RESPIRATORY DISTRESS SYNDROME (HYALINE MEMBRANE DISEASE)

RDS occurs aIter the onset oI breathing and is associated with an insuIIiciency oI pulmonary surIactant.
Lung Development
The lining oI the alveolus consists oI 90 type I cells and 10 type II cells. AIter 20 weeks oI gestation, the
type II cells contain vacuolated, osmophilic, lamellar inclusion bodies, which are packages oI surIace-active
material (Fig. 61-1). This lipoprotein surIactant is 90 lipid and is composed predominantly oI saturated
phosphatidylcholine (lecithin), but also contains phos-phatidylglycerol, other phospholipids, and neutral lipids.
The surIactant proteins SP-A, SP-B, SP-C, and SP-D are packaged into the lamellar body and contribute to
surIace-active properties and recycling oI surIactant. SurIactant prevents atelectasis by reducing surIace tension
at low lung volumes when it is concentrated at end expiration as the alveolar radius decreases; surIactant
contributes to lung recoil by increasing surIace tension at larger lung volumes when it is diluted during
inspiration as the alveolar radius increases. Without surIactant, surIace tension Iorces are not reduced, and
atelectasis develops during end expiration as the alveolus collapses.
The timing oI surIactant (lecithin) production in quantities suIIicient to prevent atelectasis depends on an
increase in Ietal cortisol levels that begins between 32 and 34 weeks oI gestation. By 34 to 36 weeks, suIIicient
surIace-active material is produced by the type II cells in the lung, is secreted into the alveolar lumen, and is
excreted into the amniotic Iluid. The concentration oI lecithin in amniotic Iluid indicates Ietal pulmonary
maturity. Because the amount oI lecithin is diIIicult to quantiIy, the ratio oI lecithin (which increases with
maturity) to sphingomyelin (which remains constant during gestation) (L/S ratio) is determined. L/S ratio oI 2:1
usually indicates pulmonary maturity. The presence oI minor phospho-lipids, such as phosphatidylglycerol, also
is indicative oI Ietal lung maturity and may be useIul in situations in which the L/S ratio is borderline or possibly
aIIected by maternal diabetes, which reduces lung maturity. The absence oI phosphatidylglycerol suggests that
surIactant might not be mature.
Clinical ManiIestations
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Figure 61-1 Proposed pathway of synthesis, transport, secretion, and reuptake of surfactant in the type II
alveolar cell. Phospholipids are synthesized in the smooth endoplasmic reticulum (ER). The glucose/glycerol
precursor may be derived Irom lung glycogen or circulating glucose. Phospholipids and surIactant proteins are
packaged in the Golgi apparatus (GZ), emerge as small lamellar bodies (SLB), coalesce to mature lamellar
bodies (MLB), migrate to the apical membrane, and are released by exocytosis into the liquid hypophase below
the air-liquid interIace. The tightly coiled lamellar body unravels to Iorm the lattice (tubular) myelin Iigure
(LMF), the immediate precursor to the phospholipid monolayer at the alveolar surIace. Reuptake by endocytosis
Iorms multivesicular bodies (MVB) that recycle surIactant. The enzymes, receptors, transporters, and surIactant
proteins are controlled by regulatory processes at the transcriptional level in the nucleus (N). Corticosteroid and
thyroid hormones are regulatory ligands that may accelerate surIactant synthesis. (From Hansen T, Corbet A:
Lung development and Iunction. In Taeusch HW, Ballard R, Avery ME |eds|: Diseases oI the Newborn, 6th ed.
Philadelphia, WB Saunders, 1991, p 465.)
A deIiciency oI pulmonary surIactant results in atelectasis, decreased Iunctional residual capacity, arterial
hypoxemia, and respiratory distress. SurIactant synthesis may be reduced as a result oI hypovolemia,
hypothermia, acidosis, hypoxemia, and rare genetic disorders oI surIactant synthesis. These Iactors also produce
pulmonary artery vasospasm, which may contribute to RDS in larger premature inIants who have developed
suIIicient pulmonary arteriole smooth muscle to produce vasoconstriction. SurIactant deIiciency-induced
atelectasis causes alveoli to be perIused but not ventilated, which results in a pulmonary shunt and hypoxemia.
As atelectasis increases, the lungs become increasingly diIIicult to expand, and lung compliance decreases.
Because the chest wall oI the premature inIant is very compliant, the inIant attempts to overcome decreased lung
compliance with increasing inspiratory pressures, resulting in retractions oI the chest wall. The sequence oI
decreased lung compliance and chest wall retractions leads to poor air exchange, an increased physiologic dead
space, alveolar hypoventilation, and hypercapnia. A cycle oI hypoxia, hyper-capnia, and acidosis acts on type II
cells to reduce surIactant synthesis and, in some inIants, on the pulmonary arterioles to produce pulmonary
hypertension.
