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848 Part  XII   The   Fetus  and  the  Neonatal  Infant

Chapter 101

Respiratory Tract Disorders

Waldemar A. Carlo and Namasivayam Ambalavanan

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

Neonate with acute respiratory distress

Yes Abnormal lungs by chest radiograph No Abnormalities in Common Respiratory distress Uncommon Diapragmatic
Yes
Abnormal
lungs by chest
radiograph
No
Abnormalities in
Common
Respiratory distress
Uncommon
Diapragmatic hernia
Tracheoesophageal
fistula
Cysts and tumors
Perfusion
Neuro-
Diaphragm
syndrome
BP
muscular
or chest
Transient
HCT
findings
wall
tachypnea
Pneumonia
aspiration
syndromes
Pneumothorax and
air leaks
Pulmonary edema
Pleural effusion
Pulmonary hemorrhage
Congenital lobar
emphysema
Pulmonary hypoplasia
Accessory or sequestered lobes
Pulmonary
lymphangiectasia
Pulmonary
arteriovenous fistula
Anemia
Asphyxia
Chest wall
Polycythemia
Intracranial
disorders
Hypotension
hemorrhage
Diaphragmatic
Hypovolemia
Neuromuscular
disorders
disorders
Drugs
CVS
Other
Airway
Abdominal
findings
or mixed
findings
findings
or echo
findings
Upper airway
Persistent fetal
Ascites
Sepsis
Laryngeal
circulation
Necrotizing
Acidosis
Lower airway
Cyanotic congenital
enterocolitis
Hypothermia,
heart disease
Abdominal mass
cold stress
Congestive heart
Omphalocele
Hyperthermia
failure
Gastroschisis
Hypoglycemia
Methemoglobinemia

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

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Chapter 101   Respiratory   Tract  Disorders  849

It is occasionally difficult to distinguish respiratory from nonrespira- tory etiologies on the basis of clinical signs alone. Signs of respiratory distress are an indication for a physical examination and diagnostic evaluation, including a blood gas or pulse oximetry determination and chest x-ray. Timely and appropriate therapy is essential to improve outcome.

101.1 Transition  to Pulmonary  Respiration

Waldemar A. Carlo

Successful establishment of adequate lung function at birth depends on airway patency, functional lung development, and maturity of respi- ratory control. Fetal lung fluid must be removed and replaced with gas. This process begins before birth as active sodium transport across the pulmonary epithelium drives liquid from the lung lumen into the interstitium with subsequent absorption into the vasculature. Increased levels of circulating catecholamines, vasopressin, prolactin, and gluco- corticoids enhance lung fluid adsorption and trigger the change in lung epithelia from a chloride-secretory to a sodium-reabsorptive mode. Functional residual capacity (FRC) must be established and main- tained in order to develop a ventilation–perfusion relationship that will provide optimal exchange of oxygen and carbon dioxide between alveoli and blood (see Chapter 421).

