Resiratory Disorders in The Newborn

19 Respiratory Disorders in
the Newborn
NOAH H. HILLMAN, MD, and HUGH SIMON LAM, MBBChir, MD
Respiratory disorders are the most common reason for admis- lung growth. Fetal lung fluid is secreted by the airway epi-
sion to a neonatal intensive care unit (NICU) and are a major thelium as a filtrate of the interstitial fluid of the lung by
source of neonatal mortality and morbidity. This chapter the active transport of chloride.7 The fetal lung fluid is high
describes the etiology, presentation, management, and in chloride but very low in protein and bicarbonate. Although
outcome of neonatal respiratory disorders, as well as the the secretion rate has not been precisely measured in the
initiation of respiration at birth and resuscitation. human fetus, the fetal sheep during the middle of gestation
has a secretion rate of about 4–5 mL/kg per hour.8 Fetal
lung fluid flows intermittently up the trachea with fetal
Initiation of Respiration at Birth breathing because the pressure in the trachea exceeds the
amniotic fluid pressure by approximately 1 cm H2O. Intermit-
One of the most important and well-coordinated physiologic tent glottis closure in utero causes increased fetal lung fluid
events in a person’s life is the transition from the fetal state volume and pressure, and assists with lung development.9
to the newborn infant. Within the first minute of life, the Abnormal flow and pressure in the lungs during develop-
newborn must clear the fetal lung fluid from the airways ment lead to either lung hypoplasia (e.g., in oligohydramnios)
and establish gas exchange. Although most infants complete or large dysplastic lungs (e.g., in chronic upper airway
this transition without problems, inadequate initiation of obstruction). The fetal lung is fully expanded near term with
respiration at birth can be catastrophic to both the respira- a fluid volume of about 40 mL/kg, which is approximately
tory and cardiovascular system.1 twice the functional residual capacity (FRC) of the air breath-
The human fetus is breathing long before the infant is ing newborn.8 As the pregnancy gets closer to term gestation,
born, and fetal breathing is necessary for normal lung devel- the rate of liquid formation and the volume of liquid within
opment. Fetal breathing is detected as early as 12–14 weeks the fetal lung decreases.10
gestational age (GA), and the frequency and duration cor-
respond to the GA and sleep state of the fetus.2 Fetal breath- CLEARANCE OF LUNG FLUID FROM
ing and swallowing occur during active sleep, with limited
AIRWAYS AT BIRTH
amounts during quiet sleep.2 During active sleep, the fetus has
an irregular breathing pattern (20–30 bpm) characterized by The fetal lung fluid is cleared through (1) active transport
long inspiratory and expiratory times with movement of fetal of sodium by epithelial sodium channels (ENaCs) during
lung fluid into and out of the lung. Central chemoreceptors labor, (2) mechanical forces during birthing process, and
in the fetus respond to fetal hypoxia with decreased breath- (3) newborn breathing after birth. Although the fetal lung
ing (opposite of newborn physiology) and to hypercarbia fluid is generated throughout gestation by active secretion
by increased breathing and initiation of active sleep.2 Fetal of chloride through apical epithelial cells into the airways,
breathing is probably controlled by prostaglandin secretion. in late gestation the number and activity of ENaCs increase
Fetal sheep given prostaglandin E2 infusions stop breath- and generate a Na+ gradient in the lung’s interstitial space.
ing, and treatment with prostaglandin synthetase inhibitors, Water follows the sodium out of the airspace through dif-
such as indomethacin, cause continuous fetal breathing.3 fusion or through specific water channels (aquaporins).
At birth, the rapid onset of regular breathing is likely due Aquaporins also increase throughout gestation and can be
to a combination of removal of prostaglandin production upregulated by antenatal steroids. Increases in fetal cortisol,
from placenta, tactile and cold stimuli from the skin, activa- thyroid hormones, and catecholamines near term gestation
tion of Hering-Breuer reflexes, and changes in arterial blood contribute to the reversal of fluid movement in the lungs.11
oxygenation levels (PaO2).2,4 Most of term infants (85%) will In preterm fetal sheep, infusion of cortisol and T3 will activate
begin spontaneous breathing by 10–30 seconds of life, with the sodium pump, which normally occurs at term.12 Exposure
another 10% requiring only drying and stimulation to begin to postnatal oxygen tension also increases sodium transport
a regular breathing pattern.5 Most preterm infants <28 weeks across the pulmonary epithelium. Blockage of or genetic
and <1000 g (69%) have an audible cry and start breathing mutations of the alpha-subunit of these amiloride-sensitive
immediately after birth.6 ENaCs leads to respiratory failure and death due to inability
to clear fetal lung fluid.13 The critical role of ENaCs at birth
has been questioned by the lack of respiratory distress at
Fetal Lung Fluid birth in mice missing the other two subunits of the ENaC.14
Cyclic nucleotide-gated channels on the type I pneumocytes
The airspaces of the fetal lung are filled with fluid created also assist in Na transport out of cells.15 Overall, activation
by the airway epithelial cells. Production and maintenance of the ENaC assists in fluid clearance from the lungs at birth
of the normal volume of fetal lung fluid is essential for normal and throughout life.
338
19 • Respiratory Disorders in the Newborn 338.e1
ABSTRACT KEYWORDS
The most common reasons for admission of newborn infants congenital
to the neonatal intensive care unit are respiratory disorders. neonatal
Despite advances in neonatal intensive care, respiratory dis- respiratory disorders
orders remain an important cause of mortality and morbidity neonatal resuscitation
amongst newborns. As infants transition from an in utero ventilatory control
to external environment, many changes in respiratory regu-
lation and hemodynamic status must occur in order for the
baby to adapt successfully. However, some babies may be
unable to transition successfully and require resuscitation
and further treatment. The changes in cardiopulmonary
physiology can also be vulnerable to disruptions and may
give rise to disorders such as periodic breathing or apnea of
prematurity, in the case of premature infants. Common neo-
natal respiratory disorders include respiratory distress syn-
drome, transient tachypea of the newborn, meconium
aspiration syndrome, pneumonia, and congenital airway
abnormalities. In this chapter the mechanisms of respiratory
control, indications and procedures for neonatal resuscita-
tion, and the etiology, presentation, management, and
outcome of common neonatal respiratory disorders will be
described.
19 • Respiratory Disorders in the Newborn 339
Although there is some evidence for a small amount of resuscitation is progressing, there is a high degree of vari-
lung fluid to be cleared during the progression through the ability in the Apgar scores assigned to infants and color has
vaginal vault, most lung fluid excreted through the nose and recently been removed from the algorithm for neonatal resus-
mouth, when the infants head is exposed, is due to fetal citation.5 Persistently low Apgar scores, especially <5 at 10
repositioning and spinal flexion caused by uterine contrac- minutes, have been associated with higher infant mortality,
tions.10 It is difficult to quantify the percent of lung fluid cognitive delays, increased risk of cerebral palsy and increased
excreted by these physical mechanisms, but the combined educational needs throughout childhood.24,25 Infants with
relative contribution to fluid clearance is likely as high as severe birth asphyxia, metabolic acidosis, and neurologic
33% of lung fluid.16 Elective cesarean sections (C-sections), signs of encephalopathy should receive therapeutic hypo-
without labor or rupture of membranes, will not have this thermia.5 Birth asphyxia can affect all the organ systems
physical clearance of lung fluid or activation of ENaCs prior and management will be individualized based on laboratory
to initiation of breathing. findings.26
Even with the reduction of fetal lung fluid volume during
late gestation and labor and the expulsion of fluid by spinal
flexion, there is greater than 15 mL/kg of fluid in the airways Delivery Room Resuscitation
at the time of birth.1 This fluid is cleared from the airways
and driven into the interstitial space surrounding the airway Approximately 10% of infants require some form of assistance
within the first few seconds of life by a few large, negative at birth; approximately 2% require intubation and PPV, and
pressure breaths.17,18 An FRC is formed following the first less than 0.5% require chest compressions and epinephrine.5,22
breath in normal term infants. Using phase-contrast x-rays, The percent of infants requiring resuscitation increases with
Hooper and coworkers demonstrate that fluid leaves airways decreasing GA. Every 5 years, the International Liaison
during inspiration with some reflooding during expiration Committee on Resuscitation (ILCOR) reviews all studies on
(Video 19.1).1,17 Positive end-expiratory pressure (PEEP) can newborn resuscitation and provides treatment guidelines for
decrease the backflow of interstitial fluid into airways, improve infants who fail to breathe adequately at birth; the following
the uniformity of lung recruitment, and decrease the injury comments reflect their most recent recommendations from
from mechanical ventilation.1,19 The components of fetal 2015 (Fig. 19.1).5 The new guidelines stress the importance
lung fluid then are cleared directly into the vasculature or of the first “golden” minute of life, when breathing should
via lymphatics from the lung interstitium over multiple have spontaneously begun or respirations are being assisted.
hours.20 All newborn infants, including nonvigorous ones exposed to
meconium, should receive stimulation and drying at birth.5
Routine oropharyngeal suction should not be done unless the
Respiratory Depression at Birth oral pharynx appears occluded. If the infant is not breathing,
is gasping, or HR is less than 100 at 30 seconds of life, the
Although most infants initiate respirations at birth, failure infant should receive PPV with PEEP via a T-piece or resusci-
can occur because of fetal hypoxia (birth asphyxia), maternal tation bag. Resuscitation with room air is recommended for
medications leading to suppression of breathing, congenital term infants, whereas most preterm infants can be resusci-
malformations, or failure of the central nervous system che- tated with 0.21–0.30 fraction of inspired oxygen (FiO2).5,27
moreceptors. The combination of immature lungs and Pulse oximetry should be applied and the oxygen titrated
reduced respiratory drive makes preterm infants more likely to maintain infants within the normal ranges during the
to need assistance with breathing at birth.5 Primary apnea first minutes of life.28 It should be noted that the fetal PaO2
occurs in newborns after birth and often responds to tactile is low and normal transitional oxygen saturations are not
stimulation. In utero the fetus responds to hypoxia with greater than 85% for almost 5 minutes. If after 30 seconds
decreased fetal respiration thereby decreasing metabolic of PPV ventilation, with an initial pressure of 20–25 cm
requirements; thus a severely hypoxic infants will not breath H2O, the HR is not greater than 100, the resuscitator should
at birth.21 Many of these infants will respond to stimulation progress through a series of ventilation corrective steps (i.e.,
and continuous positive airway pressure (CPAP). Room air MR.SOPA—Mask adjustments/Reposition airway/Suction and
(21%) has been shown to be preferable to 100% oxygen and Open mouth and nose/increase Pressure/consider Alternative
is recommended for the initial resuscitation of the term airway) and consider intubation of the infant. Intubation
infant.5 If the infant in primary apnea is not assisted and should be confirmed by chest rise, condensate in ET tube,
hypoxia continues, the infant progresses into secondary improved HR, and carbon dioxide detector (PediCap). If HR
apnea, where the heart rate (HR) decreases and responds remains less than 60 bpm after intubation, chest compres-
only to positive-pressure ventilation (PPV). Continued dete- sions should be started using a two-handed encircling chest
rioration of blood pressure will follow and metabolic acidosis approach.5 The sternum is compressed approximately a third
will develop if respiration is not initiated. PPV through either the diameter of the chest (approximately 2 cm) at a ratio of
a face mask or endotracheal (ET) tube should restore car- 3 : 1 for 120 events (90 compressions and 30 breaths) in a
diopulmonary function in the majority of infants, as less minute. Pulse oximetry and a three-lead electrocardiography
than 1% of infants should need epinephrine in the delivery (ECG or EKG) can be used to help assess the HR. If adequate
room.22 Pulse oximetry is now recommended for any infant ventilation and compressions do not return HR greater than
suspected of needing resuscitation.5 Apgar scores, named 60, then the infant should receive intravenous (IV) epineph-
after Virginia Apgar, are assigned to the infant at 1 minute, rine (0.01–0.03 mg/kg) through an umbilical venous cath-
5 minute, and 10 minutes for HR, breathing, color, reflex, eter (UVC) or IV catheter. ET epinephrine (0.05–0.1 mg/kg)
and tone.23 Although a useful guide for how a newborn can be tried until IV access is obtained but has a decreased
340 SECTION 1 • General Basic and Clinical Considerations
Antenatal counseling
Team briefing and equipment check
Birth
Infant stays with mother for routine

Term gestation? Yes care: warm and maintain normal
Good tone? temperature, position airway, clear
Breathing or crying? secretions if needed, dry.
Ongoing evaluation
No
Warm and maintain normal temperature,

1 minute
position airway, clear secretions if

needed, dry, stimulate
Apnea or gasping? No Labored breathing or

HR below 100/min? persistent cyanosis?
Yes Yes
PPV Position and clear airway

SpO2 monitor SpO2 monitor
Consider ECG monitor Supplementary O2 as needed
Consider CPAP
No Postresuscitation care
HR below 100/min?
Team debriefing
Yes
Check chest movement

Ventilation corrective steps if needed
ETT or laryngeal mask if needed Targeted Preductal SpO2
After Birth
1 min 60%–65%
No
HR below 60/min? 2 min 65%–70%
Yes 3 min 70%–75%
Intubate if not already done 4 min 75%–80%