InIants at greatest risk Ior RDS are premature and have an immature L/S ratio. The incidence oI RDS increases
with decreasing gestational age. RDS develops in 30 to 60 oI inIants between 28 and 32 weeks oI gestation.
Other risk Iactors include delivery oI a previous preterm inIant with RDS, maternal diabetes, hypothermia, Ietal
distress, asphyxia, male sex, white race, being the second born oI twins, and delivery by cesarean section without
labor.
RDS may develop immediately in the delivery room in extremely immature inIants at 26 to 30 weeks oI
gestation. Some more mature inIants (34 weeks' gestation) may not show signs oI RDS until 3 to 4 hours aIter
birth, correlating with the initial release oI stored surIactant at the onset oI breathing accompanied by the
ongoing inability to replace the surIactant owing to inadequate stores. Manifestations oI RDS include cyanosis,
tachypnea, nasal Ilaring, intercostal and sternal retractions, and grunting. runting is caused by closure oI the
glottis during expiration, the eIIect oI which is to maintain lung volume (decreasing atelectasis) and gas
exchange during exhalation. Atelectasis is well documented by radiographic examination oI the chest, which
shows a ground-glass haze in the lung surrounding air-Iilled bronchi (the air bronchogram) (Fig. 61-2). Severe
RDS may show an airless lung Iield or a "whiteout" on a radiograph, even obliterating the distinction between
the atelectatic lungs and the heart.
During the Iirst 72 hours, inIants with RDS have increasing distress and hypoxemia. In inIants with severe RDS,
the development oI edema, apnea, and respiratory Iailure necessitates assisted ventilation. ThereaIter,
uncomplicated cases show a spontaneous improvement that oIten is heralded by diuresis and a marked resolution
oI edema. Complications include the development oI a pneumothorax, a PDA, and bronchopulmonary dysplasia
(BPD). The diIIerential diagnosis oI RDS includes diseases associated with cyanosis and respiratory distress (see
Table 58-13).
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Figure 61-2 Respiratory distress syndrome. The inIant is intubated, and the lungs show a dense reticulonodular
pattern with air bronchograms (A). To evaluate rotation on the Irontal chest, the lengths oI the posterior ribs are
compared Irom leIt to right arrows). Because the inIant is supine, the side oI the longer ribs indicates to which
side the thorax is rotated. In this case, the leIt ribs are longer, and this radiograph is a leIt posterior oblique view.
SurIactant was administered, resulting in signiIicant improvement in the density oI the lung (B). The right lung is
slightly better aerated than the leIt. Uneven distribution oI clearing is common. (From Hilton S, Edwards D:
Practical Pediatric Radiology, 2nd ed. Philadelphia, WB Saunders, 1994.)
Prevention and Treatment
Strategies to prevent preterm birth include maternal cervical cerclage, bed rest, treatment oI inIections, and
administration oI tocolytic medications. Additionally, prevention oI neonatal cold stress, birth asphyxia, and
hypovolemia reduces the risk oI RDS. II premature delivery is unavoidable, the antenatal administration oI
corticosteroids (e.g., betamethasone) to the mother (and thus to the Ietus) stimulates Ietal lung production oI
surIactant; this approach requires multiple doses Ior at least 48 hours.
AIter birth, RDS may be prevented or its severity reduced by intratracheal administration oI exogenous
surIactant immediately aIter birth in the delivery room or within a Iew hours oI birth. A mammalian-derived
surIactant is currently preIerred. Exogenous surIactant can be administered repeatedly during the course oI RDS
in patients receiving endotracheal intubation, mechanical ventilation, and oxygen therapy. Additional
management includes the general supportive and ventilation care presented in Tables 58-14, 61-2, and 61-3.
The PaO
2
level should be maintained between 60 and 70 mm Hg (oxygen saturation 90), and the pH should be
maintained greater than 7.25. An increased concentration oI warm and humidiIied inspired oxygen administered
by an oxygen hood or nasal cannula may be all that is needed Ior larger premature inIants. II hypoxemia (PaO
2

50 mm Hg) is present, and the needed inspired oxygen concentration is 70 to 100, nasal continuous positive
airway pressure should be added at a distending pressure oI 8 to 10 cm H
2
O. II respiratory Iailure ensues (PCO
2

~60 mm Hg, pH 7.20, and PaO
2
50 mm Hg with 100 oxygen), assisted ventilation using a respirator is
indicated. Conventional rate (25 to 60 breaths/min), high-Irequency jet (150 to 600 breaths/min), and oscillator
(900 to 3000 breaths/min) ventilators all have been successIul in managing respiratory Iailure caused by severe
RDS. Suggested starting settings on a conventional ventilator are Iraction oI inspired oxygen, 60 to 100;
peak inspiratory pressure, 20 to 25 cm H
2
O; positive end-expiratory pressure, 5 cm H
2
O; and respiratory rate,
30 to 50 breaths/min.
