoracic cavity, consistent with
ing support and, in rare cases, lung transplantation.
a CDH.
Novel Strategies for Infants with Congenital
Diaphragmatic Hernia
as a result of intestinal obstruction or mild respiratory symptoms. The most reliable prenatal prognosticators of outcomes in children
Occasionally, incarceration of the intestine proceeds to ischemia with with CDH studied is fetal ultrasonography. A prospective study using
sepsis and shock. Unrecognized diaphragmatic hernia is a rare cause this modality at 24-26 wk compared fetal lung : head size ratio. There
of sudden death in infants and toddlers. Group B streptococcal sepsis were no survivors when the lung : head size ratio was <1, and all babies
has been associated with delayed onset of symptoms and a CDH (often with lung : head size ratio >1.4 survived. A second important consid-
right side). eration was the presence of liver in the thoracic cavity, which is a poor
prognostic feature. Human studies have shown no benefit for in utero
Treatment repair of CDH.
Initial Management Tracheal occlusion in utero is based on the observation that in utero
Aggressive respiratory support is often needed in children with CDH. fetal lung fluid plays a critical role in lung growth and maturity. A
This includes rapid endotracheal intubation, sedation, and possibly deficiency of lung fluid results in pulmonary hypoplasia. Initial studies
paralysis. Arterial (preductal and postductal) and central venous in affected fetuses have not demonstrated success, but new preliminary
(umbilical) lines are mandated, as are a urinary catheter and naso­ reports are showing some efficacy. Partial liquid ventilation after birth
gastric tube. A preductal arterial oxygen saturation (Spo2) value ≥85% is an experimental therapy under investigation in adults and children
should be the minimum goal. Prolonged mask ventilation in the deliv- with severe respiratory failure. Partial liquid ventilation increases
ery room, which enlarges the stomach and small bowel and thus FRC by recruiting collapsed alveoli, thereby improving ventilation–
makes oxygenation more difficult, must be avoided. Volutrauma is a perfusion mismatches and compliance. It also may reduce lung injury
significant problem. Gentle ventilation with permissive hypercapnia and increase surfactant production.
reduces lung injury, need for ECMO, and mortality. Factors that con-
tribute to pulmonary hypertension (hypoxia, acidosis, hypothermia) Surgical Repair
should be avoided. Echocardiography is important to guide therapeu- The ideal time to repair the diaphragmatic defect is under debate.
tic decisions by measuring pulmonary and system vascular pressures Most experts wait at least 48 hr after stabilization and resolution of
and defining the presence of cardiac dysfunction. Routine use of ino- the pulmonary hypertension. Good relative indicators of stability are
tropes is indicated in the presence of left ventricular dysfunction. the requirement for conventional ventilation only, a low peak inspira-
Babies with CDH may be surfactant deficient. Although surfactant is tory pressure, and a Fio2 <50. If the newborn is on ECMO, an ability
commonly used, no study has proven that it is beneficial in treatment to be weaned from this support should be a consideration before
of CDH. surgical repair. In some centers, the repair is done with the cannulas
in place; in other centers, the cannulas are removed. A subcostal
Ventilation Strategies approach is the most frequently used (Fig. 101-12). This allows for
Conventional mechanical ventilation, HFOV, and ECMO are the 3 good visualization of the defect and, if the abdominal cavity cannot
main strategies to support respiratory failure in the newborn with accommodate the herniated contents, a polymeric silicone (Silastic)
CDH. The goal is to maintain oxygenation and carbon dioxide elimina- patch can be placed. Both laparoscopic and thoracoscopic repairs
tion without inducing volutrauma. The first modality to be used is have been reported, but these should be reserved for only the most
conventional ventilation. Hyperventilation to induce alkalosis and stable infants.
decrease ductal shunting has not proved effective and should be The defect size and amount of native diaphragm present are variable.
avoided. Permissive hypercapnia has reduced lung injury and mortality Whenever possible, a primary repair using native tissue is performed.
rates in several studies. HFOV can be used early to prevent lung injury If the defect is too large, a porous polytetrafluoroethylene (Gore-Tex)
by using lower airway pressures. patch is used.