Chest compressions
5 min 80%–85%
Coordinate with PPV
100% O2 10 min 85%–95%
ECG monitor
Consider emergency UVC
HR below 60/min?
Yes
IV epinephrine
If HR persistently below 60/min
Consider hypovolemia
Consider pneumothorax
© 2015 American Heart Association
Fig. 19.1 Newborn Resuscitation Algorithm: 2015 International Liaison Committee on Resuscitation guidelines for initial management of infants in
need for assistance during the transition at birth. CPAP, Continuous positive airway pressure; ECG, electrocardiography; ETT, endotracheal tube; HR,
heart rate; IV, intravenous; PPV, positive-pressure ventilation; UVC, umbilical venous catheter. (Reprinted from American Heart Association, Wyckoff et al.
Pediatrics. 2015.)
response rate compared with IV epinephrine.29 The use of Obstetricians and Gynecologists (ACOG) recommendation
sodium bicarbonate and naloxone are no longer recommended for antenatal corticosteroids in 1994, so it is unclear what
during the newborn resuscitation. Normal saline or group O the results would be in the current era. Multiple studies
Rh-negative blood (10 mL/kg body weight) should be given comparing CPAP and surfactant treatment have been con-
over 5–10 minutes if the infant is hypotensive due to blood ducted in the past 10 years, and each has shown a trend
loss. If there is no HR and Apgar score is 0 after 10 minutes towards improved respiratory outcomes in the infants receiv-
of adequate resuscitation, it is appropriate to discontinue ing CPAP.34,35 Meta-analysis of all the trials demonstrated
further resuscitation due to the poor neurologic outcome.5,29 approximately a 10% reduction in bronchopulmonary dys-
Because most infants will respond to appropriate ventilation, plasia (BPD) with early CPAP.36 Recently it has been recom-
resuscitators should consider other underlying conditions that mended to attempt to support preterm infants with CPAP if
might impede ventilation, such as pneumothorax, hypoplas- they are breathing in the delivery room.5 Remarkably, almost
tic lungs from oligohydramnios, congenital diaphragmatic 50% of infants born less than 750 g will be successful on
hernia (CDH), or other congenital anomalies. CPAP alone.37 This is possible because an endogenous sur-
factant pool size of only approximately 5 mg/kg (5% of term
levels) is necessary for preterm lambs to respond to CPAP
RESUSCITATION OF THE PRETERM INFANT
and lambs with approximately 10% the endogenous pool
The GA of the preterm infant will determine many of the size have reduced injury from mechanical ventilation.38 If
steps taken during resuscitation. The care of late preterm given the opportunity, the majority of very preterm infants
infants (34–37 weeks) often follows the resuscitation guide- will successfully initiate breathing without extensive resus-
lines for term infants, but they should be monitored closely citation.6 Extremely preterm infants that require extensive
after birth due to increased newborn morbidities (jaundice, resuscitation in the delivery room have significant morbidities
temperature control, transient tachypnea of the newborn and increased mortality.39
[TTN], feeding). Infants less than 32 weeks have immaturity Although there are clear benefits to resuscitation of term
of most organ systems, with the lungs and brain being the infants with room air, the consensus is less clear on the start-
most vulnerable to injury and most likely to affect resusci- ing oxygen levels for preterm infants. The 2015 guidelines
tation. Antenatal steroids prior to preterm delivery stimu- recommend starting preterm infants at a FiO2 between 0.21
late maturation of many of the organs. Fortunately, more and 0.30 and then titrating oxygen based on pulse oximetry.5
than 90% of preterm infant less than 34 weeks GA will Preterm infants resuscitated with room air often require an
receive some portion of a steroid course prior to delivery increase in FiO2 to maintain saturations.40 Studies comparing
and this improves response to resuscitation. The extremely 30%–90% oxygen for preterm infants demonstrated that most
immature brain may have decreased respiratory drive infants in the lower oxygen group had an increased oxygen
requiring PPV ventilation. Thermoregulation is extremely requirement to 40%, whereas the higher group had decreases
important for the very preterm infant, due to brain imma- in oxygen requirements. Eventual oxygen requirements ended
turity and lack of brown fat sources, and they ought to be up at approximately 30% oxygen in both groups.41,42
placed in a plastic bag or thermal wrap immediately after To overcome the resistance created by the air-fluid inter-
delivery.29 faces in small airways of preterm infants, physicians have
Lung immaturity has the largest influence on the resus- used prolonged inspiratory times, commonly called sustained
citation of the preterm infant, and many preterm infants inflation (SI), to recruit FRC.17,43–45 In preterm lambs, SI aug-
require assistance in the transition from fetal life.5,29 Lung mented the cardiorespiratory transition at birth and improved
development, maturation, and the surfactant system are the HR response to resuscitation after asphyxiation.43,46 In
covered extensively in other chapters in this book. Although a few small human studies, SI at birth decreased the need
the lack of labor may lead to increased fetal lung fluid at for mechanical ventilation at 72 hours and may lead to a
birth (see earlier), antenatal steroids or the maternal condi- decrease in BPD.44,47 In preterm infants, SI generates an
tions that led to preterm birth may have primed the preterm average FRC volume recruitment of only 8 mL/kg and lung
lung for gas exchange. Although increased surfactant levels volume recruitment occurs only in spontaneously breathing
are probably not present until closer to 48 hours after ante- infants.45,48 Adduction of the glottis, a normal fetal occur-
natal steroids, preterm sheep lungs have decreased thickness rence, blocks airflow in the nonbreathing infants.1,48 Multiple
of the lung parenchyma by 15 hours (likely due to decreased clinical trials are currently underway to determine if clearing
interstitial fluid) and decreased injury from mechanical ven- airway fluid with an SI to achieve FRC will benefit preterm
tilation by 24 hours after steroids.30,31 Surfactant-deficient infants. ILCOR removed the recommendation for three brief
preterm babies may lack the muscle strength to generate SIs (added in 2010) from the 2015 guidelines until results
sufficient negative pressure to overcome their compliant chest are known.5
wall and high airway surface tension.11 The amount of sur-
factant stored in type II cells is low in preterm infants not
exposed to antenatal steroids, so less is available for secretion Ventilatory Control
in response to birth.32 Without the assistance of surfactant
in reducing surface tension, it is difficult for very small infants Complex networks of respiratory neurons within the medulla
to develop an FRC. Since the approval of exogenous surfactant and pons generate and regulate the involuntary component
replacement therapy in the early 1990s, there has been a of respiratory rhythm.49 Specifically, studies suggest that this
trend towards intubation and treatment of the smallest infants spontaneous inspiratory rhythm originates from pacemaker
with surfactant.33 It should be noted that all the surfactant neurons within the pre-Bötzinger complex, one of the net-
studies were performed prior to the American College of works of neurons that make up the ventral respiratory group
in the ventral medulla.50,51 The phasic transition from inspi- Very immature infants respond to hypoxia by becoming
ration to expiration is modulated by signals from the stretch apneic, which is like the fetal response. The biphasic response
receptors in the lungs and airways via the vagus nerves and to hypoxia disappears by 12–14 days, and the adult pattern
neurons in the pneumotaxic and apneustic centers of the is subsequently observed (i.e., stimulation of breathing
pons.51 The rhythm is transmitted to the cervical and thoracic without depression). However, an animal model suggests
spinal motor neurons that innervate the diaphragm and that the acute hypoxic ventilatory response of an individual
intercostal muscles. These descending pathways activate the could be attenuated by exposure to sustained hypoxia fol-
inspiratory muscles while inhibiting the expiratory muscles. lowed by chronic intermittent hypoxia during the neonatal
Breathing pattern is further influenced by afferents from the period.58 In contrast, exposure to hyperoxia causes a tem-
forebrain, hypothalamus, central and peripheral chemore- porary suppression of breathing due to withdrawal of periph-
ceptors, muscles, joints, and pain receptors. Most areas eral chemoreceptor drive. After a few minutes of hyperoxia,
contain multiple neuromodulators that are partly released ventilation increases to greater than control levels probably
from the same neurons, implying that neuromodulation is because of hyperoxic cerebral vasoconstriction resulting in
integrated at many levels.52 increased brain tissue carbon dioxide. Immaturity and pro-
Several neurotransmitters play important roles in respira- longed exposure to supplementary oxygen reduce the response
tory regulation. Glutamate is an excitatory neurotransmitter to hyperoxia. The fetus and newborn respond to increased
that activates receptors involved in generating and transmit- carbon dioxide levels with an increase in breathing activity.
ting respiratory rhythms to spinal and cranial respiratory The slope of ventilatory response to carbon dioxide is less in
neurons. Serotonergic neurons in the medulla oblongata term infants during active than quiet sleep, but it increases
are part of a critical system that modulates autonomic and with postnatal growth. Other chemoreceptors include sub-
respiratory effector neurons.53 The most consistent effect of epithelial chemoreceptors in the trachea, bronchi, and bron-
serotonin (5HT) is to restore a normal breathing pattern after chioles that respond by changing the frequency and depth
hypoxic or ischemic insult. Opioids (endorphins and exog- of respiration after exposure to toxic gases such as nitrogen
enous drugs) suppress respiration by peripheral and central dioxide and sulfur dioxide. This response is decreased during
actions; the latter are due to suppression of recurrent excita- active sleep and in the premature infant.59
tion by glutaminergic input within the primary respiratory Respiratory activity is also regulated by nonchemical
network. Both γ-aminobutyric acid (GABA) and glycine are means, such as stimulation by the many respiratory reflexes.51
essential for generating respiratory rhythm; they are released Hering and Breuer described three respiratory reflexes: infla-
by late and postinspiratory neurons and inhibit inspiratory tion, expiratory, and deflation. The Hering-Breuer inflation
neurons, thus facilitating the transition from inspiration to reflex is stimulated by lung inflation and results in cessation
expiration. Deficiency of glycinergic inhibition in knockout of respiratory activity. In the newborn the reflex produces a
mice results in a slower frequency of breathing. pattern of rapid, shallow tidal breathing and operates within
Central and peripheral chemoreceptors are core compo- the tidal volume range. In older subjects the reflex prevents
nents of the chemical regulation of breathing patterns. These excessive tidal volumes and can only be stimulated if the
chemoreceptors modify respiratory activity in response to inflating volume is increased greater than a critical thresh-
changes in oxygen, carbon dioxide, and acid-base balance.54 old.60 The Hering-Breuer expiratory reflex is stimulated if
The central chemoreceptors are situated near the ventral inflation is prolonged; the active expiration seen in infants
surface of the medulla, whereas the peripheral chemorecep- ventilated at slow rates and long inflation times, and which
tors are situated at the bifurcation of the common carotid may result in pneumothoraces, may be a manifestation of
arteries (carotid bodies) and above and below the aortic arch this reflex.61 In animal models the Hering-Breuer deflation
(aortic bodies). In the fetus the arterial chemoreceptors are reflex is evidenced by a prolonged inspiration generated in
active but have reduced sensitivity.55 The peripheral chemo- response to deflating the lung rapidly or following an unusu-
receptors are not essential for the initiation of respiration ally vigorous expiratory effort that takes the lung below its
and are virtually silenced when the arterial oxygen level end-expiratory level.62 In the newborn, this reflex may have
rises at birth. Resetting of the carotid chemoreceptors to a role in maintaining the FRC. Head’s paradoxical reflex, also
hypoxia occurs within 24–48 hours of birth56; this may result called the inspiratory augmenting reflex or provoked aug-
from changes in dopamine levels. The fetus responds to mented inspiration, is the underlying mechanism of the first
hypoxia with a suppression of ventilation. The lateral part breath and sighing. A rapid inflation stimulates a stronger
of the lower pons mediates the hypoxic suppression of ven- diaphragmatic contraction. The reflex improves compliance
tilation. In response to hypoxia, there is a redistribution of and reopens partially collapsed airways63; it has an important
the circulation to favor the heart, brain, and adrenals. This role in promoting lung expansion during resuscitation. Rapid
minimizes oxygen consumption and conserves oxygen sup- chest wall distortion via the intercostal phrenic inhibitory
plies for vital organs. The newborn has a biphasic response reflex results in a shortening of inspiratory efforts. This reflex
to hypoxia, a transient increase in minute ventilation followed response is inhibited by an increase in FRC or applying CPAP.
by a decrease to or below baseline levels. The initial increase The mechanism may improve chest wall stability.64 The airway
in ventilation may be due to activation of peripheral che- is protected from bronchospasm induced by cold exposure
moreceptors and reconfiguration within the pre-Bötzinger by upper airway reflexes that can increase upper airway
complex leading to a change from eupneic rhythm to a gasping resistance and decrease inspiratory air flow. The laryngeal
pattern.57 The subsequent reduction in ventilation may result afferents defend the lower airway from inadvertent inha-
from a fall in carbon dioxide tension following the initial lation of foreign bodies, with maturation of the laryngeal
hyperventilation or the suppressant effect of hypoxia, which reflex being characterized by an increase in coughing and
occurs in the fetal state and persists into the neonatal period. a decrease in swallowing and apnea.65 For a discussion of
ventilatory control in sleep-disordered breathing, please refer to of clinical situations and show any long-term advantages
Chapter 81. remain to be seen. Noninvasive ventilatory support (e.g.,
CPAP, noninvasive positive-pressure ventilation [NIPPV], and
high-/low-flow nasal cannulas) may be considered for infants
APNEA
with frequent or prolonged apnea despite treatment with
Apnea is defined as cessation of breathing for at least 20 caffeine. The frequency of apnea has been shown to be
seconds or at least 10 seconds if associated with oxygen decreased by increasing the FRC, stabilizing oxygenation, or
desaturation or bradycardia.54 Apneas are classified as central, by splinting the upper airway. Positive pressure support of
obstructive, or mixed.66 Most apneas are central in nature the airway may be particularly effective in infants whose
(46%–69%), with the rest being either purely obstructive episodes are precipitated or prolonged by relative upper airway
(6%–12%) or a combination of central and obstructive (i.e., obstruction as both the pharynx and laryngeal aperture
mixed) (20%–44%).67 Central apnea is characterized by ces- could be distended to reduce the risk of mixed and obstruc-
sation of inspiratory efforts in the absence of upper airway tive apneas. However, a neural component to the effects of
obstruction. In contrast, in obstructive apnea, despite the positive pressure/flow has been suggested as even delivery
presence of central signals for breathing and the correspond- of low-flow air has been shown to be effective, suggesting
ing respiratory muscle activities, there is an absence of airflow the possibility of the stabilization of the mechanoreceptors
through the airways due to upper airway obstruction. Bra- in the upper airway by the airflow.68 Infants with severe and
dycardia may occur within a few seconds of onset of apnea refractory apnea unresponsive to the relatively noninvasive
with accompanying disturbances in blood pressure and modalities of treatment would need to be intubated and sup-
cerebral blood flow velocity. In infants without adequate ported by mechanical ventilation.
cerebrovascular autoregulation, cerebral perfusion may
decrease to very low levels during prolonged apnea and
PERIODIC BREATHING
potentially exacerbate hypoxic-ischemic brain injury. The
incidence of apnea of prematurity is inversely associated Periodic breathing is a common breathing pattern that, unlike
with GA and usually resolves by approximately 37–40 weeks apnea of prematurity, can occur in infants of all GA.75,76 In
postconceptional age. contrast to apnea of prematurity, periodic breathing does
Frequent episodes of apnea that respond to gentle stimula- not usually occur within the first 48 hours of life75 and can
tion may be considered normal for preterm infants. However, last for 6 months or longer.76,77 The literature suggests that
additional investigations and treatment are required if the among healthy term babies, 78% exhibit periodic breath-
apneas become frequent and/or associated with prolonged ing within the first 2 weeks of life, decreasing to 29% by
desaturation, because there are several potentially treatable 1 year of age.76 The definition of periodic breathing can
associated factors that may be present (e.g., infection, intra- be arbitrarily defined as three episodes of apnea of more
cranial abnormality or hemorrhage, anemia, metabolic dis- than 3-second duration each that are interrupted by periods
orders [e.g., hypoglycemia], temperature instability, and of breathing that are 20 seconds or less.78 The etiology of
gastroesophageal reflux [GER] [see later in the chapter]). In periodic breathing is thought to be increased sensitivity of
addition, several pharmacologic agents (e.g., benzodiazepines chemoreceptors involved in ventilatory control, leading to
and opioid analgesics) can also cause apnea. After excluding overregulation of the breathing pattern in response to small
other treatable conditions, neonatal apnea may be treated changes in PaO2 or PaCO2 levels.79 This overcompensation
with methylxanthines (e.g., theophylline) and caffeine, which leads to periodic overshooting of the target to be compensated
have all been shown to reduce apnea in preterm infants, for and the oscillation between apnea and normal breathing
possibly by increasing the chemoreceptor sensitivity to carbon that is observed in this condition. Periodic breathing has
dioxide.68 Caffeine is the preferred agent in view of its rela- previously been thought to be a benign condition. However,
tively long half-life, which allows once-daily dosing, and its with improvements in computing power, detailed longitudinal
higher therapeutic index compared with theophylline. Side analyses of neonatal breathing patterns have been made, and
effects of theophylline include hyperactivity, tachycardia, showed that preterm infants often exhibit increased percent-
cardiac dysrhythmias, feeding intolerance, and seizures. Caf- age of time spent in periodic breathing before a diagnosis of
feine treatment in infants with, or at risk for, apnea of pre- necrotizing enterocolitis (NEC) or septicemia is made.79 Fur-
maturity has also been shown to reduce BPD69 and improve thermore, in another longitudinal study of preterm infants,
survival without neurodevelopmental delay.70 In addition, it has been found that periodic breathing can be associated
prophylactic caffeine reduces apnea/bradycardia and episodes with significant desaturations and reduction in cerebral oxy-
of oxygen desaturation in preterm infants following postop- genation, especially during sleep.80 Although the use of CPAP
erative anesthesia.71 Doxapram, a respiratory stimulant that or caffeine may be associated with less periodic breathing,79
is thought to act via the peripheral chemoreceptors, has been because the long-term clinical implications of these events
used to treat apnea in newborns but has been associated are unknown, further follow-up studies are warranted before
with many side effects (e.g., elevated blood pressure, abdomi- evidence-based diagnostic or treatment recommendations
nal distension, irritability, increased gastric residuals, and can be made.
emesis). Furthermore, the long-term effects of this drug have
not been adequately investigated.68 Relatively novel treat-
ments include olfactory stimulation,72 inhalation of low-dose Respiratory Distress Syndrome
carbon dioxide,73 and limb proprioception stimulation.74
However, although some of these treatments show initial Respiratory distress syndrome (RDS), also referred to as
promise, whether they can be replicated in a wide variety hyaline membrane disease, is a respiratory condition that
occurs in many preterm infants at birth and is defined by PATHOPHYSIOLOGY