In response to persistent hypercapnia, alveolar ventilation (tidal volume-dead space rate) must be increased.
Ventilation can be increased by an increase in the ventilator's rate or an increase in the tidal volume, which is the
gradient between peak inspiratory pressure and positive end-expiratory pressure. In response to hypoxia, the
inspired oxygen content may be increased. Alternatively, the degree oI oxygenation depends on the mean airway
pressure. Mean airway pressure is directly related to peak inspiratory pressure, positive end-expiratory pressure,
Ilow, and inspiratory-to-expiratory ratio. Increased mean airway pressure may improve oxygenation by
improving lung volume, enhancing ventilation-perIusion matching. Because oI the diIIiculty in distinguishing
sepsis and pneumonia Irom RDS, broad-spectrum parenteral antibiotics (ampicillin and gentamicin) are
administered Ior 48 to 72 hours, pending the recovery oI an organism Irom a previously obtained blood culture.
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Table 61-3. Ventilator Management oI Respiratory Distress Syndrome
$etting Result Rationale Risks
FIO
2
PO
2
Alveolar O
2
Oxygen toxicity
PIP PO
2
Paw Pneumothorax, barotrauma, cardiac output?
PCO
2
Tidal volume
PEEP PO
2
Paw PCO
2
by tidal volume
Cardiac output?
Rate PCO
2
Alveolar ventilation Expiratory time causes gas trapping
I : E ratio PO
2
Paw Expiratory time causes gas trapping

FIO
2
, Iraction oI inspired oxygen; I : E, inspiratory-to-expiratory time ratio; Paw, mean airway
pressure; PEEP, positive end-expiratory pressure; PIP, peak inspiratory pressure.

61 Respiratory Diseases oI the Newborn

Respiratory distress that becomes maniIested by tachypnea, intercostal retractions, reduced air exchange,
cyanosis, expiratory grunting, and nasal Ilaring is a nonspeciIic response to serious illness. Not all oI the
disorders producing neonatal respiratory distress are primary diseases oI the lungs. The diIIerential diagnosis oI
respiratory distress includes pulmonary, cardiac, hematologic, inIectious, anatomic, and metabolic disorders that
may involve the lungs directly or indirectly. SurIactant deIiciency causes RD$, resulting in cyanosis and
tachypnea; infection produces pneumonia, shown by interstitial or lobar inIiltrates; meconium aspiration results
in a chemical pneumonitis with hypoxia and pulmonary hypertension; hydrops fetalis causes anemia and
hypoalbuminemia with high-output heart Iailure and pulmonary edema; and congenital or acquired pulmonary
hypoplasia causes pulmonary hypertension and pulmonary insuIIiciency. It also is clinically useIul to
diIIerentiate the common causes oI respiratory distress according to gestational age (Table 61-1).
In addition to the speciIic therapy Ior the individual disorder, the supportive care and evaluation oI the inIant
with respiratory distress can be applied to all the problems mentioned earlier (Table 61-2; see also Table 58-14).
Blood gas monitoring and interpretation are key components oI general respiratory care.
Table 61-1. Etiology oI Respiratory Distress
Preterm Infant
Respiratory distress syndrome (RDS)*
Erythroblastosis Ietalis
Nonimmune hydrops
Pulmonary hemorrhage
Full-Term Infant
Primary pulmonary hypertension oI the neonate*
Meconium aspiration pneumonia*
Polycythemia
Amniotic Iluid aspiration
Preterm and Full-Term Infant
Bacterial sepsis (GBS)*
Transient tachypnea*
Spontaneous pneumothorax
Congenital anomalies (e.g., congenital lobar emphysema, cystic adenomatoid malIormation, diphragmatic
hernia)
Congenital heart disease
Pulmonary hypoplasia
Viral inIection (e.g., herpes simplex, CMV)
Inborn metabolic errors

*Common.
CMV, cytomegalovirus; GBS, group B streptococcus.