THE FIRST BREATH

During vaginal delivery, intermittent compression of the thorax facili- tates removal of lung fluid. Surfactant lining the alveoli enhances the aeration of gas-free lungs by reducing surface tension, thereby lower- ing the pressure required to open alveoli. Although spontaneously breathing infants do not need to generate an opening pressure to create airflow, infants requiring positive-pressure ventilation at birth need an opening pressure of 13-32 cm H 2 O and are more likely to establish FRC if they generate a spontaneous, negative pressure breath. Expira- tory esophageal pressures associated with the first few spontaneous breaths in term newborns range from 45-90 cm H 2 O. This high pres- sure, due to expiration against a partially closed glottis, may aid in the establishment of FRC but would be difficult to mimic safely with use of artificial ventilation. The higher pressures needed to initiate respira- tion are required to overcome the opposing forces of surface tension (particularly in small airways) and the viscosity of liquid remaining in the airways, as well as to introduce about 50 mL/kg of air into the lungs, 20-30 mL/kg of which remains after the first breath to establish FRC. Air entry into the lungs displaces fluid, decreases hydrostatic pressure in the pulmonary vasculature, and increases pulmonary blood flow. The greater blood flow, in turn, increases the blood volume of the lung and the effective vascular surface area available for fluid uptake. The remaining fluid is removed via the pulmonary lymphatics, upper airway, mediastinum, and pleural space. Fluid removal may be impaired after cesarean section or as a result of surfactant deficiency, endothelial cell damage, hypoalbuminemia, high pulmonary venous pressure, or neonatal sedation. Initiation of the first breath is caused by a decline in Pao 2 and pH and a rise in Paco 2 as a result of interruption of the placental circula- tion, a redistribution of cardiac output, a decrease in body temperature, and various tactile and sensory inputs. The relative contributions of these stimuli to the onset of respiration are uncertain. When compared with term infants, preterm infants have a very compliant chest wall and may be at a disadvantage in establishing FRC. The FRC is lowest in the most immature infants because of the decrease in alveolar number. Abnormalities in ventilation : perfusion ratio are greater and persist for longer periods in preterm infants and may lead to hypoxemia and hypercarbia as a result of atelectasis, intrapulmonary shunting, hypoventilation, and gas trapping. The smallest immature infants have the most profound disturbances as a consequence of respi- ratory distress syndrome (RDS). However, even in healthy term infants, oxygenation is impaired immediately after birth, and oxygen saturation improves to exceed 90% only around 5 min. In addition, right-to-left

shunting is common soon after birth; if pulse oximetry is performed soon after birth, the recommendation is to measure oxygen saturation in the right upper extremity.

BREATHING PATTERNS IN NEWBORNS

During sleep in the 1st few mo after birth, normal full-term infants may have episodes when regular breathing is interrupted by short pauses. This periodic breathing pattern, which shifts from a regular rhythmicity to cyclic brief episodes of intermittent apnea, is more common in preterm infants, who may have apneic pauses of 5-10 sec followed by a burst of rapid respirations at a rate of 50-60 breaths/min for 10-15 sec. They rarely have an associated change in color or heart rate, and periodic breathing often stops without apparent reason. Peri- odic breathing, a normal characteristic of neonatal respiration, has no prognostic significance.

101.2 Apnea

Waldemar A. Carlo

Apnea is a common problem in preterm infants that may be the result of prematurity or an associated illness. In term infants, apnea is always worrisome and demands prompt diagnostic evaluation. Periodic breathing must be distinguished from prolonged apneic pauses, because the latter may be associated with serious illnesses. Apnea is a feature of many primary diseases that affect neonates (Table 101-1). These disorders produce apnea by direct depression of the central nervous system’s control of respiration (hypoglycemia, meningitis, drugs, hemorrhage, seizures), disturbances in oxygen delivery (shock, sepsis, anemia), or ventilation defects (obstruction of the airway, pneu- monia, muscle weakness). Idiopathic apnea of prematurity occurs in the absence of identifi- able predisposing diseases. Apnea is a disorder of respiratory control and may be obstructive, central, or mixed. Obstructive apnea (pha- ryngeal instability, neck flexion) is characterized by absence of airflow but persistent chest wall motion. Pharyngeal collapse may follow the negative airway pressures generated during inspiration or it may result from incoordination of the tongue and other upper airway muscles

Table  101-1

Potential Causes of Neonatal Apnea and Bradycardia

Central nervous system

Intraventricular hemorrhage, drugs, seizures, hypoxic injury, herniation, neuromuscular disorders, Leigh syndrome, brainstem infarction or anomalies (e.g., olivopontocerebellar atrophy), spinal cord injury after general anesthesia

Respiratory

Pneumonia, obstructive airway lesions, upper airway collapse, atelectasis, extreme prematurity, laryngeal reflex, phrenic nerve paralysis, pneumothorax, hypoxia

Infectious

Sepsis, meningitis (bacterial, fungal, viral), respiratory syncytial virus, pertussis