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864  Part XII  ◆  The Fetus and the Neonatal Infant

Diaphragm
defect

Diaphragm with
patch repair

Figure 101-13 A chest radiograph demonstrating a Morgagni


hernia.

B energy required to breathe. Many children normalize and “catch up”


in growth by the time they are 2 yr old.
Figure 101-12 A, An intraoperative picture of a CDH before repair. Neurocognitive defects are common and may result from the
B, An intraoperative picture of a patch repair of a CDH. disease or the interventions. The incidence of neurologic abnormalities
is higher in infants who require ECMO (67% vs. 24% of those who do
not). The abnormalities are similar to those seen in neonates treated
There is a higher recurrence rate of CDH among children with with ECMO for other diagnoses and include transient and permanent
patches (the patch does not grow as the child grows) than among those developmental delay, abnormal hearing or vision, and seizures. Serious
with repairs with native tissue. A loosely fitted patch may reduce the hearing loss may occur in up to 28% of children who underwent
recurrence rates. Pulmonary hypertension must be monitored care- ECMO. The majority of neurologic abnormalities are classified as mild
fully, and in some instances, a postoperative course of ECMO is to moderate.
needed. Other recognized complications include bleeding, chylotho- Other long-term problems occurring in this population include
rax, and bowel obstruction. pectus excavatum and scoliosis. Survivors of CDH repair, particularly
those requiring ECMO support, have a variety of long-term abnor-
Outcome and Long-Term Survival malities that appear to improve with time but require close monitoring
Overall survival of liveborn infants with CDH is 67%. The incidence and multidisciplinary support.
of spontaneous fetal demise is 7-10%. Relative predictors of a poor
prognosis include an associated major anomaly, symptoms before Bibliography is available at Expert Consult.
24 hr of age, severe pulmonary hypoplasia, herniation to the contra-
lateral lung, and the need for ECMO.
Pulmonary problems continue to be a source of morbidity for long-
term survivors of CDH. Children receiving CDH repair who were 101.9  Foramen of Morgagni Hernia
studied at 6-11 yr of age demonstrated significant decreases in forced Akhil Maheshwari and Waldemar A. Carlo
expiratory flow at 50% of vital capacity and decreased peak expiratory
flow. Both obstructive and restrictive patterns can occur. Those without The anteromedial diaphragmatic defect through the foramen of
severe pulmonary hypertension and barotrauma do the best. Those at Morgagni accounts for 2-6% of diaphragmatic hernias. Failure of the
highest risk include children who required ECMO and patch repair, sternal and crural portions of the diaphragm to meet and fuse produces
but the data clearly show that CDH survivors who did not require this defect. These defects are usually small, with a greater transverse
ECMO also need frequent attention to pulmonary issues. At discharge, than anteroposterior diameter, and are more commonly right-sided
up to 20% of infants require oxygen, but only 1-2% require oxygen past (90%) but may be bilateral (Fig. 101-13). The transverse colon or small
1 yr of age. BPD is frequently documented radiographically but will intestine or liver is usually contained in the hernial sac. The majorities
improve as more alveoli develop and the child ages. of children with these defects are asymptomatic and are diagnosed
Gastroesophageal reflux disease is reported in more than 50% of beyond the neonatal period. The diagnosis is usually made on chest
children with CDH. It is more common in those children whose dia- radiograph when a child is evaluated for another reason. The antero-
phragmatic defect involves the esophageal hiatus. Intestinal obstruc- posterior radiograph shows a structure behind the heart, and a lateral
tion is reported in up to 20% of children and may result from a midgut film localizes the mass to the retrosternal area. Chest CT or MRI will
volvulus, adhesions, or a recurrent hernia that became incarcerated. confirm the diagnosis. When symptoms occur, they can be recurrent
Recurrent diaphragmatic hernia is reported in 5-20% in most series. respiratory infections, cough, vomiting, or reflux; in rare instances,
Children with patch repairs are at highest risk. incarceration may occur. Repair is recommended for all patients, in
Children with CDH typically have delayed growth in the 1st 2 yr of view of the risk of bowel strangulation, and can be accomplished lapa-
life. Contributing factors include poor intake, gastroesophageal reflux roscopically or by an open approach. Prosthetic material is rarely
disease, and a caloric requirement that may be higher because of the required.