Treatment oI hypoxemia requires knowledge oI normal values. In term inIants, the arterial PaO
2
level is 55 to 60
mm Hg at 30 minutes oI liIe, 75 mm Hg at 4 hours, and 90 mm Hg at 24 hours. Preterm inIants have slightly
lower values. PaCO
2
levels should be 35 to 40 mm Hg, and the pH should be 7.35 to 7.40. It is imperative that
arterial blood gas analysis be perIormed in all inIants with signiIicant respiratory distress, whether or not
cyanosis is perceived. Cyanosis becomes evident when there is 5 g oI unsaturated hemoglobin; anemia may
interIere with the perception oI cyanosis. Jaundice also may interIere with the appearance oI cyanosis. Capillary
blood gas determinations are useIul in determining blood pH and the PaCO
2
level. Because oI the nature oI the
heel-stick capillary blood gas technique, venous blood may mix with arterial blood, resulting in Ialsely low
blood PaO
2
readings. Serial blood gas levels may be monitored by an indwelling arterial catheter placed in a
peripheral artery or through the umbilical artery to the aorta at the level oI the T6-10 or the L4-5 vertebrae. This
placement avoids catheter occlusion oI the celiac (T12), superior mesenteric (T12-L1), renal (L1-2), and inIerior
mesenteric (L2-3) arteries. Another method Ior monitoring blood gas levels is to combine capillary blood gas
techniques with noninvasive methods used to monitor oxygen (pulse oximetry or transcutaneous oxygen
diIIusion).
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Table 61-2. Initial Laboratory Evaluation oI Respiratory Distress
Test Rationale
Chest radiograph To determine reticular granular pattern oI RDS; to determine presence oI pneumothorax,
cardiomegaly, liIe-threatening congenital anomalies
Arterial blood gas To determine severity oI respiratory compromise, hypoxemia, and hypercapnia and type oI
acidosis; the severity determines treatment strategy
Complete blood
count
Hemoglobin/hematocrit to determine anemia and polycythemia; white blood cell count to
determine neutropenia/sepsis; platelet count and smear to determine DIC
Blood culture To recover potential pathogen
Blood glucose To determine presence oI hypoglycemia, which may produce or occur simultaneously with
respiratory distress; to determine stress hyperglycemia
Echocardiogram,
ECG
In the presence oI a murmur, cardiomegaly, or reIractory hypoxia; to determine structural
heart disease or PPHN

DIC, disseminated intravascular coagulation; PPHN, primary pulmonary hypertension oI the
newborn; RDS, respiratory distress syndrome.
Metabolic acidosis, deIined as a reduced pH (7.25) and bicarbonate concentration (18 mEq/L) accompanied
by a normal or low PCO
2
level, may be caused by hypoxia or by insuIIicient tissue perIusion; the origin oI the
disorder may be pulmonary, cardiac, inIectious, renal, hematologic, nutritional, metabolic, or iatro-genic. The
initial approach to metabolic acidosis is to determine the cause and treat the pathophysiologic problem. This
approach may include, as in the sequence oI therapy Ior hypoxia, increasing the inspired oxygen concentration;
applying continuous positive airway pressure nasally, using oxygen as the gas; or initiating mechanical
ventilation using positive end-expiratory pressure and oxygen. Patients with hypotension produced by
hypovolemia require Iluids and may need inotropic or vasoactive drug support. II metabolic acidosis persists
despite speciIic therapy, sodium bicarbonate (1 mEq/kg/dose) may be given by slow IV inIusion. Near-normal or
low PCO
2
levels should be documented beIore sodium bicarbonate inIusion. The buIIering eIIect oI sodium
bicarbonate results in increased PCO
2
levels, unless adequate ventilation is maintained.
Respiratory acidosis, deIined as an elevated PCO
2
level and reduced pH without a reduction in the bicarbonate
concentration, may be caused by pulmonary insuIIiciency or central hypoventilation. Most disorders producing
respiratory distress can lead to hyper-capnia. Treatment involves assisted ventilation but not sodium bicarbonate.
II CNS depression oI respirations is caused by placental passage oI narcotic analgesics, assisted ventilation is
instituted Iirst, then the CNS depression is reversed by naloxone.

COMPLICATIONS OF RESPIRATORY DISTRESS SYNDROME

Complications oI RDS include clinical conditions associated with prematurity in general and conditions that
arise as complications oI therapy.
Patent Ductus Arteriosus
PDA is a common complication that occurs in many LBW inIants who have RDS. The incidence oI PDA is
inversely related to the maturity oI the inIant. In term newborns, the ductus closes within 24 to 48 hours aIter
birth. In preterm newborns, the ductus Irequently Iails to close, however, requiring medical or surgical closure.
The ductus arteriosus in a preterm inIant is less responsive to vasoconstrictive stimuli, which when complicated
with hypoxemia during RDS, may lead to a persistent PDA that creates a shunt between the pulmonary and
systemic circulations.