Gastrointestinal

Oral feeding, bowel movement, necrotizing enterocolitis, intestinal perforation

Metabolic

Glucose, calcium, / sodium,

ammonia, organic acids,

ambient temperature, hypothermia

Cardiovascular

Hypotension, hypertension, heart failure, anemia, hypovolemia, vagal tone

Other

Immaturity of respiratory center, sleep state

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850 Part  XII   The   Fetus  and  the  Neonatal  Infant

involved in maintaining airway patency. In central apnea, which is caused by decreased central nervous system (CNS) stimuli to respira- tory muscles, both airflow and chest wall motion are absent. Gesta- tional age is the most important determinant of respiratory control, with the frequency of apnea being inversely related to gestational age. The immaturity of the brainstem respiratory centers is manifested by an attenuated response to carbon dioxide and a paradoxical response to hypoxia that results in apnea rather than the hyperventilation observed after the 1st few mo of life. The most common pattern of idiopathic apnea in preterm neonates is mixed apnea (50-75% of cases), with obstructive apnea preceding (usually) or following central apnea. Short episodes of apnea are usually central, whereas prolonged ones are often mixed. Apnea depends on the sleep state; its frequency increases during active (rapid eye movement) sleep.

CLINICAL MANIFESTATIONS

The incidence of idiopathic apnea of prematurity varies inversely with gestational age. The onset of idiopathic apnea can be during the 1st 1-2 wk after birth but is often delayed if there is RDS or other causes of respiratory distress. Apneic episodes have been noted to be as fre- quent on day 1 as throughout the 1st wk in premature infants without respiratory disease. In preterm infants, serious apnea is defined as cessation of breathing for longer than 20 sec or for any duration if accompanied by cyanosis and bradycardia. The incidence of associated bradycardia increases with the length of the preceding apnea and cor- relates with the severity of hypoxia. Short apnea episodes (10 sec) are rarely associated with bradycardia, whereas longer episodes ( >20 sec) have a higher incidence of bradycardia. Bradycardia follows the apnea by 1-2 sec in more than 95% of cases and is most often sinus, but on occasion it can be nodal. Vagal responses and, rarely, heart block are causes of bradycardia without apnea. Short oxygen desaturation epi- sodes noted with oxygen saturation monitoring are normal in neo- nates, and treatment is not necessary.

TREATMENT

Infants at risk for apnea should get cardiorespiratory monitoring. Gentle tactile stimulation is often adequate therapy for mild and inter- mittent episodes. The onset of apnea in a previously well preterm neonate after the 2nd wk of life or in a term infant at any time is a critical event that warrants prompt investigation. Recurrent apnea of prematurity may be treated with caffeine or theophylline. Methyl- xanthines increase central respiratory drive by lowering the threshold of response to hypercapnia as well as enhancing contractility of the diaphragm and preventing diaphragmatic fatigue. Caffeine and theophylline are as effective, but caffeine has fewer side effects (less tachycardia and feeding intolerance). Loading doses of 5-7 mg/kg of theophylline (orally) or aminophylline (intravenously) should be fol- lowed by doses of 1-2 mg/kg given every 6-12 hr by the oral or intra- venous route. Loading doses of 20 mg/kg of caffeine citrate are followed 24 hr later by maintenance doses of 5 mg/kg/24 hr qd, either orally or intravenously. These doses should be monitored through observation of vital signs and clinical response. Serum drug determi- nations (therapeutic levels: theophylline, 6-10 µ g/mL; caffeine, 8-20 µ g/mL) are optional because important side effects of these medi- cations are rare. Higher doses of methylxanthines may be more effec- tive, do not necessarily result in more frequent side effects, and may reduce major neurodevelopmental disabilities. Withholding respira- tory stimulants in infants with RDS may result in ventilator depen- dency, increased bronchopulmonary dysplasia (BPD), and death. Doxapram, known to be a potent respiratory stimulant, acts predomi- nantly on peripheral chemoreceptors and is effective in neonates with apnea of prematurity that is unresponsive to methylxanthines. Transfu- sion of packed red blood cells to reduce the incidence of idiopathic apnea is reserved for severely anemic infants. Gastroesophageal reflux is common in neonates, but data do not support a causal relationship between gastroesophageal reflux and apneic events or the use of anti- reflux medications to reduce the frequency of apnea in preterm infants. Nasal continuous positive airway pressure (continuous positive airway pressure [CPAP], 3-5 cm H 2 O) and high-flow humidification

using nasal cannula (1-2.5 L/min) are therapies for mixed or obstruc- tive apnea, but CPAP is preferred because of its proven efficacy and safety. The efficacy of CPAP is related to its ability to splint the upper airway and prevent airway obstruction.