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Chapter 101  ◆  Respiratory Tract Disorders  864.e1

Bibliography Konduri GG, Vohr B, Robertson C, et al: Early inhaled nitric oxide therapy for
Congenital Diaphragmatic Hernia Study Group: Surfactant replacement therapy on term and near-term newborn infants with hypoxic respiratory failure:
ECMO does not improve outcomes in neonates with congenital diaphragmatic neurodevelopmental follow-up, J Pediatr 150:235–240, 2007.
hernia, J Pediatr Surg 39:1632–1637, 2004. Morini F, Goldman A, Pierro A: Extracorporeal membrane oxygenation in infants
Harrison MR, Keller RL, Hawgood SB, et al: A randomized trial of fetal with congenital diaphragmatic hernia: a systematic review of the evidence, Eur J
endoscopic tracheal occlusion for severe congenital diaphragmatic hernia, Pediatr Surg 16:385–391, 2006.
N Engl J Med 349:1916–1924, 2003. Rollins MD: Recent advances in the management of congenital diaphragmatic
Jaillard SM, Pierrat V, Dubois A, et al: Outcome at two years of infants with hernia, Curr Opin Pediatr 24:379–385, 2012.
congenital diaphragmatic hernia: a population based study, Ann Thorac Surg Van Meures K, Congenital Diaphragmatic Hernia Study Group: Is surfactant
75:250–256, 2003. therapy beneficial in the treatment of the term newborn infant with congenital
Keszler M: Congenital diaphragmatic hernia: not quite there yet, J Pediatr diaphragmatic hernia?, J Pediatr 145:312–316, 2004.
163:15–16, 2013.

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Chapter 101  ◆  Respiratory Tract Disorders  865