During the acute phase oI RDS, hypoxia, hypercapnia, and acidosis lead to pulmonary arterial vasoconstriction
and increased pressure. The pulmonary and systemic pressures may be equal, and Ilow through the ductus may
be small or bidirectional. When RDS improves and pulmonary vascular resistance declines, Ilow through the
ductus arteriosus increases in a leIt-to-right direction. SigniIicant systemic-to-pulmonary shunting may lead to
heart Iailure and pulmonary edema. Excessive IV Iluid administration may increase the incidence oI
symptomatic PDA. The inIant's respiratory status deteriorates because oI increased lung Iluid, hypercapnia, and
hypoxemia. In response to poor blood gas levels, the inIant is subjected to higher inspired oxygen concentrations
and higher peak inspiratory ventilator pressures, both oI which can damage the lung and cause chronic lung
disease.
linical manifestations oI a PDA usually become apparent on day 2 to 4 oI liIe. Because the leIt-to-right shunt
directs Ilow to a low-pressure circulation Irom one oI high pressure, the pulse pressure widens; a previously
inactive precordium now shows an extremely active precordial impulse, and the peripheral pulses become easily
palpable and bounding. The murmur oI a PDA may be continuous in systole and diastole, but usually only the
systolic component is auscultated. Heart Iailure and pulmonary edema result in rales and hepatomegaly. A chest
radiograph shows cardiomegaly and pulmonary edema; a two-dimensional echocardio-gram shows patency,
whereas Doppler studies show markedly increased leIt-to-right Ilow through the ductus.
Treatment oI a PDA during RDS involves an initial period oI Iluid restriction and diuretic administration. II
there is no improvement aIter 24 to 48 hours, indomethacin, a prostaglandin synthetase inhibitor, is administered
(0.2 mg/kg) intravenously every 12 to 24 hours Ior three doses. Contraindications to using indomethacin include
thrombocytopenia (platelets 50,000/mm
3
), bleeding, serum creatinine measuring more than 1.8 mg/dL, and
oliguria. Because 20 to 30 oI inIants do not respond initially to indomethacin and because the PDA reopens
in 10 to 20 oI inIants who do, a repeat course oI indomethacin or surgical ligation is required in some
patients.
Pulmonary Air Leaks
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Assisted ventilation with high peak inspiratory pressures and positive end-expiratory pressures may cause
overdistention oI alveoli in localized areas oI the lung. Rupture oI the alveolar epithelial lining may produce
pulmonary interstitial emphysema as gas dissects along the interstitial space and the peribronchial lymphatics.
Extravasation oI gas into the parenchyma reduces lung compliance and worsens respiratory Iailure. Gas
dissection into the mediastinal space produces a pneumomediastinum, occasionally with gas dissecting into the
subcutaneous tissues around the neck, causing subcutaneous emphysema.
Alveolar rupture adjacent to the pleural space produces a pneumothorax. II the gas is under tension, the
pneumothorax shiIts the mediastinum to the opposite side oI the chest, producing hypotension, hypoxia, and
hypercapnia. The diagnosis oI a pneu-mothorax may be based on unequal transillumination oI the chest and may
be conIirmed by chest radiograph (Fig. 61-3). Treatment oI a symptomatic pneu-mothorax requires insertion oI a
pleural chest tube connected to negative pressure or to an underwater drain. Prophylactic or therapeutic use oI
exogenous surIactant has reduced the incidence oI pulmonary air leaks.
Pneumothorax also is observed aIter vigorous resuscitation, meconium aspiration pneumonia, pulmonary
hypoplasia, and diaphragmatic hernia. Spontaneous pneumothorax is seen in less than 1 oI deliveries and may
be associated with renal malIormations.
Bronchopulmonary Dysplasia (Chronic Lung Disease)
BPD is a clinical diagnosis deIined by oxygen dependence at 36 weeks' postconceptual age and accompanied by
characteristic clinical and radiographic Iindings that correspond to anatomic abnormalities. Oxygen
concentrations greater than 40 are toxic to the neonatal lung. Oxygen-mediated lung injury results Irom the
generation oI superoxides, hydrogen peroxide, and oxygen Iree radicals, which disrupt membrane lipids.
Assisted ventilation with high peak pressures produces barotrauma, compounding the damaging eIIects oI highly
inspired oxygen levels. In most patients, BPD develops aIter ventilation Ior RDS that may have been
complicated by PDA or pulmonary interstitial emphysema. InIlammation Irom prolonged assisted ventilation
and repeated systemic and pulmonary inIections may play a major role. Failure oI RDS to improve aIter 2
weeks, the need Ior prolonged mechanical ventilation, and oxygen therapy required at 36 weeks' postconception
age are characteristic oI patients with RDS in whom BPD develops. BPD also may develop in inIants weighing
less than 1000 g who require mechanical ventilation Ior poor respiratory drive in the absence oI RDS. FiIty
percent oI inIants oI 24 to 26 weeks' gestational age require oxygen at 36 weeks' corrected age.
The radiographic appearance oI BPD may involve phases that are characterized initially by lung opaciIication
and subsequently by development oI cysts accompanied by areas oI overdistention and atelectasis, giving the
lung a spongelike appearance. The histopathology oI BPD reveals interstitial edema, atelectasis, mucosal
metaplasia, interstitial Iibrosis, necrotizing obliterative bronchiolitis, and overdistended alveoli.