clinical and radiographic descriptions. Infants with RDS
develop oxygen requirements within 6 hours of life, typically RDS is due to structural immaturity of the preterm lung and
require respiratory support at 24 hours of life, and a have a deficiency in surfactant pool size. Increased lung fluid,
a chest x-ray with findings consistent with RDS.81 The sever- inadequate respiratory efforts, and underdevelopment of the
ity of RDS has decreased with the introduction of surfactant chest wall and respiratory muscles also contribute to the
and antenatal steroids, so the classic hyaline membranes, infant’s inability to maintain expansion of the distal airspaces.
seen at autopsy, rarely occur in our current premature Surfactant production and maturation are covered in detail
infants.82 Because many infants are ventilated in the delivery in Chapter 5, so only a summary will follow. Surfactant is
room and given surfactant, the radiologic evidence of air produced in alveolar type II cells, which are cuboidal cells
bronchograms may not be present. And some infants will covering approximately 2% of the alveolar surface that
be maintained on mechanical ventilation due to immature become more prominent between 22 and 24 weeks GA.
respiratory drive, yet have mature lungs with plenty of sur- Surfactant is a complex mixture of phospholipids, neutral
factant. Because it is difficult to define RDS in the era of lipids, and proteins (surfactant proteins A, B, C, and D). Lipids
surfactant therapy and antenatal steroids, there will be varia- make up more than 90% of surfactant, with 80% being
tions in the number of preterm infants with RDS across phospholipids (phosphatidylcholine [PC] and phosphatidyl-
studies.82 Some may argue the alternative name for RDS glycerol [PG] make up largest portion) and 10% neutral lipids
may have changed from “hyaline membrane disease” to (cholesterol, triacylglycerol, and free fatty acids).95 Sphingo-
“respiratory instability of prematurity,” a phrase created by myelin, which is used in the lecithin to sphingomyelin (L:S)
Bancalari and Jobs to describe the extremely preterm infants ratio, represents less than 2% of surfactant lipid. Surfactant
born in recent years.82 is synthesized in the endoplasmic reticulum, collected in the
lamellar bodies then released into airspace as active tubular
myelin. The tubular myelin mixes with a combination of
EPIDEMIOLOGY
saturated and unsaturated phospholipids to make a surface
It is difficult to determine the exact incidence of RDS film that decreases surface tension. The surface film is recycled
because multiple definitions exist. The incidence of RDS over time by the type II cells or degraded by the macrophages.
decreases as the GA increases. Prior to the introduction More than 90% of the PC on the alveolar surface is repro-
of antenatal steroids (1983–86), the incidence of RDS cessed, the turnover time being approximately 10 hours.
was: >95% at 25 weeks GA (average weight 800 g); 75% The phospholipid monolayer structure allows the surfactant
at 28 weeks (average weight 1000 g); 50% at 30 weeks to change shape throughout respiration, with the most dis-
GA (average weight 1400 g); and still approximately 20% tended form allowing decreased surface tension and the most
at 34 weeks GA.83 Antenatal steroids have been shown compressed form in exhalation providing stability to the
to reduce RDS by an average of 40% in randomized trials.84 alveoli. In RDS the immature lung has a lower level of PG
In the 1990s, when the more routine use of antenatal and PC, the spreading agents for surfactant in the lung, thus
steroids was beginning (ACOG recommended steroid use in the monolayer formed is unstable and does not decrease
1994), the incidence of RDS was approximately 70% between surface tension or maintain alveolar patency as well. The
500 and 1500 g.85 Of note, in the Vermont Oxford network, immature surfactant system in preterm infants with RDS
the antenatal steroid rate increased from 23% in 1991 to leads to difficulty in generating an FRC and increased work
72% in 1999, but there was no difference in the rate of of breathing. The addition of PEEP or treatment with exog-
RDS.85 Between 1997 and 2003, in the era of moderately enous surfactant allows for formation of an FRC and decreased
high antenatal steroid use, approximately 63% of infants injury from ventilation.19,96 In RDS the resultant alveolar
between 500 and 1000 g have RDS.86 Although antenatal hypoventilation results in ventilation perfusion imbalance
corticosteroids have traditionally been given to mothers at and hypoxia. The increased alveolar surface tension from
risk of preterm birth prior to 34 weeks GA, a randomized the surfactant deficiency promotes the flow of protein-rich
trial demonstrated a benefit of corticosteroids in late preterm fluid from the intravascular space to the alveolar spaces. The
infants.87 The rates of RDS vary between races and sex. Female leak of protein is increased by mechanical ventilation and
infants have a lower incidence of RDS than do male infants from continued hypoxic damage to the alveolar-capillary
at all GAs,88 which is consistent across most mammalian membrane. These plasma proteins further inhibit surfactant
species. Late preterm males have an odds ratio (OR) of 1.68 function and make up a major component of the hyaline
of having RDS compared with their female counterparts.89 membrane found in infants who do not survive RDS.
Race plays an important role in the development of RDS, The four surfactant-associated proteins, SP-A, SP-B, SP-C,
with African-American infants having a lower rate than do and SP-D, compose approximately 10% of surfactant and
white infants.90 In one study, only 40% of African infants play a role in the structure of tubular myelin (SP-A), the
less than 32 weeks GA developed RDS compared with 75% stabilization of the phospholipid monolayer (SP-B, SP-C),
of the white infants.91 Genetic variability as a risk factor for and in host-defense (SP-A, SP-D). ABCA3 is a protein that
RDS has been confirmed in twin studies, in which mono- assists in transport of lipids with type II cells and is required
zygotic twins were more likely than dizygotic twins to both for proper lamellar body formation. Genetic mutations in the
have RDS.92,93 The largest influences on development of surfactant proteins or ABCA3 lead to respiratory disease in
RDS are GA, gender, race, and antenatal steroids. Genetic the newborn that ranges from mild (SP-A) to lethal (SP-B).97
polymorphisms of surfactant proteins have been found to Some of the clinical manifestations of these conditions do
be strongly associated with risk of RDS in preterm infants not appear until childhood or adulthood. The role of gene
(see Chapter 57).94 mutations in human lung diseases and surfactant production
are covered in depth in Chapters 5 and 57. Term or late age. Extremely preterm infants often require ongoing ventila-
preterm infants with severe RDS at birth that does not have tor support due to chest wall weakness and central respiratory
a persistent response to surfactant therapy may need to be drive issues. The introduction of exogenous surfactant treat-
evaluated for these mutations. ment and antenatal steroids has altered the traditional clinical
Many factors influence lung maturation and surfactant progression over a course of days because most larger infants
production and thus the development of RDS. Both fetal with significant respiratory distress will receive surfactant
cortisol and thyroxine can stimulate lung maturation. Con- and this will be recycled by their type II cells multiple times
versely, insulin delays the maturation of alveolar type II cells, prior to their own endogenous production.
decreasing the proportion of saturated PC, and inhibits the
production of SP-A and SP-B.98 Infants of diabetic mothers DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
also have delayed appearance of PG, and the infant’s L:S
ratio is less predictive of lung maturation.99 The increased The diagnosis of RDS is made on clinical history (described
incidence of RDS in males (1.7 : 1) may be due to the increased previously) and chest radiographic appearance. The chest
levels of fetal androgens. Fetal androgens delay lung matura- radiograph shows fine granular opacification in both lung
tion and PG production (by approximately a week) through fields due to diffuse atelectasis and air bronchograms, where
direct action on lung fibroblasts.100 Any factors that affect the air-filled bronchi stand out against the atelectatic lungs
the integrity of the alveolar capillary membrane (asphyxia, (Fig. 19.2). In severe cases the lungs are collapsed to the
hypothermia, or hypoxia) will lead to increased airspace extent that the cardiac silhouette is indistinguishable from
protein and deactivation of surfactant function. Although the lungs. If the radiograph is taken during the first 4 hours,
often necessary in the resuscitation of preterm infants, PPV the retention of fetal lung fluid can make interpretation dif-
can release proteins and cause inflammation that worsens ficult. As the fluid clears, the chest radiograph appearance
RDS.101,102 Increased intrauterine inflammation from cho- may show marked improvement. It should be noted that an
rioamnionitis matures the lung and decreases the risk of infant on mechanical ventilation with adequate tidal volume
RDS but may increase the risk of BPD.103,104 ventilation and PEEP will have a moderately clear x-ray,
even in the setting of significant surfactant deficiency. This
difference can be determined clinically because the infants
CLINICAL PRESENTATION
with surfactant deficiency will require higher pressures
Infants with RDS typically present within 4 hours of birth to maintain tidal volumes. Preterm infants with low lung
with tachypnea (respiratory rate > 60 breaths/min), inter- compliance (i.e., requiring peak inspiratory pressure [PIP]
costal and subcostal retraction, nasal flaring, and abdominal greater than approximately 20 cm H2O to generate a tidal
breathing. Although severe cases of RDS present with cya- volume of 5 mL/kg) would benefit from exogenous surfactant
nosis, milder cases of RDS are discovered by routine use of therapy. Although measurement of surfactant in a tracheal
pulse oximetry in infants unable to maintain their saturations aspirate can be performed, this is currently not clinically
greater than 90 on RA. The high surface tension in the alveoli available.107 Tracheal secretions or gastric contents can be
created by the surfactant deficiency and the weaker chest aspirated and a bubble shake test can be performed to give a
wall muscles of the preterm infant may make it difficult for
the infant to develop the normal FRC of 25–30 mL/kg, and
thus the infant’s lungs remain in a partially deflated state.
The infant may attempt to increase their FRC through an
expiratory grunt, created when the infant simultaneously
contracts the diaphragm and the constrictor muscles of the
larynx to close the upper airway. The resultant exhalation
of air is exaggerated and creates the grunting sound found
in RDS. The diffuse collapse of the alveoli and smaller airways
creates the classic chest radiograph findings of ground-glass
appearance with air bronchograms. In infants who are not
treated with exogenous surfactant, the symptoms worsen
over the first 24–36 hours due to collapse of alveoli recruited
by the initial breaths at birth and the deactivation of the
small amounts of surfactant present in an infant with RDS.
The ongoing lung injury from atelectasis and poor ventila-
tion leads to further leak of inhibitory plasma proteins into
the airspace, a cycle that can be prevented by the treatment
with exogenous surfactant or CPAP.105 Without antenatal
steroids, endogenous levels of surfactant begin to increase
in the airspaces by 24 hours after birth.106 Between 36 and
48 hours of age, the endogenous production of surfactant
is sufficient to maintain alveolar patency and clinical symp-
toms improve. Often this process is associated with a spon-
taneous diuresis. With eventual development of surfactant Fig. 19.2 Respiratory distress syndrome: chest x-ray demonstrates
production, recovery from RDS with decreasing oxygen ground-glass appearance and air bronchograms due to atelectasis
requirements normally occurs by approximately 1 week of because of surfactant deficiency from prematurity.
basic assessment of surfactant levels, but this is rarely done in is not a clear consensus among neonatologists about the
the NICU.108 best approach to take in the delivery room. Everyone would
Fetal lung fluid normally moves up the trachea and is probably agree that RDS is due to a combination of chest wall
swallowed by the fetus, but some of the fluid mixes with immaturity and surfactant deficiency and that all treatment
the amniotic fluid, allowing surfactant to be measured. As methods are merely approaches to bridge the time until the
the lung matures, the amount of dipalmitoylphosphatidylcho- infant begins to develop sufficient endogenous surfactant
line (DPPC) in the amniotic fluid increases, but the amount (typically over 48 hours) and grows stronger to maintain
of sphingomyelin remains unchanged throughout gestation; adequate respiration (days to weeks). The three typical man-
thus lung maturity can be assessed from the L:S ratio.109 The agement styles for RDS (described in detail later) all derive
lower the L:S ratio, the more likely that the infant will develop from these principles: (1) use of CPAP to maintain alveolar
RDS: 80% of infants with a L:S ratio < 1.5 have RDS, compared distention during spontaneous breathing,34,35 (2) giving exog-
with 21% of infants with a ratio of 1.5–2.0, and approxi- enous surfactant while the infant is spontaneously breath-
mately 5% if L:S ratio > 2.0 (usually is associated with lung ing (minimally invasive surfactant therapy [MIST] or less
maturity).109 Because of the abnormalities in PG formation invasive surfactant therapy [LIST]),114,115 or (3) mechanical
(not measured in L:S ratio) in infants of diabetic mothers and ventilation and administration of surfactant therapy, with
infants with severe hemolytic disease, these infants may have rapid extubation as part of INSURE (Intubation, Surfactant,
a mature L:S ratio but have significant RDS.99 L:S ratios can Rapid Extubation) protocols.33,116 Other forms of noninvasive
be altered by the presence of blood, meconium, or vaginal respiratory support (high-flow nasal cannula and NIPPV)
secretions in the sample. Lung maturity can also be assessed have also been tried for RDS.
by the lamellar body count in the amniotic fluid.109,110 Lamellar Since its introduction in the early 1990s, exogenous
body counts are more sensitive than L:S ratio and >37,000 surfactant therapy has had a dramatic effect on the survival
correlates well with lung maturity, even in diabetic patients and long-term morbidity from RDS. The first description of
(30,000 in nondiabetic women).109,111 Lamellar body counts surfactant deficiency was published by Avery in 1959,117
can be easily obtained by running amniotic fluid through an but it took nearly 30 years to get an animal-extracted
automated hematology analyzer because they are the same surfactant approved for clinical use in premature infants.
size as platelets. Some investigators suggest that examining Surfactant therapy, when given as “rescue therapy” in infants
lamellar body counts in gastric aspirates of preterm infants with established RDS, decreased the rates of pneumotho-
may be helpful to guide the early use of surfactant.112 rax, mortality, and the combined outcome of mortality and
It is nearly impossible to differentiate severe early-onset BPD.118 Surfactant therapy has also been shown to be more
sepsis or pneumonia from RDS, either clinically or radio- effective if given as “prophylactic therapy” to infants born
graphically. Because these conditions can also coexist, infants less than 28 weeks gestation versus given as rescue therapy,
experiencing respiratory distress at birth should have an with decreased risk of pneumothorax, pulmonary intersti-
appropriate workup performed for bacterial infections (blood tial emphysema (PIE), and mortality or BPD.33 It should be
cultures, complete blood count [CBC], and C-reactive protein noted that the majority of the surfactant therapeutic trials
at >4 hours) and should then be started on antibiotics.113 were conducted prior to the ACOG recommendation for
Clinicians may consider holding antibiotics in the setting of antenatal steroid use in 1994 and the infants included
preterm delivery for maternal reasons (preeclampsia, Hemo- in the studies may be slightly less mature than extremely
lysis, Elevated Liver enzymes, and Low Platelet count [HELLP] preterm infants who have received steroids.119 The benefit of
syndrome). Antibiotics should be stopped after blood cultures prophylactic surfactant in the setting of antenatal steroids
and other lab results are negative. Ampicillin and gentamicin has been addressed by multiple trials of surfactant versus
act synergistically against group B streptococcus (GBS) and CPAP (discussed later).120 Most intubated extremely preterm
are also effective against many organisms that cause early- infants, even in the setting of intubation for respiratory drive
onset septicemia and pneumonia. It is important to know the or apnea, would benefit from surfactant therapy because
local antibiotic resistance patterns as gentamicin resistant mechanical ventilation alone may release proteins that inhibit
gram-negative bacteria have become more prevalent. Infants the endogenous surfactant.107 Benefits are shown after a
with high oxygen requirements, but a clear chest x-ray or single dose of 100 mg/kg surfactant, but most studies dem-
low lung compliance, may be suffering from pulmonary onstrate that better results are obtained with more than one
hypertension. This can often be diagnosed with preductal dose.121 The results of additional surfactant begin to dimin-
and postductal pulse-oximetry or echocardiography and can ish after the second dose of natural surfactants. There may
be treated with sedation and inhaled nitric oxide (iNO). TTN be differences between bovine surfactant (beractant) and
(discussed later) can present with similar findings to RDS but porcine surfactant (poractant alfa), with further benefits on
typically improves more quickly as the excessive water in the BPD, mortality, and patent ductus arteriosus (PDA) seen with
lungs is absorbed and the function of the (already present) poractant. These differences between surfactants may be due
surfactant improves. Respiratory distress that presents after to the higher dosing concentrations given with poractant
4–6 hours of age is usually due to pneumonia; the differen- (200 mg/kg) versus the beractant (100 mg/kg).122 Natural
tial diagnosis includes air leak, heart failure secondary to (animal-derived) surfactants when compared with synthetic
congenital heart disease, and aspiration. surfactant (protein free) are associated with a significant
reduction in mortality and pneumothorax but may be associ-
ated with an increased risk of NEC.123 The most well-studied
MANAGEMENT
protein-free surfactant, colfosceril palmitate (Exosurf), is no
The appropriate management of preterm infants with RDS longer being produced. Synthetic surfactants are now avail-
has been studied extensively over the past decade, yet there able that contain synthetic polypeptide proteins designed to
mimic surfactant proteins B or C. The most studied polypeptide CPAP versus intubation and surfactant in extremely preterm
is KL4, designed to mimic the C-terminal end of surfactant infants less than 29 weeks. Even with the use of early CPAP
protein B,124 which when mixed with DPPC, POPG phos- in the delivery room, the decrease in the incidence of BPD
pholipids, and palmitic acid is called lucinactant (Surfaxin). is modest at approximately 10%.36,129 The increased rate of
KL4 appears to be more resistant to the inhibitory effects of pneumothorax found in the COIN trial was not found in any
proteins than natural surfactants.125 Transient hypoxemia and of the other clinical trials, with an overall pneumothorax
bradycardia may be present during surfactant treatment via rate in all trials of CPAP 6.3% versus surfactant 5.8%. Based
ET tube. A transient perturbation in cerebral hemodynamics on these studies, the 2015 ILCOR resuscitation guidelines
is also present but is not associated with increased risk of recommend treating spontaneously breathing preterm infants
cerebral hemorrhage. Pulmonary hemorrhage has been noted (<30 weeks) with CPAP instead of intubation.5 Preterm infants
following surfactant administration. Surfactant, once instilled started on CPAP may initially do well (FiO2 less than 30%),
into the trachea or bronchus, will quickly spread throughout and then having increasing oxygen requirements and hyper-
the lungs with each breath. Although surfactant dosing is capnia as alveoli begin to collapse. Although PcCO2 > 60 mm
approved for four quadrants, most clinicians instill surfac- Hg and a FiO2 > 0.6 is used by some centers as criteria for
tant with only two positions. In some surfactant-deficient CPAP failure (including some centers with very low BPD
preterm infants, the ET tube serves mainly as a conduit for rates), 84% of preterm infants on CPAP with a FiO2 of >0.4
administering surfactant, but intubation may expose the will reach >0.6.130 Earlier rescue surfactant, given when FiO2
infant to injurious ventilation and cardiovascular changes. < 0.45, has been shown to be beneficial for air leaks,126
To avoid continued ventilation after surfactant treatment, the and it is our practice to intubate these infants and give
INSURE technique has been adopted by many neonatologists, them surfactant if they require FiO2 > 0.4 on high levels
especially for more mature infants (>28 weeks GA) in need of CPAP. Increasing the level of CPAP increases the lung
of surfactant treatment.126 To avoid intubation in spontane- volume and hence improves oxygenation, but it is possible
ously breathing infants on CPAP with higher oxygen needs, to cause overdistension, carbon dioxide retention, and air
surfactant can be given through a thin catheter into the leaks. CPAP can be generated by a mechanical ventila-
trachea of extremely preterm infants.114,115 MIST or LIST tor, a T-piece resuscitator, or an underwater seal (bubble)
involve direct visualization of the vocal cords by direct laryn- device (bubble continuous positive airway pressure
goscopy and insertion of a feeding tube into the upper trachea [BCPAP]). BCPAP is attractive, especially for low-resource
(www.youtube.com/watch?v=OUvgJ57FQR8). Surfactant is countries, because the CPAP is regulated by submerging
then quickly instilled through the feeding tube. MIST therapy the expiratory limb of the gas circuit a set distance under
has been shown to be effective and may avoid unnecessary water (actual cm H2O). It should be noted that the distending
mechanical ventilation in preterm infants.127 Surfactant can pressure generated by BCPAP is flow dependent and intraprong
also be given through a laryngeal mask airway (LMA), but pressures may be higher (up to 1.3 cm H2O) than expected
LMAs small enough for extremely preterm infants are still for the depth of submersion in water.131 Unlike ventilator-
in development. Nebulization of surfactant in spontaneously derived CPAP, BCPAP generates a variable distending pressure,
breathing infants on CPAP is being studied in clinical trials. It often referred to as the “noise” of BCPAP.132 In intubated
is known that some extremely preterm infants are surfactant sheep, BCPAP had improved gas exchange, oxygenation,
deficient and need surfactant treatment, but the best way to and pH compared with ventilator-derived CPAP,132 and
deliver it is still being determined. similar benefit was seen on oxygenation in preterm infants
Not all infants with clinical signs of RDS are surfactant on BCPAP.133 When the pressure fluctuations are further
deficient, especially in the setting of greater than 48 hours increased (high-amplitude BCPAP), the oscillatory pressure
of antenatal steroids, and many of these infants require only wave can achieve similar blood gas values in paralyzed, saline-
CPAP to support the weak respiratory muscles and to stimu- lavaged rabbits to conventional mechanical ventilation.134
late breathing.35,128 The mildest forms of RDS can sometimes The transmission of the oscillatory bubbles and the CPAP
be managed with supplemental oxygen, but most babies pressure may differ based on the nasal interface used, with
need some form of distending pressure to prevent atelecta- the RAM cannula losing more CPAP pressure than other
sis and improve oxygenation. Many centers are trialing all nasal-prong interfaces. Heated humidified high-flow nasal
infants on CPAP in the delivery room, and approximately 50% cannula (HHHFNC) is used by some units to treat RDS and has
of infants born less than 750 g can be maintained on only been shown not to be “inferior” to CPAP in clinical trials.135
CPAP, with much higher rates in more mature infants.36,37,129 The variability of pressures generated in preterm infants on
The ability to be maintained on CPAP is likely due to the HHHFNC, often caused by leaks through the mouth, makes
small amount of endogenous surfactant (>5% of term it a less predictable form of distending pressure.
surfactant pool size needed in preterm sheep) necessary to Preterm infants may need PPV due to poor respiratory
maintain alveolar expansion.38 Over the past decade, during drive (apnea of prematurity), inability to maintain chest
an era of greater than 80% antenatal steroid rates, five expansion on CPAP (surfactant deficiency, respiratory
major trials (Continuous Positive Airway Pressure or Intu- muscle weakness), or ineffective gas exchange (hypoxia or
bation at Birth trial [COIN]; Surfactant, Positive Pressure, hypercarbia). PPV can be given via an ET tube (traditional
and Oxygenation Randomized Trial [SUPPORT]; Vermont- mechanical ventilation) or through nasal prongs (NIPPV).
Oxford Network [VON] delivery room study; an international In meta-analysis of studies comparing NIPPV with CPAP
randomized controlled trial to evaluate the efficacy of com- following extubation, NIPPV reduced the incidence of extuba-
bining prophylactic surfactant and early nasal continuous tion failure but had no effect on BPD or mortality.136 Although
positive airway pressure in very preterm infants [CUPAP]; earlier studies demonstrated a benefit of synchronized
and Neocosur Network) have been conducted to compare NIPPV on BPD, more recent, larger studies, which used
unsynchronized NIPPV with lower average PIPs, found no and who have low lung compliance, should be evaluated for
difference.137 In unsynchronized NIPPV, only 25% of breaths pulmonary hypertension.
were coordinated with infant’s breaths and only these breaths
led to an increase tidal volume. The ability to synchronize PREVENTATIVE STRATEGIES
breaths can now be done with neurally adjusted ventila-
tory assist (NAVA), which uses an esophageal catheter to Antenatal steroids (dexamethasone or betamethasone)
measure diaphragmatic electrical activity to both synchronize can cross the placenta to mature the fetal lung and brain.142
breaths and adjust ventilator pressures. NAVA has been shown In the lung, antenatal steroids can decrease the fetal lung
to decrease BPD in some small studies138 but needs to be fluid through activation of ENaCs, induce the production
studied in a randomized trial for prevention of BPD. Conven- of surfactant proteins and lipid synthesis, and alter preterm
tional mechanical ventilators deliver intermittent positive- responses to oxidative stress.142,143 Randomized trials have
pressure inflations and PEEP at a preset rate and inspiratory demonstrated that administration of antenatal corticoster-
time. The ventilator inflations are often not synchronized oids significantly reduces the incidences of RDS, neonatal
with the infant’s breaths, and this can contribute to air death, cerebral hemorrhage, and NEC.84 Guidelines recom-
leak syndromes. Many neonatologists now use higher rates mend the routine use of antenatal steroids for mothers at
and lower tidal volumes to improve asynchrony and decrease risk for preterm delivery from 24 weeks to 34 weeks GA.144
possible lung injury from alveolar overdistention. Volutrauma, Betamethasone (two doses 24 hours apart), rather than
from high tidal volumes, and atelectrauma, from inadequate dexamethasone (four doses 12 hours apart), is preferred.
stenting of the airways with PEEP at the end of expiration, Antenatal steroids can be considered at 23 weeks GA but
are likely more dangerous to the developing lung than the are not currently recommended at 22 weeks GA.144 Studies
pressures used to generate these volumes. The development have also demonstrated decreased respiratory complications
of infant mechanical ventilators with accurate flow sensors at in late preterm infants (34–36 weeks) randomized to ante-
the end of the ET tube has allowed for the more reliable use natal corticosteroids, and revisions to ACOG guidelines are
of volume ventilation in the NICU. Studies comparing volume underway.87,142 Studies of antenatal steroids prior to elec-
to pressure ventilation in preterm infants demonstrate a tive C-section also demonstrate some benefit on respiratory
benefit for volume ventilation of reduced death or BPD, symptoms at birth.145 The benefit of steroids is maximal in
duration of ventilation, pneumothoraces, periventricular infants delivered between 24 and 168 hours after maternal
leukomalacia, and severe intraventricular hemorrhage.139 therapy, but benefits on the lungs are seen in less than 24
Volume ventilation also allows for rapid changes in inspiratory hours.119 The use of repetitive courses of antenatal steroids
pressures in response to changes in lung compliance, espe- showed some benefits for respiratory outcomes, but more
cially in the setting of exogenous surfactant administration than five weekly courses caused decreased fetal growth and
or use of postnatal corticosteroids. An alternative approach head circumference.142 Infants who received repetitive dosing
to conventional mechanical ventilation, which generates did not show differences in adverse neurologic outcomes at
a tidal volume of 4–6 mL/kg through either pressure or 18-month follow-up. Some obstetricians will give an addi-
volume control, is to use extremely small volumes but very tional dose of steroids to a mother with persistent threat of
high rates. During high-frequency jet ventilation (HFJV), preterm delivery 1–2 weeks after initial course. Antenatal
high-velocity bursts of gas are fired at rates of 200–600 steroids do not increase the risk of infection in pregnancies
per minute to generate gas flow down the ET tube. There are complicated by preterm prelabor rupture of the membranes.
few randomized trials comparing HFJV with conventional There is not a consensus opinion about the use of antenatal
ventilation, but the largest included approximately 130 steroids for infants of mothers with possible chorioamnionitis.
infants and demonstrated a slight decrease in BPD rates Thyroid hormones induce surfactant synthesis in animal
and need for home oxygen.140 High-frequency oscillatory models. Randomized trials of antenatal administration of
ventilation (HFOV) uses a piston to generate a gas gradient thyrotropin-releasing hormone (the only component of the
within the dead space of the trachea, with gas exchange pathway that crosses the placenta) did not reduce the risk
reliant on oxygen moving down the gradient into the lungs of neonatal respiratory distress or BPD, and unfortunately
and carbon dioxide diffusing along its gradient out of the increased the risk of lower 5-minute Apgar scores and caused
lung. Because HFOV relies on forming oxygen and carbon transient suppression of the pituitary system.146 Other drugs
dioxide gradients, extremely active infants or those breathing such as aminophylline, ambroxol, and terbutaline have also
against the ventilator may affect the gas exchange ability been tried, with variable success.
of the ventilator. Randomized trials comparing HFOV to
conventional ventilation have variable results, but a meta- MORTALITY AND MORBIDITY
analysis demonstrated that HFOV is associated with a modest
reduction in BPD, with no excess of intraventricular hemor- Overall the mortality from RDS is 5%–10%; the mortality
rhage (IVH) or periventricular leukomalacia (PVL).141 Sur- rate is inversely proportional to GA. The use of antenatal
prisingly, especially because many clinicians use HFOV in steroids and exogenous surfactant therapy has decreased the
setting of PIE, HFOV was also associated with a mild increase mortality from RDS, but significant morbidities still exist in
in air leaks.141 Use of open lung strategies with HFOV, where the extremely preterm infants that survive. The acute com-
mean airway pressure (MAP) is increased until there is no plications of RDS include air leaks, PDA, and pulmonary
longer an improvement in oxygenation and then decreased hemorrhage (discussed separately later). BPD, defined as
by 2 cm H2O, may lead to improved pulmonary responses either oxygen dependency 28 days after birth or at 36 weeks
in preterm infants. Infants with RDS whose hypoxia is more corrected GA, develops in more than 40% of infants born
severe than would be anticipated from the chest radiograph, prior to 29 weeks of gestation. BPD is discussed at length in
Chapter 20. Some of these infants require tracheostomy and