hernia, pleural effusion, chylothorax), and thoracic abnormalities


101.10  Paraesophageal Hernia (thoracic dystrophies).
Akhil Maheshwari and Waldemar A. Carlo Gas from a ruptured alveolus escapes into the interstitial spaces of
the lung, where it may cause interstitial emphysema or dissect along
Paraesophageal hernia is differentiated from hiatal hernia in that the the peribronchial and perivascular connective tissue sheaths to the
gastroesophageal junction is in the normal location. The herniation of hilum of the lung. If the volume of escaped air is great enough, it may
the stomach alongside or adjacent to the gastroesophageal junction is collect in the mediastinal space (pneumomediastinum) or rupture into
prone to incarceration with strangulation and perforation. A previous the pleural space (pneumothorax), subcutaneous tissue (subcutane-
Nissen fundoplication and other diaphragmatic procedures are risk ous emphysema), peritoneal cavity (pneumoperitoneum), and/or
factors. This unusual diaphragmatic hernia should be repaired promptly pericardial sac (pneumopericardium). Rarely, increased mediastinal
after identification. pressure may compress the pulmonary veins at the hilum and thereby
interfere with pulmonary venous return to the heart and cardiac output.
On occasion, air may embolize into the circulation (pulmonary air
embolism) and produce cutaneous blanching, air in intravascular cath-
101.11  Eventration eters, an air-filled heart and vessels on chest roentgenograms, and death.
Akhil Maheshwari and Waldemar A. Carlo Tension pneumothorax occurs if an accumulation of air within the
pleural space is sufficient to elevate intrapleural pressure above atmo-
Eventration of the diaphragm is an abnormal elevation, consisting of spheric pressure. Unilateral tension pneumothorax results in impaired
a thinned diaphragmatic muscle that causes elevation of the entire ventilation not only in the ipsilateral lung but also in the contralateral
hemidiaphragm or, more commonly, the anterior aspect of the hemi- lung owing to a shift in the mediastinum toward the contralateral side.
diaphragm. This elevation produces a paradoxical motion of the Compression of the vena cava and torsion of the great vessels may
affected hemidiaphragm. Most eventrations are asymptomatic and do interfere with venous return.
not require repair. A congenital form is the result of either incomplete
development of the muscular portion or central tendon or abnormal CLINICAL MANIFESTATIONS
development of the phrenic nerves. Congenital eventration may affect The physical findings of a clinically asymptomatic pneumothorax are
lung development, but it has not been associated with pulmonary hyperresonance and diminished breath sounds over the involved side
hypoplasia. The differential diagnosis includes diaphragmatic paraly- of the chest with or without tachypnea.
sis, diaphragmatic hernia, traction injury, and iatrogenic injury after Symptomatic pneumothorax is characterized by respiratory distress,
heart surgery. Eventration is also associated with pulmonary sequestra- which varies from merely high respiratory rate to severe dyspnea,
tion, congenital heart disease, and chromosomal trisomies. Most even- tachypnea, and cyanosis. Irritability and restlessness or apnea may be
trations are asymptomatic and do not require repair. The indications the earliest signs. The onset is usually sudden but may be gradual; an
for surgery include continued need for mechanical ventilation, recur- infant may rapidly become critically ill. The chest may appear asym-
rent infections, and failure to thrive. Large or symptomatic eventra- metric with an increased anteroposterior diameter and bulging of the
tions can be repaired by plication through an abdominal or thoracic intercostal spaces on the affected side; other signs may be hyperreso-
approach that is minimally invasive. nance and diminished or absence of breath sounds. The heart is
displaced toward the unaffected side, resulting in displacement of
Bibliography is available at Expert Consult. the cardiac apex and point of maximal impulse of the heart. The
diaphragm is displaced downward, as is the liver with right-sided pneu-
mothorax, and may result in abdominal distention. Because pneumo-
101.12  Extrapulmonary Air thorax may be bilateral in approximately 10% of patients, symmetry of
findings does not rule it out. In tension pneumothorax, signs of shock
Leaks (Pneumothorax, may be noted.
Pneumomediastinum, Pulmonary Pneumomediastinum can occur in patients with pneumothorax
Interstitial Emphysema, and is usually asymptomatic. The degree of respiratory distress
depends on the amount of trapped gas. If it is great, bulging of the
Pneumopericardium) midthoracic area is observed, the neck veins are distended, and blood
Waldemar A. Carlo pressure is low. The last 2 findings are a result of tamponade of the
systemic and pulmonary veins. Although often asymptomatic, subcu-
Asymptomatic pneumothorax, usually unilateral, is estimated to occur taneous emphysema in newborn infants is almost pathognomonic of
in 1-2% of all newborn infants; symptomatic pneumothorax and pneu- pneumomediastinum.
momediastinum are less common (see Chapter 94). The incidence of Pulmonary interstitial emphysema may precede the development
pneumothorax is increased in infants with lung diseases such as meco- of a pneumothorax or may occur independently and lead to increasing
nium aspiration and RDS; in those who receive assisted ventilation, respiratory distress as a result of decreased compliance, hypercapnia,
especially if high ventilator support is necessary; and in infants with and hypoxemia. Hypoxemia is caused by an increased alveolar–arterial
urinary tract anomalies or oligohydramnios. oxygen gradient and intrapulmonary shunting. Progressive enlarge-
ment of blebs of gas may result in cystic dilation and respiratory
ETIOLOGY AND PATHOPHYSIOLOGY deterioration resembling pneumothorax. In severe cases, pulmonary
The most common cause of pneumothorax is overinflation resulting interstitial emphysema precedes the development of BPD. Avoidance
in alveolar rupture. It may be “spontaneous” or caused by underlying of high inspiratory or mean airway pressures may prevent the develop-
pulmonary disease, such as lobar emphysema or rupture of a congeni- ment of pulmonary interstitial emphysema. Treatment may include
tal lung cyst or pneumatocele, to trauma, or to a “ball-valve” type of bronchoscopy in patients with evidence of mucous plugging, selective
bronchial or bronchiolar obstruction resulting from aspiration. intubation and ventilation of the uninvolved bronchus, oxygen, general
Pneumothorax associated with pulmonary hypoplasia is common, respiratory care, and HFV.
tends to occur during the 1st few hr after birth, and is caused by
reduced alveolar surface area and poorly compliant lungs. It is associ- DIAGNOSIS
ated with disorders of decreased amniotic fluid volume (Potter syn- Pneumothorax and other air leaks should be suspected in newborn
drome, renal agenesis, renal dysplasia, chronic amniotic fluid leak), infants who show signs of respiratory distress, are restless or irritable,
decreased fetal breathing movement (oligohydramnios, neuromus­ or have a sudden change in condition. The diagnosis of pneumothorax
cular disease), pulmonary space-occupying lesions (diaphragmatic is established by radiography, with the edge of the collapsed