The clinical manifestations oI BPD are oxygen dependence, hypercapnia, compensatory metabolic alkalosis,
pulmonary hypertension, poor growth, and development oI right-sided heart Iailure. Increased airway resistance
with reactive airway bronchoconstriction also is noted and is treated with bronchodilating agents. Severe chest
retractions produce negative interstitial pressure that draws Iluid into the interstitial space. Together with cor
pulmonale, these chest retractions cause Iluid retention, necessitating Iluid restriction and the administration oI
diuretics.
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Patients with severe BPD may need treatment with mechanical ventilation Ior many months. To reduce the risk
oI subglottic stenosis, a tracheotomy may be indicated. To reduce oxygen toxicity and barotrauma, ventilator
settings are reduced to maintain blood gases with slightly lower PaO
2
(50 mm Hg) and higher PaCO
2
(50 to 75
mm Hg) levels than Ior inIants during the acute phase oI RDS. Dexamethasone therapy may reduce
inIlammation, improve pulmonary Iunction, and enhance weaning oI patients Irom assisted ventilation.
Dexamethasone may increase the risk, however, oI cerebral palsy or abnormal neuromotor developmental
outcome. Older survivors oI BPD have hyperinIlation, reactive airways, and developmental delay. They are at
risk Ior severe respiratory syncytial virus pneumonia and as inIants should receive prophylaxis against
respiratory syncytial virus.
Retinopathy oI Prematurity (Retrolental Fibroplasia)
Retinopathy oI prematurity (ROP) is caused by the acute and chronic eIIects oI oxygen toxicity on the
developing blood vessels oI the premature inIant's retina. The completely vascularized retina oI the term inIant is
not susceptible to ROP. ROP is a leading cause oI blindness Ior VLBW inIants (1500 g). Excessive arterial
oxygen tensions produce vasoconstriction oI the immature retinal vasculature in the Iirst stage oI this disease.
The vasoconstriction is Iollowed by vaso-obliteration iI the duration and extent oI hyper-oxia are prolonged
beyond the time when vasoconstriction is reversible. Hypercarbia and hypoxia may contribute to ROP. The
subsequent proliIerative stages are characterized by extraretinal Iibrovascular proliIeration, Iorming a ridge
between the vascular and avascular portions oI the retina, and by the development oI neovascular tuIts. In mild
cases, vasopro-liIeration is noted at the periphery oI the retina. Severe cases may have neovascularization
involving the entire retina, retinal detachment resulting Irom traction on vessels as they leave the optic disc,
Iibrous proliIeration behind the lens producing leukokoria, and synechiae displacing the lens Iorward and leading
to glaucoma. Both eyes usually are involved, but severity may be asymmetric.
The incidence oI ROP may be reduced by careIul monitoring oI arterial blood gas levels in all patients receiving
oxygen. Although there is no absolutely saIe PaO
2
level, it is wise to keep the arterial oxygen level between 50
and 70 mm Hg in premature inIants. InIants who weigh less than 1500 g or who are born beIore 28 weeks'
gestational age (some authors say 32 weeks) should be screened when they are 4 weeks old or more than 34
weeks' corrected gestational age, whichever comes Iirst. Laser therapy or (less oIten) cryotherapy may be used
Ior vitreous hemorrhage or Ior severe, progressive vasoproliIeration. Surgery is indicated Ior retinal detachment.
Less severe stages oI ROP resolve spontaneously and without visual impairment in most patients.
Transient Tachypnea oI the Newborn
Transient tachypnea oI the newborn is a selI-limited condition characterized by tachypnea, mild retractions,
hypoxia, and occasional grunting, usually without signs oI severe respiratory distress. Cyanosis, when present,
usually requires treatment with supplemental oxygen in the range oI 30 to 40. Transient tachypnea oI the
newborn usually is noted in larger premature inIants and in term inIants born by precipitious delivery or cesarean
section without prior labor. InIants oI diabetic mothers and inIants with poor respiratory drive as a result oI
placental passage oI analgesic drugs are at risk. Chest radiographs show prominent central vascular markings,
Iluid in the lung Iissures, overaeration, and occasionally a small pleural eIIusion. Air bronchograms and a
reticulogranular pattern are not seen in transient tachypnea oI the newborn, and their presence suggests another
pulmonary process, such as RDS or pneumonia. Transient tachypnea oI the newborn may be caused by retained
lung Iluid or slow resorption oI lung Iluid.
Meconium Aspiration Syndrome
Meconium-stained amniotic Iluid is seen in 15 oI predominantly term and post-term deliveries. Although the
passage oI meconium into amniotic Iluid is common in inIants born in the breech presentation, meconium-
stained Iluid should be considered clinically as a sign oI Ietal distress Ior all inIants. The presence oI meconium
in the amniotic Iluid suggests in utero distress with asphyxia, hypoxia, and acidosis.