prolonged mechanical ventilation (see Chapter 21). Changes
in antenatal steroid use, modes of respiratory support, and
endogenous surfactant have fortunately created a very dif-
ferent form of RDS than was first described by Northway
in 1967.
Transient Tachypnea of
the Newborn
EPIDEMIOLOGY
Although the exact numbers are unclear, TTN occurs in less

than 1% of term vaginal deliveries but is more frequent in
late preterm infants.87 Each week of GA after 35 weeks reduces
the risk of respiratory symptoms, particularly if primary
C-section is performed.147 Other risk factors for TTN include
C-section birth, with or without labor (threefold higher risk),
male sex, macrosomia, maternal diabetes, and maternal
history of asthma. Infants of asthmatic mothers may have
a genetic predisposition to decreased responsiveness of Fig. 19.3 Transient tachypnea of the newborn: excess lung fluid causes
β-adrenergic stimulation of ENaCs, increasing the risk of transient deactivation of surfactant and similar appearance to mild
TTN and RDS.148 Antenatal corticosteroids given to women respiratory distress syndrome. Increased fluid is visible in fissures, with
increased vascular markings in the lungs.
at risk for preterm labor at 34–36 weeks decreased the risk
of respiratory support and oxygen need.87
and fluid in the fissures (Fig. 19.3). Some infants with TTN
PATHOPHYSIOLOGY
will develop pulmonary hypertension, and this should be
This syndrome is thought to result directly from ineffective suspected in infants requiring high concentrations of oxygen.
clearance of fetal lung fluid at the time of birth (see previous
description of lung clearance). The lack of uterine contrac- MANAGEMENT
tions causing spinal flexion, and catecholamine surge from
labor, lead to increased fetal lung fluid at birth and an Most infants with TTN can be managed with supplemental
increased risk of TTN with elective C-section.1 The excessive oxygen or CPAP. CPAP will help to drive the excessive fluid
fluid in the lung interacts with the surfactant, which is often out of airways and into the interstitial spaces, where it is
at adequate levels to maintain alveolar expansion, and leads absorbed over a few hours. Except in the setting of elective
to relative inactivation of the surfactant until the fluid is C-section or C-section for maternal reasons not related to
absorbed. A subpopulation of term infants with TTN, often infection, IV antimicrobials should be considered because
ones who have prolonged hypoxia and tachypnea, have a sepsis and pneumonia in the term infant can mimic TTN
degree of surfactant deficiency that contributes to the respi- clinically. TTN is usually self-limiting, and affected infants
ratory distress.149 Inadequate Na+ transport out of the airways, usually have significant clinical improvement within the first
either because of decreased numbers of ENaCs or lack of 24 hours and complete recovery within a few days of birth.
activation of these channels, contributes to the excess Complications are rare, but air leaks may occur. Many infants
fluid.14,150 The number of water channels (aquaporins) may with TTN have respiratory rates too high for safe oral feeding,
also differ in infants with TTN.15 Preterm infants also have so intravenous fluids or gavage feeds may be necessary until
decreased Na+ transport, and late preterm infants with TTN the tachypnea improves. Trials of furosemide or racemic epi-
have low amounts of surfactant.151 The increased fluid accu- nephrine to increase fluid clearance have not shown clear
mulates in the interstitial space generating increased pressure benefits. More recently, it has been suggested that affected
and increased refilling of the airways with fluid during expi- infants may derive clinical benefit from inhaled β-adrenergic
ration, which can be overcome by CPAP in many infants.1 agonist therapy153,154; however, larger trials are required.
CLINICAL PRESENTATION
Infants with TTN are tachypneic with respiratory rates that
Meconium Aspiration Syndrome
can be greater than 80 breaths/min. The clinical presenta- EPIDEMIOLOGY
tion can resemble mild RDS, although the infants have grunt-
ing less often.152 The chest may be barrel shaped because of Meconium-stained amniotic fluid (MSAF) complicates approxi-
hyperinflation. The chest radiograph shows hyperinflation, mately 13% of live births,155,156 affecting term more than
prominent perihilar vascular markings due to engorgement preterm infants. MSAF occurs in less than 5% of preterm
of the periarterial lymphatics, edema of the interlobar septae, pregnancies, and when it does occur it suggests infection.
Five percent of babies born through MSAF will develop meco-

nium aspiration syndrome (MAS). In a large study of perinatal
registry data in a developed setting, it was found that the
overall incidence of MAS was 0.43/1000 live births. The
incidence has been decreasing with time; it is associated with
factors including advanced GA, low Apgar scores, and
C-section delivery.157 MAS is therefore a condition that pre-
dominantly affects term and postterm babies.
PATHOPHYSIOLOGY
MASF occurs when there is antenatal passage of meconium.
This phenomenon has been associated with fetal distress
and hypoxic-ischemic insult. MAS is an inflammatory lung
condition caused by aspiration of MSAF by the infant into
the airways during the peripartum period.
It has been found that antenatal passage of meconium is
associated with higher levels of motilin in the baby.158 Motilin
is produced mainly by endocrine M cells of the duodenoje-
junal mucosa and stimulates peristalsis.159 Levels are very
low in preterm infants and nonasphyxiated term infants but
are raised in asphyxiated term babies who pass meconium
during the peripartum period. Prolonged severe fetal hypoxia
can stimulate fetal gasping in utero leading to inhalation of Fig. 19.4 Meconium aspiration syndrome: chest x-ray with hyperinfla-
MSAF. It is also thought that inhalation can occur perinatally tion and patchy infiltrates throughout both lung fields.
with the first breaths of the baby who is delivered through
MSAF. Although meconium is mainly made up of water
(approximately 80%), it is chemically complex, containing pneumothorax and pneumomediastinum, are very common,
components of various substances, including digestive juices, occurring in approximately 20% of infants. In those with
lipids, intestinal epithelial cells, lanugo hair, bile, and amniotic pulmonary hypertension, right-to-left shunting at ductal and
fluid.160,161 It is of variable consistency and, when inhaled, atrial levels may be seen by echocardiography. Differential
can create a ball-valve mechanism within the airways. This diagnoses include pneumonia, surfactant deficiency, persistent
obstructive pathology predisposes the lungs to air trapping pulmonary hypertension of the newborn (PPHN), congenital
and hyperinflation. In addition, meconium irritates the lungs, cardiac disease, and aspiration of blood.164
activating numerous inflammatory mediators, toll-like recep-
tors, and the complement system.161 An inflammatory pneu- MANAGEMENT
monitis and systemic inflammatory response can ensue, with
an associated release of vasoactive substances that can cause Although infants mildly affected by MAS may require no
vasoconstriction and raised pulmonary arterial pressure. In specific treatment, a substantial proportion of infants will
addition, meconium impairs surfactant function, increas- require intensive care management of the many complica-
ing the possibility of atelectasis. Meconium harbors micro- tions that can arise. The risk of pulmonary hypertension is
biota that are associated with amniotic fluid and placental high in infants with MAS, and hypoxemia should be avoided.
microbiota.162 In addition, meconium is thought to enhance Supplemental oxygen should be administered to keep oxygen
bacterial growth by serving as a growth factor and inhibit- saturations greater than 94%. One should also consider using
ing bacteriostatic properties of amniotic fluid,163 facilitating PaO2 to guide oxygen use. With increasing evidence that
the growth of pathogens such as Escherichia coli. Meconium high oxygen concentrations can cause harm, ventilatory
has been suggested to significantly impair mechanisms of support measures such as CPAP or mechanical ventilation
intracellular microbial killing, inhibiting phagocytosis and should be considered if the FiO2 requirement is persistently
the neutrophil oxidative burst. high. Traditionally MAS has been conceptualized as a pri-
marily obstructive condition; however, it is now increasingly
recognized that areas of hyperinflation may coexist with
CLINICAL FEATURES
atelectasis in a setting of ventilation-perfusion mismatch.164
Infants with MAS generally present with signs of respiratory It is therefore essential that ventilatory support should be
distress such as tachypnea and use of accessory muscles of initiated with close monitoring of the progress of the infant.
respiration. The obstructive pathology can lead to increased Use of CPAP or mechanical ventilation may improve oxy-
anteroposterior diameter of the chest, whereas the ventilation- genation but may also increase the risk of air leak. The
perfusion mismatch and pulmonary hypertension can lead thresholds at which ventilatory support should be initiated
to cyanosis. Initial chest radiographs may show hyperinflated are therefore not evidence based and may need to be adjusted
lung fields and widespread patchy infiltrates (Fig. 19.4). Small depending on the condition of the individual baby. In general,
pleural effusions occur in approximately 20% of patients. mechanical ventilation would be considered in infants with
With development of pneumonitis and interstitial edema PaCO2 > 8 kPa (>60 mm Hg) and PaO2 < 6 kPa (<50 mm
the radiographic appearance can progress to diffuse, homo- Hg) despite initial oxygen supplementation, especially in
geneous opacification of both lung fields. Air leaks, such as infants with evidence of PPHN. Conventionally, the ventilator
strategy should be based on a relatively low PEEP and long exercised when deciding whether to initiate ET suctioning,
expiratory time, but in practice, the appropriateness of this taking care not to delay PPV and other important resuscita-
strategy will depend on the relative balance between atelec- tion measures in the process.
tasis and hyperinflation. In infants with severe disease, and
particularly if associated with pulmonary hypertension,
PROGNOSIS
HFOV and adjunctive use of inhaled NO should be consid-
ered.165,166 In a meta-analysis that included four randomized The mortality of MAS in a developed setting has been reported
trials, it was suggested that surfactant administration could to be 2.5%.157 In contrast, mortality can be as high as 32%
reduce the severity of respiratory illness and decrease the in developing regions of the world.177 Most deaths are from
number of infants with progressive respiratory failure requir- respiratory failure, pulmonary hypertension, or air leaks.
ing support with extracorporeal membrane oxygenation Fifty percent of babies who require mechanical ventilation
(ECMO),167 especially if administered as a bolus. Surfactant because of MAS suffer an air leak. Neurodevelopmental delays
administration both as lung lavage and as a bolus reduced have been observed even in infants who respond well to con-
duration of mechanical ventilation and length of hospital ventional ventilation.178 Children with a history of MAS have
stay but did not reduce mortality.168 The use of antibiotics been found to exhibit long-term lung function abnormalities,
has not been shown to benefit infants with MAS in terms of increased bronchial hyperreactivity, and higher reported
duration of ventilation, hospital stay, or mortality.168,169 rates of recurrent cough and wheeze.179
However, despite this, it is widespread practice to commence
broad-spectrum antibiotics empirically in view of the difficulty
in differentiating between MAS and pneumonia. Results of Acute Respiratory
a randomized trial suggested that ECMO improved survival Distress Syndrome
in infants with an oxygenation index (OI) of >40.170 However,
with improving intensive care strategies, the need for ECMO PATHOPHYSIOLOGY
has been reduced.165 There has been interest in the protective
effects of hypothermia for lung conditions such as MAS, and Acute respiratory distress syndrome (ARDS) in the newborn
some centers have started to incorporate it into the manage- occurs when a systemic injury leads to lung inflammation
ment of these infants.171 and injury in previously healthy lungs and is often associated
with multiorgan failure.180 Like adults, ARDS can occur fol-
lowing asphyxia, shock (cardiogenic or hypovolemic), or
PREVENTION
sepsis. Myocardial dysfunction from birth asphyxia or from
There is an inverse association between amniotic fluid volume severe metabolic acidosis can lead to pulmonary edema and
and fetal HR decelerations, possibly due to either cord or need for ventilator support. The direct injury from the hypoxia
head compression. Amnioinfusion has been thought to dilute on the lung tissue or the injury sustained from mechanical
meconium, especially in cases of thick MSAF, and correct ventilation leads to release of proteins into the air spaces,
oligohydramnios, thereby relieving umbilical cord compres- thus worsening the lung disease by inactivation of surfac-
sion.172 However, results of a meta-analysis suggested that tant.105 Sepsis will lead to increased capillary leak of fluid
amnioinfusion did not improve perinatal outcomes in settings and protein into the lungs. Preterm infants may be predis-
of standard peripartum surveillance and was only beneficial posed to lung inflammation from chorioamnionitis, and severe
in settings with limited facilities to monitor the baby during chorioamnionitis may have systemic responses—fetal inflam-
labor.172 Furthermore, amnioinfusion carries increased risk matory response syndrome (FIRS).181
of several adverse outcomes, including cord prolapse, infec-
tion, and requirement for instrumental delivery. There has CLINICAL PRESENTATION
been much debate in the value of meticulous clearing of
the airway during and after delivery in an infant delivered ARDS presents with worsening tachypnea and oxygen require-
through MSAF,173 with recommendations being based more ments after a systemic event. Clinically it may look very like
on biologic plausibility and expert opinion than a strong primary lung diseases such as pneumonia or MAS (discussed
body of evidence. Avoidance of postterm delivery is the key in other sections of this chapter). Some infants who have
factor in reducing the incidence of MSAF and thus MAS. the clinical appearance of RDS, but who are not premature
With increasing numbers of studies and meta-analyses, there and do not have a good response to exogenous surfactant
has been a failure to obtain evidence that routine efforts to therapy, may have underlying lung disease more consistent
clear the airway of meconium by ET or oropharyngeal suc- with ARDS. The tachypnea may result initially from stimula-
tioning can prevent MAS or lead to improved outcomes of tion by metabolic acidosis or damage to the central nervous
affected infants.174 It has been argued that MAS incidence in system, but the hypoxia will progressively worsen as the lung
these studies was low. However, even in a setting with a high tissue becomes edematous and inflammation develops. The
incidence of MAS, intrapartum suctioning was not shown chest radiograph demonstrates diffuse pulmonary infiltrates,
to be of benefit.175 In another recent study in a develop- with some severe cases having complete opacification of the
ing setting, ET suctioning was not shown to be superior to lungs. Blood cultures and tracheal aspirates may guide the
routine resuscitation even for nonvigorous babies delivered antibiotic management of these infants.
through MSAF.162 Because of the accumulating evidence of
lack of benefit of routine suctioning to prevent MAS, ILCOR MANAGEMENT
no longer recommends routine ET suctioning of nonvigorous
babies delivered through MSAF.176 Clinical judgement regard- Treatment of the underlying cause of the ARDS (sepsis,
ing the presence of significant airway obstruction should be birth asphyxia, cardiogenic shock) is essential for the lungs
to recover. The newborn lung is moderately resistant to chronic infants that die soon after birth are found to have pneumonia
injury and should be able to recover if the infant can survive at autopsy.184 Most cases caused by ascending infection are
the initial insult. Surfactant administration can improve oxy- due to Streptococcus agalactiae (GBS), and antenatal testing
genation in ARDS, similar to MAS, but may require larger for GBS is recommended for all pregnant women. The use of
doses than used in RDS.180 Efforts to increase the mean airway antenatal GBS prophylaxis has decreased the rates of early
pressure, through either higher PEEP or longer inspiratory onset GBS sepsis and pneumonia but has not changed the
time, will help to increase FRC and improve oxygenation. HFOV, rates of late-onset disease. There are 10 identifiable sub-
especially when using a series of recruitment steps to reach types of GBS based on capsular polysaccharide antigens;
an open lung, may have benefits for improving oxygenation most neonatal infections are caused by types Ia, II, III, and
in ARDS though its superiority over conventional ventilation V, but the pathogenic subtypes differ between countries.187
has not been demonstrated.182 In recent studies in adults with The incidence of early-onset GBS sepsis is 0.67 per 1000
ARDS, HFOV did not decrease mortality over conventional live births in the Americas and 0.53 per 1000 in Europe.
mechanical ventilation.183 Fluid management is important Countries reporting no use of intrapartum antibiotics have
in treating ARDS as the clinician tries to decrease flooding had a 2.2-fold increase in early-onset disease.187 E. coli is the
of the lung with fluid restriction, while still maintaining second most common cause of early-onset neonatal sepsis
proper perfusion of other organs. Broad-spectrum antimi- and pneumonia.188,189 A large percentage of E. coli strains
crobials (usually ampicillin plus an aminoglycoside if in the that cause early-onset sepsis possess the capsule type K1,
first few days after birth but with broader coverage, especially which confers antiphagocytic properties and resistance to
for staphylococcus, when systemic infection is suspected after complement mediated killing; antibiotic resistance to both
3 days) should be administered. Aminoglycoside levels must be ampicillin and gentamicin have been increasingly reported
carefully monitored because these infants are at high risk of in E. coli. Other organisms that cause ascending infection
renal dysfunction. Air leaks and infection are commonly seen include Haemophilus influenzae, Streptococcus pneumoniae, L.
in infants with ARDS. Pulmonary hypertension can occur in monocytogenes, Klebsiella pneumoniae, Candida albicans, and
ARDS and infants may benefit from sedation or inhaled NO viruses such as adenovirus, CMV, HSV, and echovirus.
therapy. Severe ARDS that does not respond to HFOV may Risk factors for early-onset pneumonia include prolonged
require ECMO, often arteriovenous due to cardiac dysfunc- rupture of the membranes, premature labor, and colonization
tion, until the lungs recover. The mortality and morbidity of the vagina with GBS or other pathogens. Chorioamnionitis
of ARDS are high, and this is due to a combination of the increases the risk of early-onset pneumonia and may predis-
hypoxia from the lung disease and the effects of the systemic pose the infant to an altered immune/inflammatory response
disease that caused the ARDS. to microorganisms acquired during labor.189 In developed
countries, approximately 20%–30% of women are colonized
with GBS in the vaginal vault and 50% of infants born vagi-
Early-Onset Pneumonia nally will become colonized. Fortunately, only 1% of these
infants will develop invasive GBS disease.187 Although not
Early-onset pneumonia presents clinically within the first 48 routinely tested clinically, the highest transmission rate is
hours to 1 week after birth.184 Because early-onset or con- in GBS colonized women who have low levels of circulating
genital pneumonias are often present at birth, it is sometimes anti-GBS immunoglobulin. Women infected with HIV are
difficult to distinguish pneumonia from RDS, TTN, or MAS. considerably more susceptible to many perinatal infections,
Radiographically diagnosed pneumonia was found in 1.5% especially L. monocytogenes. HSV is usually transmitted during
of infants born at 34 weeks versus 0.2% of infants born at delivery through an infected maternal genital tract.
term.185 Pneumonias can be acquired either transplacentally
from mother, during labor with prolonged rupture of mem- CLINICAL PRESENTATION
branes or chorioamnionitis, or during delivery. The timing of
clinical presentation will depend on the mode of transmis- The timing of presentation depends on whether the infection
sion. The term newborn lung is immature with respect to was acquired transplacentally, usually present at birth, or
ciliary clearance of microbes, lung macrophage function, and during labor, when it may take up to 48 hours to develop.
humoral immune responses (immunoglobulin A, surfactant GBS is a fast-growing microorganism, and most of these
protein A and D); and this predisposes the newborn lung to infections will present in the first 12 hours, and rapid dete-
pneumonias. Although originally thought to be sterile, the rioration can occur without prompt treatment. In the setting
normal lung is now known to be colonized with its own micro- of chorioamnionitis, sepsis may present within 6 hours of
biome and the interactions between normal and pathologic birth.189 Many infants with pneumonia or sepsis have normal
bacteria may play a role in the development of pneumonia Apgar values at birth but develop progressive tachypnea,
or other respiratory diseases.186 The mode of delivery affects respiratory distress, hypoxia, and other signs of sepsis. Some
the respiratory microbiome, with infants delivered vaginally infants will have more subtle findings, such as poor feeding,
having bacteria closer to the mother’s vaginal secretions, irritability, hypothermia, or fever.152 Infants who are overtly
whereas C-section infants have a lung biome closer to mater- septic with poor peripheral perfusion, cyanosis, and inad-
nal skin.186 Transplacentally acquired organisms associated equate respiration have a poor prognosis.189 Infants with
with pneumonia include Listeria monocytogenes (often found severe congenital pneumonia may require high PIPs to open
in unpasteurized cheeses), Mycobacterium tuberculosis, Trepo- the inflamed lungs. Infants with congenitally acquired Lis-
nema pallidum, rubella virus, cytomegalovirus (CMV), herpes teria infection are often extremely ill at birth, with severe
simplex virus (HSV), adenovirus, and influenza type A virus. pneumonia and hepatomegaly, and at autopsy have small
A high percentage (more than 20%) of stillborn infants or pinkish-gray granulomas throughout the lung, liver, skin,
may provide additional information on the organism. If herpes