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Chapter 101  ◆  Respiratory Tract Disorders  865.e1

Bibliography Congenital Diaphragmatic Hernia Study Group: Surfactant replacement therapy on


Boloker J, Bateman DA, Wung JT, et al: Congenital diaphragmatic hernia ECMO does not improve outcomes in neonates with congenital diaphragmatic
in 120 infants treated consecutively with permissive hypercapnia/ hernia, J Pediatr Surg 39:1632–1637, 2004.
spontaneous respiration/elective repair, J Pediatr Surg 37:357–366, Harrison MR, Keller RL, Hawgood SB, et al: A randomized trial of fetal
2002. endoscopic tracheal occlusion for severe congenital diaphragmatic hernia,
Congenital Diaphragmatic Hernia Study Group: Estimating disease severity of N Engl J Med 349:1916–1924, 2003.
congenital diaphragmatic hernia in the first 5 minutes of life, J Pediatr Surg Hutcheon JA, Butler B, Lisonkova S, et al: Timing of delivery for pregnancies with
36:141–145, 2001. congenital diaphragmatic hernia, BJOG 117:1658–1662, 2010.

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For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.
866  Part XII  ◆  The Fetus and the Neonatal Infant

lung standing out in relief against the pneumothorax (Fig. 101-14); Pneumopericardium may be asymptomatic, requiring only general
pneumomediastinum is signified by hyperlucency around the heart supportive treatment, but it usually manifests as sudden shock with
border and between the sternum and the heart border (Fig. 101-15). tachycardia, muffled heart sounds, and poor pulses suggesting tam-
Transillumination of the thorax is often helpful in the emergency diag- ponade. Pneumoperitoneum from air dissecting through the dia-
nosis of pneumothorax; the affected side transmits excessive light. phragmatic apertures during mechanical ventilation may be confused
Associated renal anomalies are identified by ultrasonography. Pulmo- with intestinal perforation. Abdominal paracentesis can be helpful in
nary hypoplasia is suggested by signs of uterine compression (extrem- differentiating the two conditions. The presence of organisms on Gram
ity contractures), a small thorax on chest roentgenograms, severe stain of intestinal contents suggests the latter. Occasionally, pneumo-
hypoxia with hypercapnia, and signs of the primary disease (hypoto- peritoneum can result in an abdominal compartment syndrome
nia, diaphragmatic hernia, Potter syndrome). requiring decompression.

A B
Figure 101-14 A, Right-sided tension pneumothorax and widespread right lung pulmonary interstitial emphysema in a preterm infant receiving
intensive care. B, Resolution of pneumothorax with a chest tube in place. Pulmonary interstitial emphysema (PIE) persists. (From Meerstadt PWD,
Gyll C: Manual of neonatal emergency x-ray interpretation, Philadelphia, 1994, WB Saunders, p. 73.)

Figure 101-15 Pneumomediastinum in a newborn infant. The anteroposterior view (left) demonstrates compression of the lungs, and the lateral
view (right) shows bulging of the sternum, each resulting from distention of the mediastinum by trapped air.

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TREATMENT improve lung compliance, because the presence of intra-alveolar blood
Without a continued air leak, asymptomatic and mildly symptomatic and protein can inactivate surfactant.
small pneumothoraces require only close observation. Conservative Acute pulmonary hemorrhage may rarely occur in previously
management of a pneumothorax is effective even in selected infants healthy full-term infants. The cause is unknown. Pulmonary hemor-
requiring ventilatory support. Frequent small feedings may prevent rhage may manifest as hemoptysis or blood in the nasopharynx or
gastric dilation and minimize crying, which can further compromise airway with no evidence of upper respiratory or gastrointestinal bleed-
ventilation and worsen the pneumothorax. Breathing 100% oxygen in ing. Patients present with acute, severe respiratory failure requiring
term infants may accelerate the resorption of free pleural air into blood mechanical ventilation. Chest radiographs usually demonstrate bilat-
by reducing the nitrogen tension in blood and producing a resultant eral alveolar infiltrates. The condition usually responds to intensive
nitrogen pressure gradient from the trapped gas in the blood, but the supportive treatment (see Chapter 407).
clinical effectiveness is not proven and the benefit must be weighed
against the risks of oxygen toxicity. With severe respiratory or circula- Bibliography is available at Expert Consult.
tory embarrassment, emergency aspiration using a soft small catheter
introduced with a needle is indicated. Either immediately or after
catheter aspiration, a chest tube should be inserted and attached to
underwater seal drainage (see Fig. 101-14). If the air leak is ongoing,
continuous suction (−5 to −20 cm H2O) may be needed to evacuate
the pneumothorax completely. A pneumopericardium requires prompt
evacuation of entrapped air. Severe localized interstitial emphysema
may respond to selective bronchial intubation. Judicious use of sedation
in an infant fighting a ventilator may reduce the risk of pneumothorax.
Surfactant therapy for RDS reduces the incidence of pneumothorax.