Aspiration oI amniotic Iluid contaminated with particulate meconium may occur in utero in a distressed, gasping
Ietus; more oIten, meconium is aspirated into the lung immediately aIter delivery. AIIected inIants have
abnormal chest radiographs, showing a high incidence oI pneumonia and pneumothoraces.
Meconium aspiration pneumonia is characterized by tachypnea, hypoxia, hypercapnia, and small airway
obstruction causing a ball-valve eIIect, leading to air trapping, overdistention, and extra-alveolar air leaks.
Complete small airway obstruction produces atelectasis. Within 24 to 48 hours, a chemical pneumonia develops
in addition to the mechanical eIIects oI airway obstruction. Abnormal pulmonary Iunction may be caused by the
meconium in part through inactivation oI surIactant. PPHN Irequesntly accompanies meconium aspiration with
right-to-leIt shunting caused by increased pulmonary vascular resistance. The chest radiograph reveals patchy
inIiltrates, overdistention, Ilattening oI the diaphragm, increased anteroposterior diameter, and a high incidence
oI pneumomedi-astinum and pneumothoraces. Comorbid diseases include those associated with in utero
asphyxia that initiated the passage oI meconium.
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Treatment oI meconium aspiration includes general supportive care and assisted ventilation. InIants with a
PPHN-like presentation should be treated Ior PPHN. II severe hypoxia does not subside with conventional or
high-Irequency ventilation, surIactant therapy, and inhaled nitric oxide, extracorporeal membrane oxygenation
(ECMO) may be beneIicial.
Prevention oI meconium aspiration syndrome involves careIul in utero monitoring to prevent asphyxia. When
meconium-stained Iluid is observed, the obstetrician should suction the inIant's oropharynx beIore delivering the
rest oI the inIant's body. II the inIant is depressed with poor tone, minimal respiratory eIIort, and cyanosis, the
inIant's oropharynx should be suctioned, the vocal cords visualized, and the area below the vocal cords suctioned
to remove any meconium Irom the trachea. This procedure can be repeated two to three times as long as
meconium is present, beIore either stimulating the inIant to breathe or initiating assisted ventilation. Saline
intrauterine amnio-inIusion during labor may reduce the incidence oI aspiration and pneumonia.
Primary Pulmonary Hypertension oI the Newborn (Persistent Fetal Circulation)
PPHN occurs in post-term, term, or near-term inIants. PPHN is characterized by severe hypoxemia, without
evidence oI parenchymal lung or structural heart disease that also may cause right-to-leIt shunting. PPHN is
oIten seen with asphyxia or meconium-stained Iluid. The chest radiograph usually reveals normal lung Iields
rather than the expected inIiltrates and hyper-inIlation that may accompany meconium aspiration. Additional
problems that may lead to PPHN are congenital pneumonia, hyperviscosity-polycythemia, congenital
diaphragmatic hernia, pulmonary hypoplasia, congenital cyanotic heart disease, hypoglycemia, and hypothermia.
Total anomalous venous return associated with obstruction oI blood Ilow may produce a clinical picture that
involves severe hypoxia and that is indistinguishable Irom PPHN; however, a chest radiograph reveals severe
pulmonary venous engorgement and a small heart. Echocardiography or cardiac catheterization conIirms the
diagnosis.
SigniIicant right-to-leIt shunting through a patent Ioramen ovale, through a PDA, and through intrapul-monary
channels is characteristic oI PPHN. The pulmonary vasculature oIten shows hypertrophied arterial wall smooth
muscle, suggesting that the process oI or predisposition to PPHN began in utero as a result oI previous periods oI
Ietal hypoxia. AIter birth, hypoxia, hypercapnia, and acidosis exacerbate pulmonary artery vasoconstriction,
leading to Iurther hypoxia and acidosis. Some inIants with PPHN have extrapulmonary maniIestations as a result
oI asphyxia. Myocardial injuries include heart Iailure, transient mitral insuIIiciency, and papillary muscle or
myocardial inIarction. Thrombocytopenia, right atrial thrombi, and pulmonary embolism also may be noted.
The diagnosis is conIirmed by echocardiographic examination, which shows elevated pulmonary artery
pressures and sites oI right-to-leIt shunting. Echocar-diography also rules out structural congenital heart disease
and transient myocardial dysIunction.