infection is likely, viral cultures from the maternal lesions
and the infant should be obtained.
MANAGEMENT
Because it is difficult to determine whether respiratory dis-
tress is caused by pneumonia or TTN, many clinicians will
treat any respiratory distress requiring additional monitor-
ing with antibiotics. All infants who were well appearing at
birth and then develop respiratory distress require a work-up
for sepsis, pneumonia, and congenital heart disease. Initial
treatment for early-onset pneumonia should be a combina-
tion of ampicillin or benzylpenicillin and an aminoglycoside,
most often gentamicin. The initial management regiment
should be modified once culture results are available, or
if certain resistance patterns are present within the local
community. Cefotaxime can be substituted for gentamicin in
Fig. 19.5 Lobar pneumonia: right lower lobe is consolidated on chest infants with birth asphyxia or concerns about renal failure.
x-ray and streaky infiltrates can be seen in other portions of the lungs.
Certain bacteria, such as H. influenza, may require cefotaxime
due to development of antibiotic resistance. E. coli is often
resistant to ampicillin, and bacterial strains resistant to both
ampicillin and gentamicin have been reported. For Listeria,
the most effective antimicrobial therapy is the combination
of ampicillin plus gentamicin because Listeria is resistant to
all cephalosporins. The length of treatment depends on the
severity of the disease, the presence of systemic response, and
the organism isolated. Most early-onset cases of pneumonia
will respond to antibiotic therapy of 7–10 days, with no
clear evidence for one treatment length or the other. Lung
abscesses and empyemas should be drained, and with these
complications IV antimicrobials should be administered for
at least 2 weeks. Infections due to HSV require long-term
therapy with high-dose acyclovir.
Late-Onset Pneumonia
Late-onset pneumonia typically occurs in infants after
approximately 1 week to 3 weeks of life and can be caused
Fig. 19.6 Newborn pneumonia. Diffuse opacifications are visible through- by a variety of bacteria and respiratory viruses. The most
out lungs. Clinical correlation will often determine pneumonia verses
transient tachypnea of the newborn or respiratory distress syndrome. common causes are gram-positive cocci (coagulase-negative
Staphylococci, Staphylococcus aureus, streptococci) and gram-
negative bacilli (including Klebsiella, E. coli, Serratia marcescens,
and other organ systems. Viruses such as CMV and HSV can and Pseudomonas). These infections often occur in infants
present with pneumonia or more generalized pneumonitis. with prolonged mechanical ventilation, and hospitals have
The chest radiograph appearance is variable and can range developed respiratory hygiene protocols to attempt to decrease
from an entire lobe (Fig. 19.5) to segmental consolidation, ventilator-associated pneumonias.190 Increasing respiratory
atelectasis, or diffuse opacification (Fig. 19.6). Many pediatric support while on mechanical ventilation should be investi-
radiologists will not distinguish between neonatal pneumonia, gated for development of pneumonia. Chlamydia trachomatis
TTN, or RDS, and often a follow-up image is needed (TTN is a well-recognized cause of late-onset pneumonia, often
should have resolved on repeat x-ray). Pleural effusions can presenting at 1–3 months of age, and may develop in 7%
be present and sometimes abscesses or pneumatoceles. For of infants born to mothers infected with Chlamydia.184 Two
intubated infants, a tracheal aspirate from a new ET tube can weeks of oral erythromycin is recommended for chlamydial
sometimes be useful and should be evaluated by microscopy pneumonia. Ureaplasma urealyticum is a common cause of
for white blood cell, and culture. Blood cultures are important chorioamnionitis and pneumonia in infants, but the bac-
because many of the infections are hematogenously spread terium does not grow well on typical culture media and is
or have secondary bacterial release into the bloodstream. often not identified. In areas of the world where tuberculosis
Systemic markers of infection and inflammation, such as a is prevalent, tuberculosis pneumonia should be considered
CBC or C-reactive protein, may help to guide the clinician because the symptoms are nonspecific, and tuberculosis can
regarding antibiotic use. In the setting of suspected chorio- be acquired by transplacental spread, aspiration, ingestion
amnionitis, histologic evaluation and culture of the placenta of infected amniotic fluid, or airborne inoculation from close
contacts.184 Respiratory viruses have an increasing role in be necessary for microaspiration. Infants with consolidation
late-onset pneumonia, with adenovirus, rhinovirus, respira- of the right upper lobe may benefit from positioning this
tory syncytial virus, influenza, and human metapneumovirus side up to allow increased aeration and drainage of the lung
being the most common. With the use of respiratory virus segment. Aspiration pneumonia is more common in infants
polymerase chain reaction (PCR) panels, many previously with neurologic disease or injury, and surgical intervention
undiagnosed infections can be found and proper isolation with Nissen procedure or gastrostomy tube may be necessary
of the infant can be instituted. Viral pneumonias are often to prevent recurrent events.194 Preterm infants with BPD
nosocomial and usually occur when there are high levels of and a developmentally normal neurologic examination can
infection in the community. Fungal pneumonias, often due to be fed while on CPAP without increased risk of aspiration
candida species, can be found in very low birth weight (VLBW) pneumonia.
infants, especially after prolonged exposure to third-generation
cephalosporins, but are typically caused by hematogenous
spread. CMV pneumonia is rare in the term infant but can be a Interstitial Lung Disease
cause of persistent CMV pneumonitis in immunocompromised
or very preterm infants. CMV can be acquired from CMV- Childhood interstitial lung disease (chILD) should be in the
infected amniotic fluid or through feeding with thawed frozen differential of term newborns with severe respiratory dis-
breast milk from HCMV-Ig–positive mothers.191 Although tress, or preterm infants with prolonged ventilator support
many of the bacteria that cause late-onset pneumonia are that do not have normal responses to surfactant therapies.
covered by the combination of ampicillin and gentamicin, These conditions include problems with the surfactant system
initial treatment with a third-generation cephalosporin and (e.g., surfactant protein deficiency and ABCA3 deficiency—
vancomycin may be warranted. If the infant is worsening on reviewed in Chapters 5 and 57), pulmonary interstitial gly-
current antimicrobials, the regime should broadened to cover cogenosis (PIG), neuroendocrine cell hyperplasia of infancy
nosocomial organisms such as Pseudomonas and Serratia.184 (NEHI—previously called persistent tachypnea of infancy),
or alveolar capillary dysplasia (ACD). Interstitial lung disease
is diagnosed through high-resolution computed tomography
Aspiration Pneumonia (CT) scan or lung biopsy. Corticosteroids are commonly used
in many chILD and may decrease lung inflammation and
Aspiration pneumonia occurs in newborns either through interstitial thickening. Interstitial lung disease is covered in
aspiration of GER into airways or from inappropriate closure detail in Chapters 54–57.
of the airways during feedings. The aspirated fluid can cause
inflammation of the airways or cause physical obstruction of
the airways.192 The airway obstruction can lead to lung col- Persistent Pulmonary
lapse or increased propensity for bacterial infection (Fig. 19.7), Hypertension of the Newborn
with the right upper lobe being the most affected region. The
low pH of gastric secretions may lead to worsening chemical PPHN is caused by failure of the pulmonary vascular resis-
irritation of the airways and lung parenchyma. Infants with tance (PVR) to rapidly decrease at birth, leading to right-
chronic microaspirations may develop hypoxia and respira- to-left shunts at the level of the ductus arteriosus and the
tory distress.193 Severe aspiration pneumonia often requires foramen ovale and difficulty with oxygenation. Although
mechanical ventilation until inflammation has resolved. PPHN is sometimes referred to as persistent fetal circulation,
Broad-spectrum antimicrobial cover should be prescribed the removal of the low-resistance, high-volume placental
for aspiration pneumonia with consolidation but may not circuit creates additional work for the cardiopulmonary
system. Understanding the alterations in the normal physi-
ologic transition at birth helps clinicians to develop thera-
peutic interventions for these critically ill infants.
CHANGES IN THE CIRCULATION AT BIRTH