Bibliography is available at Expert Consult.

101.13  Pulmonary Hemorrhage


Namasivayam Ambalavanan and
Waldemar A. Carlo

Massive pulmonary hemorrhage is a relatively uncommon, but cata-


strophic complication with a high risk of morbidity and mortality.
Some degree of pulmonary hemorrhage occurs in about 10% of
extremely preterm infants. However, massive pulmonary hemorrhage
is less common and can be fatal. Autopsy demonstrates massive pul-
monary hemorrhage in 15% of neonates who die in the 1st 2 wk of life.
The reported incidence at autopsy varies from 1 to 4/1,000 live births.
Approximately 75% of affected patients weigh <2,500 g at birth. Pro-
phylactic indomethacin in extremely low birthweight infants reduces
the incidence of pulmonary hemorrhage.
Most infants with pulmonary hemorrhage have had symptoms of
respiratory distress that are indistinguishable from those of RDS. The
onset may occur at birth or may be delayed several days. Hemorrhagic
pulmonary edema is the source of blood in many cases and is associ-
ated with significant ductal shunting and high pulmonary blood flow
or severe left-sided heart failure resulting from hypoxia. In severe
cases, sudden cardiovascular collapse, poor lung compliance, profound
cyanosis, and hypercapnia may be present. Radiographic findings are
varied and nonspecific, ranging from minor streaking or patchy infil-
trates to massive consolidation.
The incidence of pulmonary hemorrhage is increased in association
with acute pulmonary infection, severe asphyxia, RDS, assisted ventila-
tion, PDA, congenital heart disease, erythroblastosis fetalis, hemor-
rhagic disease of the newborn, thrombocytopenia, inborn errors of
ammonia metabolism, and cold injury. Pulmonary hemorrhage is the
only severe complication whose rate is increased with surfactant treat-
ment. Pulmonary hemorrhage is seen with all surfactants; the inci-
dence ranges from 1-5% of treated infants and is higher with natural
surfactant. Bleeding is predominantly alveolar in approximately 65%
of cases and interstitial in the rest. Bleeding into other organs is
observed at autopsy of severely ill neonates, suggesting the possibility
of an additional bleeding diathesis such as disseminated intravascular
coagulation.
Treatment of pulmonary hemorrhage includes blood replacement,
suctioning to clear the airway, intratracheal administration of epineph-
rine, and, in some cases, HFV. Although surfactant treatment has been
associated with the development of pulmonary hemorrhage, adminis-
tration of exogenous surfactant after the bleeding has occurred can

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Chapter 101  ◆  Respiratory Tract Disorders  867.e1

Bibliography
Litmanovitz I, Carlo WA: Expectant management of pneumothorax in ventilated
neonates, Pediatrics 122:e975–e979, 2008.
Watkinson M, Tiron I: Events before the diagnosis of a pneumothorax in ventilated
neonates, Arch Dis Child Fetal Neonatal Ed 85:F201–F203, 2001.

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867.e2  Chapter 101  ◆  Respiratory Tract Disorders

Bibliography
Alfaleh K, Smyth JA, Roberts RS, et al: Prevention and 18-month outcomes of
serious pulmonary hemorrhage in extremely low birth weight infants: results
from the trial of indomethacin prophylaxis in preterms, Pediatrics 121:
e233–e238, 2008.

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For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.