Treatment involves general supportive care; correction oI hypotension, anemia, and acidosis; and management
oI complications associated with asphyxia. II myocardial dysIunction is present, dopamine or dobutamine is
needed. The most important therapy Ior PPHN is assisted ventilation. Reversible mild pulmonary hypertension
may respond to conventional assisted ventilation. Patients with severe PPHN do not always respond to
conventional therapy, however; some clinicians try hyperventilation to reverse pulmonary vasoconstriction by
reducing PCO
2
levels and increasing pH to 7.5 to 7.6. Paralysis with pancuronium may be needed to assist such
vigorous ventilation. SurIactant replacement seems to have no eIIect when PPHN is the primary diagnosis. II
mechanical ventilation and supportive care are unsuccessIul in improving oxygenation, inhaled nitric oxide, a
selective pulmonary artery vasodilating agent, should be administered. II hypoxia persists, the patient may be a
candidate Ior ECMO. InIants who require extremely high ventilator settings, marked by an alveolar-to-arterial
oxygen gradient greater than 620 mm Hg, have a high mortality rate and beneIit Irom ECMO iI they do not
respond to nitric oxide. In addition, the oxygenation index (OI) is used to assess the severity oI hypoxemia and to
guide the timing oI interventions such as inhaled nitric oxide and ECMO. The OI is calculated using the
equation: OI |(mean airway pressure Iraction oI inspired oxygen)/PaO
2
| 100. A high OI indicates severe
hypoxemic respiratory Iailure.
Apnea oI Prematurity
Although apnea typically is associated with immaturity oI the respiratory control system, it also may be the
presenting sign oI other diseases or pathophysiologic states that aIIect preterm inIants (Table 61-4). A thorough
consideration oI possible causes is always warranted, especially with the onset or unexpected increase in the
Irequency oI episodes oI apnea (or bradycardia).
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page 312
Table 61-4. Potential Causes oI Neonatal Apnea
CNS IVH, drugs, seizures, hypoxic injury
Respiratory Pneumonia, obstructive airway lesions, atelectasis, extreme prematurity (1000 g), laryngeal
reIlex, phrenic nerve paralysis, severe RDS, pneumothorax
InIectious Sepsis, necrotizing enterocolitis, meningitis (bacterial, Iungal, viral)
Gastrointestinal Oral Ieeding, bowel movement, gastroesophageal reIlux, esophagitis, intestinal perIoration
Metabolic Glucose, calcium, PO
2
, sodium, ammonia, organic acids, ambient temperature,
hypothermia
Cardiovascular Hypotension, hypertension, heart Iailure, anemia, hypovolemia, change in vagal tone
Idiopathic Immaturity oI respiratory center, sleep state, upper airway collapse

IVH, intraventricular hemorrhage; RDS, respiratory distress syndrome.
Apnea is deIined as the cessation oI pulmonary airIlow Ior a speciIic time interval, usually longer than 10 to 20
seconds. Bradycardia oIten accompanies prolonged apnea. Central apnea reIers to a complete cessation oI
airIlow and respiratory eIIorts with no chest wall movement; in obstructive apnea, no airIlow is exhibited, but
chest wall movements continue. A combination oI these two events, mixed apnea, is the most Irequent type. It
may begin as a brieI episode oI obstruction Iollowed by a central apnea. Alternatively, central apnea may
produce upper airway closure (passive pharyngeal hypotonia), resulting in mixed apnea.
A careIul evaluation to determine the cause oI apnea should be perIormed immediately in any inIant with apnea.
The incidence oI apnea increases as gestational age decreases. Idiopathic apnea, a disease oI premature inIants,
appears in the absence oI any other identiIiable disease states during the Iirst week oI liIe and usually resolves by
36 to 40 weeks oI postconceptional age (gestational age at birth postnatal age). The premature inIant's process
oI regulating respiration is especially vulnerable to apnea. Preterm inIants respond paradoxically to hypoxia by
developing apnea rather than by increasing respirations as do mature inIants. Poor tone oI the laryngeal muscles
also may lead to collapse oI the upper airway, causing obstruction. Isolated obstructive apnea also may occur as
a result oI Ilexion or extreme lateral positioning oI the premature inIant's head, which obstructs the soIt trachea.
Treatment oI apnea oI prematurity involves administration oI oxygen to hypoxic inIants, transIusion oI anemic
inIants, and physical cutaneous stimulation Ior inIants with mild apnea. Methylxanthines (caIIeine or
theophylline) are the mainstay oI pharmacologic treatment oI apnea. Xanthine therapy increases minute
ventilation, improves the carbon dioxide sensitivity, decreases hypoxic depression oI breathing, enhances
diaphragmatic activity, and decreases periodic breathing. Treatment usually is initiated with a loading dose
Iollowed by maintenance therapy. High-Ilow nasal cannula therapy and nasal continuous positive airway
pressure oI 4 to 6 cm H
2
O also are eIIective and relatively saIe methods oI treating obstructive or mixed apneas;
they may work by stimulating the inIant and splinting the upper airway. Continuous positive airway pressure
also probably increases Iunctional residual capacity, improving oxygenation.