During fetal circulation, the PVR is high and only 10%–20% of
the cardiac output goes through the pulmonary vasculature.
The low resistance, high volume of the placenta enhances
shunting of the blood away from the lungs through the
foramen ovale or the ductus arteriosus. Pulmonary blood flow
and PVR changes throughout the pregnancy in a U-shaped
curve. The PVR is high at 20 weeks GA, with 13% cardiac
output going to lungs, then PVR drops around 30 weeks
gestation to increase blood flow to lungs to 25%–30% of
cardiac output, before an increase in PVR near term causes
a drop in pulmonary blood flow to around 20%.195 The com-
bination of increased arterial oxygen content, removal of
the low resistance of the placenta, and removal of placental
Fig. 19.7 Aspiration pneumonia: aspiration often causes lobar pneu- derived prostaglandins lead to rapid transitions from fetal to
monitis or pneumonia. The right upper lobe is most often involved. newborn circulations. Removal of the placenta decreases
venous return to the right atrium, decreases right atrial causes pulmonary vasoconstriction, with PaO2 levels less than
(RA) pressure, and increases systemic vascular resistance 60 mm Hg causing exponential increases in PVR.201,202 Intra-
(SVR) leading to increased left atrial pressure, which leads uterine growth restriction infants with chronic hypoxia and
to closure of the foramen ovale. The flow through the ductus placental insufficiency also have increased muscularization of
arteriosus decreases such that it passively closes within 3–7 the pulmonary arterioles and extension of muscle layer into
days after birth. In normal newborns, PVR falls rapidly in smaller arteries. Hypoxia leads to increase in vasoconstrictor
the first minutes after birth, with recruitment of FRC and and smooth muscle mitogens (ET-1, platelet-derived growth
then more gradually over the next days. Aeration of the factor B, vascular endothelial growth factor) and decreases
lungs, through stimulation of stretch receptors, vasodilates in endothelial NO synthase.203 In the setting of meconium
the pulmonary vascular bed and increases the pulmonary aspiration, where the release of meconium is a response to
blood flow.196,197 Opening of the alveoli also leads to decrease in utero stress and chronic hypoxia over a period of days,
perivascular fluid and improved gas exchange (see clearance there may be changes to the vascular walls that contribute
of airway fluid). In utero the PVR remains high due to low to pulmonary hypertension. Higher hematocrits (Hcts) have
levels of pulmonary vasodilators (oxygen, prostacyclin [PGI2] also been associated with increased pulmonary hyperten-
and NO), and high levels of vasoconstrictors (endothelin-1 sion, but this may be due to changes from fetal hypoxia that
[ET-1]).198 PGI2 is produced by the vascular endothelial cells, also stimulate red cell production. ACD (discussed in Chapter
pulmonary stretch increases its release, and causes relaxation 56) cause disruption of the alignment of the pulmonary
of smooth muscle surrounding the arterioles. Blockade of vasculature with the distal airspaces, creating pulmonary
prostaglandins in utero does not affect resting PVR, whereas hypertension and failure to oxygenate. Infants with pulmo-
exogenous PGI2 causes vasodilation after birth.199 NO is nary hypoplasia, due to either physical obstruction in CDH or
also produced by the vascular endothelial cells through the from loss of distending pressure in severe oligohydramnios,
cleavage of L-arginine by NO synthase. NO diffuses into the have decreased arteriole numbers and increased musculature.
smooth muscles cells to stimulate vessel relaxation through These infants often have both a fixed anatomic component
production of guanosine monophosphate. Because oxygen and a reactive component (responds to treatments listed later)
tension helps to regulate NO production, fetal NO levels to their pulmonary hypertension creating a mixed response
are low in the relative hypoxic environment. Endogenous to treatment. Infants with PPHN typically have a normal
NO production responds to the increased PaO2 associated number and muscularization of the arteries, but the arteri-
with initiation of ventilation at birth. PGI2 activity may be oles fail to respond to normal transitional cues of increased
modulated by NO because NO synthase inhibitors decrease oxygen tension and expansion of the lung at birth. PPHN is
the effectiveness of exogenous PGI2. Along with increasing more common in infants with African-American or Asian
vasodilators, endogenous vasoconstrictors (thromboxane and mothers, and who are male.204 With current therapies, the
ET-1) decrease at birth to allow relaxation of the vascula- PVR of most infants will eventually decrease over the first
ture. In newborns with significant hypoxia or sepsis, levels week. Prolonged need for treatment warrants further evalua-
of ET-1 and thromboxane A2, along with leukotrienes, are tion for rare conditions such as ACD or surfactant deficiency.
increased and can cause severe pulmonary hypertension.
Prostaglandin E2, which helps to maintain ductal patency CLINICAL PRESENTATION
in utero, is produced by the placenta and PGE2 metabolism
within the lungs is enhanced by ventilation, thus decreasing Infants with PPHN usually present within 6 hours of birth
levels of PGE2 help to facilitate ductal closure. Although there with cyanosis and mild respiratory distress. Because the lungs
is some variation, most infants complete this cardiovascular are often fully expanded in PPHN, grunting and nasal flaring
transition by 8 hours of age and the ductus arteriosus typi- are uncommon with these infants. On cardiac examination,
cally closes by 24 hours of age. Pulmonary vascular pres- the second heart sound may be louder due to the increased
sure decreases to 50% of systemic vascular pressure by 24 pulmonary pressures and there may be a soft systolic murmur
hours of life, and adult levels of PVR are typically reached from tricuspid regurgitation (TR). Infants with pulmonary
by 6 weeks of age.198 hypertension from structural changes to the lung parenchyma
(CDH, pulmonary hypoplasia) will present with increased
respiratory symptoms and other physical examination findings
PATHOPHYSIOLOGY
associated with these conditions. Pulmonary hypertension
PPHN can be secondary to systemic conditions (birth asphyxia, can occur in severe GBS infection and birth asphyxia, and
sepsis, metabolic disorders, maternal exposure to selective these infants may have systemic signs of shock or neurologic
serotonin reuptake inhibitor, BPD) or due to congenital con- changes.
ditions (CDH, congenital heart disease, ACD, pulmonary
hypoplasia). There is an increased incidence of pulmonary DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
hypertension in some genetic disorders (trisomy 21, Noonan
syndrome, DiGeorge) and with rare familial mutations.200 The Pulmonary hypertension should be suspected when the
newborn pulmonary vasculature responds quickly to changes severity of hypoxemia does not correspond to the severity
in pH, PaO2, and PaCO2. Acidosis (either respiratory or meta- of radiologic or clinical symptoms. Infants with pulmonary
bolic) leads to pulmonary vasoconstriction, whereas alkalo- hypertension secondary to other systemic diseases may have
sis can temporarily improve PVR and oxygenation. Caution radiographic changes consistent with the original disease
should be used with induction of chronic respiratory alkalosis, process. Evidence of right-to-left shunting across the ductus
because overventilation and hypocapnia can injure the lung arteriosus can be determined by pulse oximetry readings
and may potentiate cerebral vasoconstriction.200 Hypoxia also between the right wrist (preductal) and the lower extremity
(postductal). PaO2 levels can be compared between a radial not in PPHN. Current European guidelines for management
artery and the umbilical artery, but this is normally not of acute PPHN recommend maintaining partial pressure
necessary due to the reliability of saturation differences on of carbon dioxide (pCO2) between 45 and 60 mm Hg and
pulse oximetry. Response to oxygen therapy is more common pH > 7.25.206 Lower pH levels increase the reactivity of the
in pulmonary hypertension than congenital heart disease, pulmonary vasculature to hypoxia. Alkalosis, either by
although some infants with severe PPHN will have PaO2 < mechanical ventilation to induce hypocapnia or through
100 mm Hg on 100% oxygen. Infants with congenital heart metabolic alkalosis with sodium bicarbonate, can transiently
disease may have a similar presentation, so echocardiogram increase oxygenation. Hyperventilation, once a main therapy
is necessary to rule out structural heart disease. Although in PPHN, is not routinely recommended because prolonged
cardiac catheterization is the only way to directly measure alkalosis can worsen lung disease and can cause changes in
pulmonary arterial pressures, echocardiogram is primarily cerebral blood flow and neurodevelopmental outcome.200,205
used clinically to diagnosis pulmonary hypertension.200 The Lung overdistention from high inflating pressure and PEEP
TR jet velocity is the most accurate echocardiographic predic- can also cause barotrauma and worsening of pulmonary
tor of pulmonary hypertension in children.200 Because many hypertension. Some centers use high-frequency oscillation
infants do not have a measurable TR, other echocardiographic or jet ventilation to maintain higher mean airway pressures
findings in PPHN include RA enlargement, right ventricular to keep the lungs inflated. ECMO is used as a rescue therapy
(RV) dilation, pulmonary artery dilation, septal flattening, for infants unresponsive to additional therapies listed later.
and directional shunting at PFO or PDA.200 Infants with fixed Oxygen is the other main therapy for PPHN available in most
pulmonary hypertension from congenital changes to the lung parts of the world. Oxygen is a potent vasodilator of the
(CDH, lung hypoplasia) may not respond to oxygen therapy. pulmonary vasculature, and this drug should be titrated in
ACD should be suspected in infants with severe pulmonary infants with PPHN to both avoid hypoxia and hyperoxia.
hypertension that is persistent and unresponsive to conven- Hypoxia causes vasoconstriction in animals at PaO2 < 50 mm
tional therapies, but it requires a lung biopsy to establish the Hg with exponential increases in PVR as hypoxia worsens.202
diagnosis. The severity of the pulmonary hypertension can be Increasing PaO2 to greater than 60 mm Hg does not decrease
measured by either oxygen index or alveolar-arterial oxygen the PVR further. High oxygen tension can lead to free radical
difference, and these parameters can be used to determine formation and worsening of the pulmonary hypertension.
response to therapies and need to escalate care towards ECMO. NO is directly inactivated by superoxide forming peroxynitrite
which is toxic, and hyperoxia enhances phosphodiesterase-5
(PDE-5) activity, leading to increased break down of NO.
MANAGEMENT
Hyperoxia can also cause vasoconstriction through activa-
Overstimulation can worsen pulmonary hypertension and tion of xanthine oxidase.207 To avoid hypoxia and hyperoxia,
oxygenation in infants with PPHN. Minimal handling by staff infants with PPHN are recommended to be maintained at
and family and reduction in nursing interventions such as an oxygen saturation by pulse oximetry (SpO2) level between
routine ET suctioning can improve oxygenation. The infant 90% and 95% with avoidance of SpO2 levels less than 85 or
should be maintained in a normothermic environment, unless greater than 97%.200,206,207 These saturation levels correspond
undergoing therapeutic hypothermia for birth asphyxia, to a PaO2 of 60–80 mm Hg. Although many infants with
because extremes of temperature can alter PVR. Because mild to moderate PPHN can have oxygenation maintained
sepsis and neonatal pneumonia are often causes of pulmo- through oxygen, CPAP, and sedation, an increasing OI should
nary hypertension in the newborn, broad-spectrum antibi- signal a need for a higher level of NICU care and initiation
otics should be considered in the initial days of treatment. of therapies listed later.
The infant’s Hct should be maintained in a normal range iNO is the only US Food and Drug Administration (FDA)-
(40%–50%) to optimize oxygen delivery without causing the approved gas for treatment of pulmonary hypertension in
increased viscosity and PVR seen with polycythemia.203 In term and late preterm infants. iNO is typically bled into a
situations of extreme polycythemia (Hct > 70%), a partial ventilator circuit, although it can be given via nasal cannulae
exchange transfusion should be considered. Many infants (NC) or CPAP in noninvasive ventilation. iNO diffuses across
with moderate to severe pulmonary hypertension will require the capillary membrane into the vascular smooth muscle
continuous sedation and pain control to improve oxygenation. to relax the arterioles. iNO then binds to hemoglobin and is
In some situations, pharmacologic paralysis can be used to quickly converted to an inactive form leaving methemoglobin
reduce PVR and prevent ECMO use; up to 73% of infants (metHg) and nitrite. This conversion limits the systemic effects
received paralysis prior to routine NO use.205 of NO, making it a selective pulmonary vasodilator. MetHg
Two of the most basic therapies for PPHN, available in is normally reduced by metHg reductase in erythrocytes,
low-resource environments, are optimizing lung expansion but this enzyme can be low in premature infants and some
and oxygen therapy. Many infants with mild PPHN can be ethnic groups (Native Americans, Siberians, Turkish). Because
treated with nasal cannula oxygen to decrease PVR. Main- MetHg poorly binds oxygen, metHg levels need to be fol-
taining lung expansion and avoiding atelectasis is important lowed on infants on NO. iNO has also been associated with
for improving ventilation-perfusion mismatch in PPHN and an increased bleeding time and possible effects on surfactant
can often be achieved with CPAP. Infants with moderate to function. For the treatment of PPHN, iNO is usually started
severe PPHN normally require intubation and mechanical at 10–20 parts per million (ppm) and has vasoactive proper-
ventilation. The addition of surfactant to infants receiving ties as low as 5 ppm. Studies have compared 20 ppm and
mechanical ventilation, especially in the setting of meconium 80 ppm in term infants with PPHN and found no difference
aspiration, should be considered.200,206 Surfactant therapy in the efficacy but an increased risk of metHg.208 Guidelines
has been shown to reduce the need for ECMO in MAS, but recommend the use of iNO in infants with an OI > 25 or
a PaO2 < 100 mm Hg on 100% FiO2.200,206 iNO improves PDA and PFO is dependent on the ratio of the PVR to the SVR.
oxygenation and decreases the need for ECMO when started Increasing the systemic blood pressure will decrease this ratio
on infants with OI > 25 but has no effect on mortality or and divert blood into the pulmonary vasculature.212 Manage-
neurologic outcome.200,206,207 Approximately 30% of infants ment of systemic perfusion involves both the RV dysfunction
do not have a sustained response to NO.209 There are conflict- due to increased afterload with pulmonary hypertension and
ing data on whether starting iNO when OI is >15 but <25 left ventricular dysfunction from preload reduction due to
is beneficial.200,207 The combination of surfactant and NO decreased pulmonary return. Increasing SVR without increas-
may lower OI. The use of HFOV has been advocated by some ing pulmonary resistance may be more difficult in some cases
research groups because the open lung ventilation styles may of pulmonary hypertension where increased muscularity of
decrease the ventilation-perfusion mismatch and improve iNO the arterioles, due to chronic in utero hypoxia, may create
delivery.200 Once the infants PVR improves, iNO should be similar increases in PVR. Dopamine and epinephrine may
weaned to avoid risks of metHg. iNO can be weaned quickly have the highest risk of similar increases in both PVR and
to 5 ppm but then should be slowly weaned to 1 ppm over a SVR but are often used to maintain systemic blood pressure in
period of hours.200 Abrupt discontinuation of iNO will lead the setting of PPHN. Norepinephrine may have less effect on
to rebound pulmonary hypertension due to a decrease in PVR than SVR and has been shown to improve oxygenation
endogenous NO production caused by the therapy. The use of in PPHN.212 Dobutamine improves cardiac contractility and
iNO in premature infants is controversial. The NIH released at lower doses (2–5 micrograms/kg per minute) increases
a consensus statement in 2011 that discouraged the use of PVR. Milrinone, a selective phosphodiesterase-3 (PDE3) inhibi-
iNO is preterm infants, except in the infant with prolonged tor, can improve cardiac output by increasing contractility
rupture of membranes or oligohydramnios, because of lack of and decreasing left ventricular afterload, and improve PVR
efficacy.210 Multiple large studies of preterm infants have been through interactions with NO and PGI2. In the setting of
conducted to test if iNO could decrease BPD, but none have 100% O2, iNO upregulates PDE3, thus milrinone may have
shown a benefit for lung disease or neurologic outcomes.211 additional benefits in PPHN refractory to iNO.199,200,212 Mil-
Because more than 30% of infants do not have a sustained rinone can cause systemic hypotension, which may limit its
improvement in oxygenation with iNO, other medications use in neonates; thus it is often used in combination with
have been used to decrease pulmonary hypertension in the other vasoactive medications.
newborn. Like iNO, these medications are designed to modu- When medical therapies fail to improve oxygenation and
late the pathways discussed earlier (PGI2, ET-1, PDE5) and OI remains higher than 40 (protocols differ between centers),
have been used in adults with pulmonary hypertension (see ECMO can be used to treat PPHN.200,203,206 ECMO is not advis-
Chapter 35). These medications can be given either intrave- able for PPHN in infants with chromosomal anomalies, lethal
nously or by nebulization with the mechanical ventilator. congenital malformations, uncorrectable heart defects, and
PGI2 modulates vascular muscle contraction by increasing major intracranial bleeds. Due to size limitations and increased
cyclic-adenosine monophosphate to cause relaxation. In risk of IVH, ECMO is not recommended for severe PPHN in
adults, PGI2 analogs (epoprostenol, treprostinil, iloprost, preterm infants less than 34 weeks GA or less than 2000 g.206
beraprost) play a vital role in treatment of pulmonary hyper- ECMO can be done via either venovenous or venoarterial
tension but are often given intravenously and can lead to methods, depending on the size and cardiac function of the
systemic hypotension. To avoid systemic hypotension, epo- infant, and many centers have protocols for duration of use
prostenol and iloprost (the only FDA-approved PGI2 analog of ECMO.203 The chance of an intracranial bleed is 10%–15%,
for inhalation) can be nebulized through the ventilator and and adverse neurologic outcome may be due to the underly-
have shown good results in PPHN refractory to iNO.199 Bosen- ing hypoxia or the vascular compromise from ligation and
tan, an ET-1 antagonist, is used for chronic therapy in adults cannulation. With the introduction of iNO, the use of ECMO
with pulmonary hypertension but is normally only available for PPHN has dramatically decreased.
in an oral solution. In the setting of iNO, the addition of
bosentan to infants with PPHN did not show additional MORTALITY AND MORBIDITY
effects.199 One of the most common adjuvant therapies to
iNO in PPHN is sildenafil.200,206 Sildenafil, a PGE5 inhibitor, Before the use of ECMO and iNO, the mortality from PPHN
inhibits the breakdown of cyclic guanosine monophosphate was nearly 50%.200,205 Even with advanced therapies, the
(cGMP) (the secondary messenger of NO pathway) to inac- mortality rate for PPHN remains between 8% and 10%.200
tive GMP in the vascular smooth muscles. Sildenafil, which The mortality rate varies according to the underlying condi-
is available in IV and oral forms, can be given in combination tion. The mortality rate for PPHN, or pulmonary hypertension
with iNO for PPHN or for helping wean infants from due to RDS or MAS, is lower than that of infants with septic
iNO.199,200,206 Guidelines recommend that sildenafil should shock (e.g., GBS). ACD is a uniformly fatal condition without
be considered as first-line therapy for PPHN in settings where lung transplantation. Infants with severe PPHN have
iNO is not available.200,206 Sildenafil is often used in infants increased risk for neurodevelopmental delays and audiologic
with BPD and pulmonary hypertension, and adjustments impairment.
have been made to FDA warnings about its use in pediatric
patients.199 Tolazoline hydrochloride and magnesium sulfate
have been used with moderate success in PPHN, but their Pulmonary Hypertension in
systemic effects and the availability of iNO have limited their Bronchopulmonary Dysplasia
use in recent years.
Maintaining adequate systemic blood pressure is crucial to BPD in the modern era, discussed in Chapter 20, is due
the management of PPHN. The right-to-left shunt across the to both alveolar and capillary simplification. Infants with
BPD have increased risk of pulmonary hypertension (25%–

37% of infants) and may progress to right heart failure.213
Screening echocardiograms should be done on infants with
established BPD.200 In infants with BPD and increased PVR,
oxygen saturations of 92%–95% may be appropriate.200 iNO
and sildenafil can be used to treat pulmonary hypertension
with BPD.
Pneumothorax
Spontaneous pneumothoraces likely occur in 1%–2% of
newborn deliveries, but only 10% of them are symptom-
atic.214,215 Elective C-section increases the risk of pneumotho-
rax compared with spontaneous vaginal delivery, probably
due to the increased fetal lung fluid present at birth.215 PPV
and ET intubation increase the incidence to almost 6%.214
High transpulmonary pressure, generated by the first
spontaneous breaths to clear the fetal lung fluid from the
airways, can cause local overdistention of the alveoli and
air leaks. Prematurity and congenital lung malformations
increase the risk of pneumothoraces. Rarely, pneumothora-
ces are caused by direct trauma to the airways by suction Fig. 19.8 Tension pneumothorax: right-sided tension pneumothorax
catheters or ET tubes, but these injuries more often lead to with collapse of the right lung, midline shift of the cardiac and trachea
pneumomediastinum. to the left.
Small asymptomatic pneumothoraces are often found on
chest films taken for other reasons. Most small pneumotho-
races can be monitored clinically without intervention. Larger
pneumothoraces will present with respiratory symptoms, second intercostal space above the rib at the midclavicular
including tachypnea, retractions, and an oxygen require- line and air aspirated. This can also be done through the
ment. Pneumothoraces large enough to cause a shift of the mid-axillary region between the fourth and sixth ribs. In
central structures of the chest (tension pneumothorax) will some larger infants, removal of the initial air by needle tho-
presents with severe desaturations and signs of shock. Breath racentesis will be enough to resolve the pneumothorax. With
sounds may be decreased with a pneumothorax, and transil- larger pneumothoraces or reaccumulation of air after needle
lumination with a fiberoptic light can be used to evaluate thoracentesis, a thoracotomy tube can be placed through the
for pneumothorax (area with pneumothorax will appear mid-axillary region and aimed in the direction of the pocket of
brighter). If the infant is clinically stable, a chest radiograph air. Using sterile techniques and local anesthesia, either a stan-
should be obtained to determine the diagnosis. A moderately dard chest tube (French gauge 10–14) or a pigtail angiocath
large pneumothorax will demonstrate absent lung markings can be inserted into the pleural space and positioned in the
and a collapsed lung on the ipsilateral side. Tension pneu- anterior chest (Fig. 19.9). The chest tube should be connected
mothorax will have eversion of the diaphragm and displace- to an underwater seal drain with suction of 5–10 cm H2O.
ment of the central structures to the contralateral side (Fig. Often the chest tube is removed from suction and placed to
19.8). Congenital lung malformations, such as pulmonary water seal for approximately 24 hours prior to removal of the
lobar emphysema or congenital pulmonary airway anomalies, chest tube.
can appear like pneumothoraces (see Chapter 18) and should
be included in the differential diagnosis of atypically appear-
ing air within the chest. Pneumomediastinum
Asymptomatic pneumothoraces do not require treatment
and will reabsorb over time. Although many institutions use Pneumomediastinum occurs in up to 2% of births, with
100% oxygen for 6 hours to wash out the nitrogen in the similar risk factors to pneumothorax.214 Most pneumome-
pneumothorax, this practice has not been shown to decrease diastinums are asymptomatic and do not require treatment.
the time of resolution of pneumothoraces and may increase On the chest radiograph, a pneumomediastinum is often
length of stay in the special care baby unit (SCBU).216 In a seen near the borders of the heart or in the mediastinal
cohort of infants >36 week GA with symptomatic spontane- region behind the sternum. The thymus can be elevated away
ous pneumothorax, approximately 71% could be managed from the central structures to form a spinnaker sail sign (Fig.
with oxygen therapy, whereas 29% required thoracentesis or 19.10) or the heart can be elevated off the diaphragm to
a thoracotomy tube.217 Infants with significant respiratory create the appearance of a continuous diaphragm. Drain-
distress or a tension pneumothorax require manual drainage age of a pneumomediastinum is difficult because the gas is
of the pneumothorax. Immediate evacuation of the pneumo- collected in multiple independent lobules. Because multiple
thorax can be accomplished with an 18–22-gauge butterfly vital vascular structures occupy the mediastinum, drain-
needle attached to a three-way stopcock and syringe. After age should only be done in situations of severe respiratory
cleaning with alcohol, the needle can be inserted into the distress.
Fig. 19.9 Pigtail catheter placement: chest tube catheter placed in right
chest through axillary approach has resolved majority of pneumothorax.
Small residual air is present on right chest and significant pulmonary Fig. 19.11 Pneumopericardium: often a medical emergency due to
interstitial emphysema is present on the left. cardiac tamponade, the chest x-ray demonstrates air within the
pericardium.
gas surrounds the heart and outlines the great arteries (Fig.
19.11). Infants with symptomatic pneumopericardium
require immediate drainage due to impaired cardiac output.
An angiocath or pigtail catheter can be inserted into the
pericardial space using a subxyphoid approach. Blood pres-
sure changes and bradycardia may suggest reaccumulation
of the air within the pericardial sac. The mortality and long-
term morbidity from pneumopericardium is high.
Pulmonary Interstitial
Emphysema
PIE is collection of air that escapes the alveoli and tracks
along the sheaths of the small blood vessels of the lung. It
rarely occurs spontaneously and is associated with PPV,
especially with high pressures in small preterm infants. PIE
occurs when the extraalveolar air remains within the lung
parenchyma and does not escape into other regions of the
chest (pneumothorax, pneumomediastinum, pneumoperi-
cardium, and rarely pneumoperitoneum). PIE commonly
Fig. 19.10 Pneumomediastinum: chest x-ray demonstrates air within involves both lungs, but it may be lobar in distribution. The
the mediastinum causing upward displacement of the thymus (spin- trapped gas can compress the vasculature and decreases
naker sign). pulmonary perfusion. The lung parenchyma is expanded
leading to airway obstruction, increased lung compliance,
and areas of hyperinflation. As a result, infants with severe
Pneumopericardium PIE can be profoundly hypoxemic and hypercarbic on pre-
sentation. PIE is usually diagnosed by chest radiograph which
Pneumopericardiums are rare and usually associated with demonstrates hyperinflation and diffuse, multiple, or small
other air leak syndromes. The gas, initially released into the nonconfluent cystic radiolucencies (Fig. 19.12). Bilateral,
space around the lungs, may dissect through a hole in the diffuse PIE may have a narrow cardiac silhouette due to
pericardial sac. It is more common in ventilated preterm mediastinal compression. As the amount of air collects within
infants and may be a consequence of severe PIE. Clinically, the lung parenchyma, large bullae or pneumatoceles may
pneumopericardium presents with sudden hypotension and form and are visible as circular air collections on the chest
bradycardia due to cardiac tamponade. On chest radiograph, radiograph. Lobar emphysema and congenital pulmonary
renal agenesis, prolonged rupture of the membranes); (4)

disorders impacting on normal lung development (e.g., neuro-
muscular disorders with reduced fetal breathing movements,
congenital heart disease associated with abnormal pulmonary
vasculature, large anterior abdominal wall defects affecting
diaphragmatic, and chest wall development).219,221–223
PATHOGENESIS
Lung development is a complicated process that has been
shown to occur in stages.219,224 The pseudoglandular stage
takes place between approximately 6 and 17 weeks of GA
and is the period when the conducting airways and initial
acinar framework develop. The canalicular stage follows from
Fig. 19.12 Pulmonary interstitial emphysema: small cystic changes
throughout both lungs represent air dissection into the parenchyma.
approximately 17–26 weeks GA, during which further devel-
opment of the lung parenchyma occurs. There is an increase
in canaliculi, widening of the peripheral respiratory tubules
with concurrent increase in pulmonary capillarization,
airway malformations are in the differential for these large forming the respiratory surface of the lung.224 Disorders that
cystic formations but are typically seen on earlier chest impact lung development before 17 weeks GA also substan-
radiographs. tially impact lung growth, bronchiolar branching, cartilage
If PIE is localized to one lobe of the lung, then placing the development, acinar complexity, and capillarization. Disorders
infant with this side down will cause partial collapse of the affecting lung growth during the canalicular stage (i.e., after
lung and may improve the PIE. This is not possible in severely 17 weeks GA) mainly affect acinar complexity.219 Risk of
ill preterm infants. Selective intubation of the opposite side pulmonary hypoplasia is much decreased by late canalicular
from the PIE has been studied, but left mainstem intubation stage, with higher risk of pulmonary hypoplasia associated
is often not possible in small infants. If the infant has diffuse with earlier insults. A review of 28 studies suggested that
PIE, the PEEP and peak inflating pressures should be reduced GA of preterm prelabor rupture of membranes was better
to the minimum compatible with acceptable oxygenation associated with pulmonary hypoplasia than either degree
and ventilation. Pneumatoceles also respond to decreased of oligohydramnios or latency period.225 A lack of intratho-
ventilator pressures. HFJV and HFOV are often used clinically racic space within which to grow and develop in the presence
in PIE to decrease the pressure fluctuations within the injured of space-occupying lesions or chest wall deformities is thought
lungs, but studies have not shown a conclusive benefit over to physically limit the growth of the lungs. Further limita-
conventional ventilation. One study supports the use of low- tions in space can also impact fetal breathing movements
frequency settings (5–6 Hz) on HFOV to decrease severe PIE.218 and the usual movements of amniotic fluid in and out of
Overall, PIE is associated with severe lung disease in the the airways. This limitation in fetal breathing movements is
preterm infant and is thus associated with high overall also seen in infants with neuromuscular conditions, such
morbidity. as type 1 spinal muscular atrophy. Lack of adequate amniotic
fluid can occur with all causes of severe oligohydramnios
(e.g., bilateral renal agenesis) and prolonged and premature
Secondary Pulmonary Hypoplasia leakage of amniotic fluid, which has been shown to be asso-
ciated with abnormal lung growth.226,227
See also Chapter 18.
CLINICAL FEATURES
EPIDEMIOLOGY
A proportion of infants may be diagnosed antenatally. Pul-
The incidence of pulmonary hypoplasia is estimated to range monary hypoplasia may be suspected if commonly associated
from 9 to 11 per 10,000 live births.219 Most cases are sec- conditions (e.g., oligohydramnios, CDH, or pleural effusion)
ondary in nature, with primary cases reported to be rare.220 are present. Once suspected, there are numerous antenatal
It is possible that mildly affected infants may not exhibit any features that have been reported to be useful to determine
clinical features, and thus the true incidence may be higher severity of pulmonary hypoplasia.219,225 Of importance is
than reported. the need to be able to distinguish between lethal and non-
lethal forms. For example, investigators have suggested that
persistent severe oligohydramnios after preterm prelabor
ETIOLOGY
rupture of membranes with onset <25 weeks GA was associ-
The causes of secondary pulmonary hypoplasia may be ated with greater than 90% mortality from pulmonary hypo-
divided into four main categories: (1) space-occupying lesions plasia.219 Other antenatal parameters include ultrasonic
within the thoracic cavity (e.g., CDH, pulmonary sequestra- detection of absence of fetal breathing movements and bio-
tion, congenital pulmonary airways malformation [CPAM], metric indices, such as thoracic circumference to abdominal
and pleural effusions); (2) chest wall deformities leading to circumference ratio, thoracic circumference to head circum-
reduced intrathoracic space (e.g., asphyxiating thoracic dys- ference ratio, thoracic area minus heart area and thoracic
trophy); (3) causes of severe oligohydramnios (e.g., bilateral area to heart area ratio. More recently, other imaging
view of the considerable risk of respiratory exacerbations,

annual influenza vaccine, pneumococcal vaccine, RSV pro-
phylaxis, and stringent infection control should be recom-
mended. Lung development and growth should be facilitated
by careful attention to nutrition.
PREVENTION
Prevention of pulmonary hypoplasia is theoretically possible
if the underlying cause has been detected sufficiently early
during the antenatal period and if the condition is amenable
to intervention. Examples of conditions that have been treated
in utero include pleural effusions, congenital lung lesions,
fetal urinary obstruction, and CDH.231–234 In utero thoracoam-
niotic shunting can drain fetal pleural effusions and cystic
lung lesions and have been associated with resolution of
hydropic features, in infants presenting with hydrops fetalis,
and improved survival.231 There is currently insufficient evi-
dence to support in utero surgical repair of CDH.233 More
Fig. 19.13 Pulmonary hypoplasia: chest x-ray demonstrates bell-shaped recently, efforts have been made to investigate the potential
chest with low lung volumes. Severe lung hypoplasia due to prolonged of early fetal endoscopic tracheal occlusion by balloon with
oligohydramnios may be incompatible with successful gas exchange. subsequent deflation and removal at 34 weeks GA.234,235 This
approach has seen some improvements in infant survival
for those predicted to have severe CDH (lung to head ratio
modalities, such as magnetic resonance imaging (MRI), have < 0.7).236
been explored.228
After birth, infants with secondary pulmonary hypoplasia PROGNOSIS
can present with the clinical features of the condition to
which the hypoplastic lung is secondary. For infants where The prognosis of infants with pulmonary hypoplasia can be
the pulmonary hypoplasia is not associated with an intra- very poor depending on severity, with estimated mortality
thoracic space-occupying lesion, the chest wall may appear of >90% in those associated with severe persistent oligohy-
disproportionally small compared with the overall size of dramnios due to preterm prelabor rupture of membranes
the infant. For those with underlying conditions not imme- with onset <25 weeks GA.219 Mortality improves when the
diately apparent, the hypoplasia may be clinically undetect- underlying condition impacting on lung development occurs
able, but, in those who present, the signs may range from later during pregnancy (>25 weeks) and is of relatively short
tachypnea and mild respiratory distress to severe hypoxemic duration (<6 days) and if there are no other associated con-
respiratory failure requiring ventilatory support with high ditions, such as PPHN.219,237,238 Long-term morbidity includes
ventilatory pressures. Chest radiography may reveal crowded limb abnormalities (incidence 27%–80%) due to the com-
ribs and low thoracic-to-abdominal ratio and a bell-shaped pression if associated with oligohydramnios,239 BPD and
chest (Fig. 19.13). Imaging may also reveal features of the recurrent wheezy episodes,240 and neurodevelopmental deficits
underlying condition or commonly associated complications. (incidence 28% if associated with rupture of membranes
Pulmonary hypoplasia is not uncommonly complicated by before 26 weeks GA).241
air leaks, such as pneumothorax. The pathologic criteria for
the diagnosis of pulmonary hypoplasia are relatively well
established and usually include an assessment of lung weight Patent Ductus Arteriosus
to body weight ratio and radial alveolar count.219 Ratios
greater than 0.018 suggest that pulmonary hypoplasia is EPIDEMIOLOGY
unlikely, whereas a ratio of <0.012 suggests likely or prob-
able pulmonary hypoplasia and need for further confirmation The incidence of PDA is inversely related to GA, with esti-
of the diagnosis. In cases with low lung weight to body weight mated incidences of <0.1% and 42% for term infants and
ratio, the diagnosis is confirmed if the radial alveolar count extremely low-birth-weight infants, respectively.242,243
is <75% of the mean normal value for GA.
ETIOLOGY
MANAGEMENT
PDA is caused by a failure of the ductus arteriosus to close
Severely affected infants have small lungs with poor compli- during the transition of the infant from a fetal to extrauterine
ance, oxygenation failure, and high ventilatory requirements. circulation after birth.
There is a substantial risk of air leaks, and thus some experts
suggest low-pressure fast-rate ventilation or HFOV.229 In cases PATHOGENESIS
with pulmonary hypertension, pulmonary vasodilators such
as iNO should be considered.230 Some infants may need home Gas exchange in the fetus occurs at the placenta rather than
oxygen therapy for several months after discharge, and, in the lungs. Blood is therefore shunted from the right ventricle
and pulmonary artery away from the lungs and directly to increased pulmonary blood flow could lead to pulmonary
the aorta via the ductus arteriosus. After birth, functional congestion and decreased pulmonary compliance. These
closure of the ductus arteriosus occurs. In term infants the infants may exhibit increasing oxygen and ventilatory require-
process is complete in 20% of cases by 24 hours, 82% by ments. Echocardiography is the gold standard for diagnosing
48 hours, and 100% by 96 hours. In preterm infants >30 PDA. In general, the PDA can be visualized by echocardiog-
weeks GA, 8% close by 24 hours, 60% by 48 hours, and raphy in the parasternal short-axis view as a third branch
almost 100% by 96 hours.244 In preterm infants, especially of the main pulmonary artery alongside the left and right
<30 weeks GA, there is decreased ductal sensitivity to oxygen, branch pulmonary arteries. Color Doppler could help to
poor intrinsic tone of the ductal wall, and the balance of determine whether the flow through the PDA is left to right,
vasodilators to vasoconstrictors favor ductal patency. Ductal right to left, or bidirectional. Additional features of a moder-
closure is therefore often delayed. Anatomic closure relies ate to large left-to-right ductal shunt are bowing of the
on changes that occur after functional closure is complete; interatrial septum to the right with enlargement of the left
ductal patency therefore prevents this process from taking atrium and ventricle. Left atrial enlargement with a left atrial
place. Other factors that are associated with delayed ductal to aortic root (LA:Ao) ratio > 1.4 : 1245 is considered hemo-
closure include thrombocytopenia, respiratory distress, and dynamically significant. The PDA size can be determined
persistently low PaO2.244,245 from the ductal size on color Doppler examination. If the
shunt is large, flow reversal will be throughout diastole.
Echocardiography is helpful to exclude other possible con-
CLINICAL FEATURES
genital cardiac abnormalities.
Clinical features of PDA typically arise because of hemody-
namically significant left-to-right shunting of blood from
PREVENTION
the aorta to the pulmonary artery. In view of the relatively
high pulmonary pressure of newborn infants, the chance In a meta-analysis,246 PDA prophylaxis with ibuprofen showed
of clinical features developing before normal functional reduced PDA incidence and need for rescue therapy/surgical
closure of the ductus is very low. As the PVR decreases, closure but no improvement in any other short-term out-
left-to-right shunting through the PDA increases and signs comes. In a randomized study, use of ibuprofen as PDA pre-
of left heart failure may develop. Clinically the infant may vention showed a trend towards decreased PVL but did not
exhibit a harsh systolic murmur best heard at the upper left affect any other clinical outcome.247 In summary, despite
sternal border, hyperdynamic precordial impulse, and bound- the availability of several ductal closure strategies, whether
ing peripheral pulses with widened pulse pressure. As the the intervention is medical246,248 or surgical,249 no long-term
left-to-right pressure gradient increases, the murmur may benefits in terms of outcomes such as BPD, neurodevelop-
become continuous. With worsening of the heart failure, ment or mortality have been demonstrated. Nevertheless,
the infant will develop increasing tachycardia, tachypnea, avoiding factors that may increase risk of PDA, such as exces-
cardiomegaly, and hepatomegaly. The chest radiograph illus- sive fluids,250 hypoxia, and sepsis, would be prudent.
trates cardiomegaly, pulmonary plethora, and a wide angle
between the left and right main bronchi due to left atrial
MANAGEMENT
dilation (Fig. 19.14). Particularly in preterm infants, the
Ductal closure occurs naturally, and the clinical impact of
PDA on individual patients can vary greatly. As with PDA
prevention, there is very little evidence of long-term benefit of
treatment of PDA.251 It has therefore been controversial when,
whom, and even whether to treat.251,252 PDA spontaneously
closes in a small proportion of extremely preterm infants
(approximately 24%) and is more likely to be refractory to
treatment.253 Initial management of PDA in a preterm infant
includes fluid restriction and diuretics. Cyclo-oxygenase inhibi-
tors are the most commonly used drugs for ductal closure
in preterm infants. Nonsteroidal antiinflammatory drugs
(NSAIDs) such as indomethacin and ibuprofen are nonse-
lective cyclo-oxygenase inhibitors which reduce the synthesis
of prostaglandin E and thus shift the balance toward ductal
closure. Indomethacin was previously the drug of choice;
however, in recent studies, ibuprofen has been shown to be as
effective in terms of ductal closure but associated with fewer
side effects, such as transient renal impairment and NEC.254
Ibuprofen is usually given as a 3-day course at 10 mg/kg on
the first day, 5 mg/kg on the second day, and 5 mg/kg on the
third day; however, there are small studies that report that
Fig. 19.14 Patent ductus arteriosus: left-to-right shunting through the higher doses may be more effective with no increase in side
patent ductus arteriosus can lead to signs of congestive heart failure, effects.255 Side effects are increased with concomitant use
including chest x-ray findings of cardiomegaly, pulmonary vessel con- of other drugs such as diuretics and corticosteroids. Use of
gestion, and diffuse haziness. diuretics in conjunction with indomethacin for the treatment
of PDA did not improve urine output but increased serum failure, RDS, hemodynamically significant PDA, and inflam-
creatinine and hyponatremia.256 It has also been shown that matory pulmonary conditions.268,269
concurrent use of NSAIDs and corticosteroids increases the
risk of gastrointestinal perforation 10-fold.257 Increasingly, PATHOGENESIS
paracetamol (acetaminophen) has been used as an alternative
therapeutic option for treatment of PDA.258 Meta-analyses Pulmonary edema occurs because of abnormal leakage of
suggest that paracetamol is as effective as ibuprofen for ductal fluid from pulmonary capillaries into the lung parenchyma
closure.259 However, maternal use of paracetamol during and alveolar spaces. This occurs when the pulmonary capil-
pregnancy has been associated with neurodevelopmental lary pressure exceeds the plasma oncotic pressure or when
disorders in children,260 and before more definitely long-term there is disruption of the respiratory membrane. Pulmonary
outcome data are available, use of paracetamol for ductal capillary pressure is increased in conditions with pulmonary
closure cannot be considered first-line therapy. Medical treat- congestion secondary to left ventricular dysfunction or fluid
ment by administration of the drugs via the oral route has overload. Abnormalities of the pulmonary lymphatics can
been suggested to be feasible,261,262 especially for countries also lead to accumulation of fluid in the lungs. Plasma oncotic
with limited access to IV forms of ibuprofen, indometha- pressure can be decreased in hypoproteinemia, which is
cin, and paracetamol. Treatment failure is more common in common in preterm infants and when inappropriately large
infants with sepsis and extremely preterm infants.263 Even for volumes of crystalloids have been infused into the infant.
those infants with hemodynamically significant PDA, there The integrity of the respiratory membrane can be disrupted
is currently insufficient evidence to conclude whether surgi- in many conditions, especially those associated with inflam-
cal ligation or medical ductal closure is preferable as first- matory or hypoxic insults. High ventilator settings can also
line treatment. Although surgery offers decreased closure cause excessive stretching of the alveoli and subsequent
failure rate, there is an increased risk of pneumothorax and epithelial protein leaks.268 In addition, epithelial ion transport
retinopathy of prematurity.264 Furthermore, despite surgi- plays an important role in lung lumen fluid clearance (see
cal closure, infants may still go on to develop BPD.265 Many earlier section on pulmonary lung fluid clearance) and may
neonatal units reserve surgical closure for infants with offer new strategies for managing this condition.270
hemodynamically significant PDA refractory to treatment
or when medical therapy is contraindicated. However, there CLINICAL FEATURES
is evidence that even in these infants, a nonintervention
approach despite failure of medical closure may be associated Newborn infants with pulmonary edema present with signs
with decreased incidence of BPD without increase in risk of of respiratory distress and may exhibit tachycardia, tachy-
NEC or IVH.266 The question of management ultimately rests pnea, and other signs related to the underlying condition.
on clinical judgment on whether the PDA is hemodynamically Chest radiograph features of pulmonary edema include
significant with a trend towards conservative management increased vascular markings, perihilar shadowing (Fig.
in those who remain “asymptomatic.” 19.15), linear septal opacities (Kerley B lines) in the lower
lung fields, linear opacities along the horizontal and oblique
fissures, cardiomegaly, and hazy lung fields. Investigations
PROGNOSIS
to determine the underlying cause should also be considered,
Complications associated with hemodynamically signifi- such as echocardiography for cardiac causes. Lung ultraso-
cant PDA include heart failure, BPD, neurodevelopmental nography may be helpful for detecting pulmonary edema,
impairment, NEC, and increased mortality.267 The complica- especially in cases in which the chest radiograph is
tions associated with both medical and surgical therapeu-
tic options are substantial, and optimizing outcomes for an
affected infant involves a balance of the risks of treatment
versus the potential risks of the PDA. Objective, validated
assessment tools to determine the hemodynamic signifi-
cance of a PDA to an individual infant could potentially
help to solve the difficult clinical problem of whether to
intervene.
Pulmonary Edema
EPIDEMIOLOGY
Although there are very little data on the epidemiology of
neonatal pulmonary edema, it is a well-known association
of several common neonatal conditions.
ETIOLOGY
Pulmonary edema is associated with several cardiopulmonary Fig. 19.15 Pulmonary edema: increased vascular markings and linear
conditions, including TTN, perinatal asphyxia, left ventricular septal opacities (Kerley B lines).
indeterminate.269 Important differential diagnoses that may

also coexist with pulmonary edema include pneumonia, RDS,
and MAS.
MANAGEMENT
Fluid restriction, administration of diuretics, appropriate
ventilatory support, and treatment of the underlying condi-
tion are the cornerstones of the management of pulmonary
edema. Some investigators have shown that corticosteroids
can upregulate epithelial ion transporters, which explains
why antenatal and postnatal corticosteroids have been found
to be helpful in conditions that are associated with pulmonary
edema.270
PREVENTION
The risk of neonatal pulmonary edema can be decreased by
management strategies that decrease pulmonary congestion,
increase plasma oncotic pressure, and minimize lung injury. Fig. 19.16 Pulmonary hemorrhage: diffuse bilateral opacification of the
lungs, usually associated with blood in endotracheal secretions and
Avoidance of excessive fluid administration and reduction clinical deterioration in oxygenation.
of ventilator pressures may be helpful.
PROGNOSIS
Presence of clotting abnormalities273 or hypoxic damage to
Outcomes of pulmonary edema usually depend on the sever- the pulmonary capillaries also appears to play important
ity of the underlying condition, with excellent prognosis for roles in the pathogenesis.271
self-limiting conditions such as TTN.
CLINICAL FEATURES
Pulmonary Hemorrhage Infants who develop severe pulmonary hemorrhage often
deteriorate suddenly on the first few days of life, with an
earlier onset associated with more mature infants.271 There
EPIDEMIOLOGY
is no standard definition of pulmonary hemorrhage but is
Pulmonary hemorrhage has increased from 0.1% to 1.2% usually recognized as the appearance of frank blood origi-
in the presurfactant era271 up to 5.9%, according to a meta- nating from the airway (usually seen in the ET tube) which
analysis of surfactant trials.272 However, its incidence may is accompanied by acute clinical deterioration (e.g., increasing
be underestimated because it has been reported to be the ventilator requirements and hemodynamic instability).271,274
cause of death of 9% of newborns who underwent autopsy.273 Pulmonary hemorrhage is usually associated with chest
radiograph changes such as whiteout lung fields and air
bronchograms (Fig. 19.16). Differential diagnoses include
ETIOLOGY
severe RDS, pneumonia, sepsis with disseminated intravas-
Pulmonary hemorrhage has been shown to be associated cular coagulopathy, and airway injury.
with the presence of a hemodynamically significant PDA in
preterm infants274 and acute left ventricular failure due to MANAGEMENT
asphyxia.273 Other risk factors associated with increased risk
of severe pulmonary hemorrhage include surfactant admin- Conventional management of infants with severe pulmonary
istration (especially if synthetic),275 hypothermia, Rhesus hemorrhage includes mechanical ventilation with high
hemolytic disease, and small for GA.276 PEEP.271,277 Heavy sedation and even paralysis is frequently
used. Despite the association between surfactant use and
pulmonary hemorrhage, it has been shown that a single
PATHOGENESIS
dose of surfactant after the pulmonary hemorrhage has
Analysis of hemorrhagic lung fluid from infants diagnosed occurred may improve oxygenation.278 In view of the clinical
with pulmonary hemorrhage revealed a relatively low Hct deterioration, broad-spectrum empirical antibiotics are usually
of only 10% and the presence of plasma proteins, suggesting commenced if not already in use. Anemia and coagulopathy
that the fluid is composed of blood diluted with plasma fil- should be corrected, with some authors suggesting the use
trate.273 It is believed that, although the hemorrhagic fluid of activated recombinant factor VII.277 Management of asso-
appears to be bloody, it may be more appropriate to describe ciated heart failure should be considered. Some authors
it as hemorrhagic pulmonary edema fluid. The association suggest that use of 4% cocaine (0.1 mL/kg, i.e., 4 mg/kg)
with acute left ventricular dysfunction suggests that patho- or 1:10,000 epinephrine (0.1 mL/kg, i.e., 0.01 mg/kg or
genesis of pulmonary hemorrhage is related to left-to-right 0.5 mL, i.e., 0.05 mg) via the ET route may be helpful for
shunting, pulmonary congestion, and pulmonary edema. short-term outcomes.271,279
and an associated cardiac lesion is present in as many as

PREVENTION
31% of cases.281
Prophylactic indomethacin reduces the rate of early serious
pulmonary hemorrhage, possibly because of its action on CLINICAL FEATURES
the PDA, but it is less effective in preventing severe pulmonary
hemorrhage that occurs after the first week of life.280 Judi- Partial obstruction can vary in severity, and presenting fea-
cious fluid management and prevention of heart failure may tures range from mild tachypnea or stridor to complete
possibly decrease the risk of pulmonary hemorrhage. obstruction. Infants born with complete upper airway obstruc-
tion present immediately after birth with persistent cyanosis
and ineffective respirations; they will remain refractory to
PROGNOSIS
conventional airway management measures284 and can
Mortality of severe pulmonary hemorrhage is high. Risk rapidly deteriorate with fatal consequences if not promptly
factors for higher mortality include early GA, lower birth treated.285
weight, and small for GA.271,280 The high ventilator set- Infants with unilateral choanal atresia may not exhibit
tings and oxygenation failure often lead to long-term any clinical signs unless the unaffected side is blocked, at
morbidity in survivors, including BPD and neurosensory which point they may develop respiratory distress. The clas-
impairment. sical presentation of bilateral choanal atresia is respiratory
distress at rest, which is absent when crying or mouth breath-
ing. Differential diagnoses include choanal stenosis, nasal
Upper Airway Obstruction injury, and abnormal structures, (e.g., encephalocele or
meningocele). Imaging by CT or MRI may be necessary to
differentiate these causes.
EPIDEMIOLOGY
Infants at risk of pharyngeal obstruction often present
Neonatal upper airway obstruction can occur at any level with dysmorphic features (e.g., retrognathia/micrognathia
and reflect many different underlying conditions. The overall in Pierre-Robin syndrome, craniosynostosis and dysmorphic
incidence of neonatal upper airway obstruction is unknown features in Crouzon syndrome, and characteristic facies in
because the exact incidence of even laryngomalacia, one of Down syndrome). Pharyngeal obstruction may produce
the most common causes, remains unknown in the general stertor which is usually worse when the baby is nursed in a
population. It has been reported that the prevalence can supine position. In cases in which it is unclear whether apneas
range from 8% to 50% in infants with neuromuscular are central or obstructive, infant polysomnography may be
disease.281 Rarer causes include choanal atresia, where the helpful to identify obstructive events.
incidence is 1–2 per 10,000 live births.282 Infants with laryngeal obstruction may present with stridor.
One of the most common conditions causing laryngeal
obstruction is laryngomalacia, which may present during
ETIOLOGY AND PATHOGENESIS
the first 10 days of life. The stridor is usually worse with
Causes associated with neonatal upper airway obstruction crying and feeding but improves when the infant is at rest.
vary with the level of obstruction encountered. Examples The severity of obstruction cannot be judged from the sever-
include: choanal atresia, basal encephalocele (nasal); Pierre- ity of the stridor, but rather from the presence of failure to
Robin syndrome, Down syndrome, Crouzon syndrome (pha- thrive, respiratory distress, obstructive sleep apnea, and
ryngeal); laryngomalacia and vocal cord palsy (laryngeal).283 feeding difficulties.281 Another commonly encountered
The most common congenital cause of nasal obstruction is example of airway obstruction is subglottic stenosis. This
choanal atresia, which can occur in isolation or as part of can be due to congenital structural abnormality but is more
a syndrome such as CHARGE (Coloboma of the iris and retina, usually acquired secondary to intubation. Infants present
Heart disease, Atresia choanae, Retarded growth, Genital with stridor or hoarseness after extubation with subsequent
hypoplasia, Ear defects) syndrome.282 Obstruction at the difficulty in intubation with the original sized tube. Vocal
pharyngeal level can occur from craniofacial anomalies. For cord palsy can also present with stridor and hoarseness, and
example, if the tongue is too large (macroglossia) or the affected infants may also develop signs of aspiration pneu-
mandible is small (retrognathia/micrognathia), the base of monia in view of the increased risk of aspiration. It may be
the tongue can fall backwards, especially when the infant life-threatening if both vocal cords are affected. Most causes
is in a supine position and it can obstruct the airway in the of laryngeal obstruction can be diagnosed endoscopically,
hypopharynx.281 At the laryngeal level, causes of obstruction so a newborn presenting with stridor should undergo laryn-
include structural lesions (e.g., laryngeal polyps/cysts) and goscopy and/or bronchoscopy to identify dynamic lesions.
functional causes (e.g., vocal cord palsy and laryngomalacia). For extrinsic structural lesions, imaging by CT or MRI should
Approximately 20% of vocal cord palsy is associated with be considered.
injury to the recurrent laryngeal nerve caused by traction
to the neck during delivery. Where vocal cord palsy is bilat- MANAGEMENT
eral, neurologic causes should be sought. Other causes include
surgical complications during ductal ligation or repair of Nasal causes of obstruction can be relieved by an appropri-
tracheoesophageal fistula. In the neonate the epiglottis and ately sized oropharyngeal airway. Choanal atresia requires
the aryepiglottic folds can collapse upon the airway in laryn- surgical intervention to correct the occlusion. For cases with
gomalacia. In these cases, structural causes should also be pharyngeal obstruction, some may respond to prone posi-
sought because an associated airway lesion is seen in 18.9% tioning. In the prone position, the base of the tongue can
fall forwards and relieve obstruction of the pharyngeal airway. features of aspiration; however, the diagnostic utilities are
Oropharyngeal or nasopharyngeal airways may be helpful, not high enough for these methods to diagnose aspiration
but ET intubation or tracheostomy may be required in more as a standalone test.290,291 The extent of reflux can be assessed
severe cases. using contrast and fluoroscopy in an upper gastrointestinal
In the absence of associated structural obstructive lesions, study, through pH or impedance monitoring, or through
many of the common causes of laryngeal obstruction may visualization of edema and irritation at the vocal cords. Even
resolve with expectant management. For example, laryngo- when GER is documented, there are still questions about the
malacia usually resolves by the age of 18–24 months,281 benefits of treatment.
whereas unilateral vocal cord palsy may resolve within weeks
after resolution of the underlying cause.286 If there are no MANAGEMENT
signs of severe disease, conservative management is recom-
mended. For those with substantial risk of life-threatening Up to 25% of extremely preterm infant are discharged home
airway obstruction (e.g., bilateral vocal cord palsy), the infant on medications for GER, usually due to a belief that it helps
may require ET intubation or tracheostomy. For infants with with apnea.287,292 According to recent surveys, more than
subglottic stenosis secondary to ET intubation, preextubation 70% of these infants were started on medications for GER
corticosteroids may be useful. Surgical intervention may be and apnea without any investigations.287 Most neonatologists
indicated in cases with severe disease (e.g., failure to thrive) stop the medications when the infants are apnea free and
and respiratory compromise. greater than 36 weeks GA. Gastric acid suppressors, H2
blockers and proton pump inhibitors, are more commonly
used than motility promoting agents (erythromycin, cisapride,
PREVENTION
metoclopramide). Randomized trials of proton pump inhibi-
The occurrence of acquired subglottic stenosis is associated tors have not shown a benefit for GER and apnea but have
with ET intubation. Minimizing the use of intubation and shown increased adverse events. There is an association of
invasive ventilation by increasing the use of noninvasive acid-blocking agents with increased risk of NEC and sepsis,
ventilation may help to prevent subglottic stenosis. There especially with gram-negative bacteria.293 Routine use of
are no effective means to prevent the other causes of upper medications to treat GER should be avoided in preterm infants.
airway obstruction. Promotility agents have had limited success in treating GER
in preterm and term infants.294 Erythromycin has had the
most success; however, the risk of hypertrophic pyloric ste-
PROGNOSIS
nosis should be balanced against the potential benefits, espe-
Mortality of upper airway obstruction can be high if complete cially during the first 2 weeks of life.295 Thickening agents
or critical airway obstruction is present. However, this is have not been shown to decrease symptoms of GER, and
relatively uncommon. The more common forms of obstruc- one was removed from the market because of an increased
tion, such as laryngomalacia and unilateral vocal cord palsy, risk of NEC. Continuous feeds or transpyloric feedings have
are often mild and resolve without specific intervention. also not been shown to decrease apnea or GER.294 Nissen
fundoplication may be necessary in some infants with severe
GER, as documented by upper gastrointestinal (GI) tract
Gastroesophageal Reflux contrast studies, and signs of aspiration pneumonia.
GER is common in preterm infants, but its correlation with References

respiratory issues and apnea are small. Reflux of fluid up Access the reference list online at ExpertConsult.com.
the esophagus will cause a reflexive closure of the vocal cords
to protect the airway and may cause obstructive apnea until Suggested Reading
the infant is able to swallow the fluid. Inability to successfully Abman SH, Hansmann G, Archer SL, et al. Pediatric pulmonary hyperten-
close the larynx during GER can lead to recurrent aspiration sion: guidelines from the American Heart Association and American
pneumonia (discussed earlier in the chapter). Apnea may Thoracic Society. Circulation. 2015;132(21):2037–2099.
also trigger GER because the lower esophageal sphincter Bancalari EH, Jobe AH. The respiratory course of extremely preterm infants:
pressure decreases when hypoxia occurs.287 Using a combi- a dilemma for diagnosis and terminology. J Pediatr. 2012;161(4):585–588.
Laudy JA, Wladimiroff JW. The fetal lung. 2: pulmonary hypoplasia. Ultra-
nation of esophageal impedance probes, pH probes, and sound Obstet Gynecol. 2000;16(5):482–494.
respiratory monitors, it was demonstrated that approximately Lindenskov PH, Castellheim A, Saugstad OD, et al. Meconium aspiration
3% of respiratory events/apneas followed a GER, whereas syndrome: possible pathophysiological mechanisms and future potential
GER occurred in 9% of infants after an apnea event.288 The therapies. Neonatology. 2015;107(3):225–230.
Oei JL, Vento M, Rabi Y, et al. Higher or lower oxygen for delivery room
GER events are associated with the clinical symptoms of resuscitation of preterm infants below 28 completed weeks gestation: a
apnea/bradycardia approximately 10% of time in term and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2017;102(1):F24–F30.
preterm infants.289 Aspiration of gastric secretions should Perlman JM, Wyllie J, Kattwinkel J, et al. Part 7: neonatal resuscitation:
be suspected in neonates with recurrent respiratory problems, 2015 International Consensus on Cardiopulmonary Resuscitation and
especially if there is right upper lobe collapse or consolida- Emergency Cardiovascular Care Science With Treatment Recommenda-
tions. Circulation. 2015;132(16 suppl 1):S204–S241.
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macrophages or pepsin have been shown in the tracheo- respiratory support in preterm infants at birth: systematic review and
bronchial secretions of infants who are fed and have clinical meta-analysis. BMJ. 2013;347:f5980.
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19 Respiratory Disorders in

Infant stays with mother for routine

Warm and maintain normal temperature,

position airway, clear secretions if

Apnea or gasping? No Labored breathing or

PPV Position and clear airway

Check chest movement

Intubate if not already done 4 min 75%–80%

occurs in many preterm infants at birth and is defined by PATHOPHYSIOLOGY

Chapter 20. Some of these infants require tracheostomy and

Although the exact numbers are unclear, TTN occurs in less

Five percent of babies born through MSAF will develop meco-

may provide additional information on the organism. If herpes

CHANGES IN THE CIRCULATION AT BIRTH

BPD have increased risk of pulmonary hypertension (25%–

renal agenesis, prolonged rupture of the membranes); (4)

view of the considerable risk of respiratory exacerbations,

indeterminate.269 Important differential diagnoses that may

and an associated cardiac lesion is present in as many as

GER is common in preterm infants, but its correlation with References

Resuscitation and Emergency Cardiovascular Care. Pediatrics.

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