PROGNOSIS

Apnea of prematurity does not alter an infant’s prognosis unless it is severe, recurrent, and refractory to therapy. The associated problems of intraventricular hemorrhage (IVH), BPD, and retinopathy of pre- maturity are critical in determining the prognosis for apneic infants. Apnea of prematurity usually resolves by 37 wk of postconceptional age, although it may persist beyond term gestation, particularly in extremely preterm infants born at <28 wk of gestation, and does not predict future episodes of sudden infant death syndrome (SIDS). Some infants with persistent apnea are discharged with cardiorespiratory monitoring performed at home. In the absence of significant events, home monitoring can be safely discontinued after 44 wk postconcep- tional age.

APNEA AND SUDDEN INFANT DEATH SYNDROME

Although preterm infants are at higher risk for SIDS, apnea of prema- turity is not a risk factor for SIDS. The epidemiologic evidence that positioning the babies to sleep on their backs reduces the rate of SIDS deaths by more than 50% suggests that position, and not prematurity, has been the primary cause of SIDS. Avoidance of cigarette smoke exposure and of overheating the infant are also important in the pre- vention of SIDS.

Bibliography is available at Expert Consult.

101.3 Respiratory  Distress Syndrome  (Hyaline  Membrane  Disease)

Waldemar A. Carlo and Namasivayam Ambalavanan

INCIDENCE

Respiratory distress syndrome occurs primarily in premature infants; its incidence is inversely related to gestational age and birthweight. It occurs in 60-80% of infants < 28 wk of gestational age, in 15-30% of those between 32 and 36 wk of gestational age, and rarely in those

> 37 wk of gestational age. The risk for development of RDS increases

with maternal diabetes, multiple births, cesarean delivery, precipitous delivery, asphyxia, cold stress, and a maternal history of previously affected infants. The incidence is highest in preterm male or white infants. The risk of RDS is reduced in pregnancies with chronic or pregnancy-associated hypertension, maternal heroin use, prolonged rupture of membranes, and antenatal corticosteroid prophylaxis.

ETIOLOGY AND PATHOPHYSIOLOGY

Surfactant deficiency (decreased production and secretion) is the primary cause of RDS. The failure to attain an adequate FRC and the tendency of affected lungs to become atelectatic correlate with high surface tension and the absence of pulmonary surfactant. The major constituents of surfactant are dipalmitoyl phosphatidylcholine (leci- thin), phosphatidylglycerol, apoproteins (surfactant proteins SP-A, SP-B, SP-C, and SP-D), and cholesterol (Fig. 101-2). With advancing gestational age, increasing amounts of phospholipids are synthesized and stored in type II alveolar cells (Fig. 101-3). These surface-active agents are released into the alveoli, where they reduce surface tension and help maintain alveolar stability by preventing the collapse of small air spaces at end-expiration. Because of immaturity, the amounts pro- duced or released may be insufficient to meet postnatal demands. Surfactant is present in high concentrations in fetal lung homogenates by 20 wk of gestation, but it does not reach the surface of the lungs until later. It appears in amniotic fluid between 28 and 32 wk of gesta- tion. Mature levels of pulmonary surfactant are present usually after 35 wk of gestation.

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Chapter 101   Respiratory   Tract  Disorders  850.e1

Bibliography

Arad-Cohen N, Cohen A, Tirosh E: The relationship between gastroesophageal reflux and apnea in infants, J Pediatr 137:321–326, 2000. Committee on Fetus and Newborn, American Academy of Pediatrics: Apnea, sudden infant death syndrome, and home monitoring, Pediatrics 111:914–917,

2003.

Kimball AL, Carlton DP: Gastroesophageal reflux medications in the treatment of apnea in premature infants, J Pediatr 138:355–360, 2001. Ramanathan R, Corwin MJ, Hunt CE, et al: Cardiorespiratory events recorded on home monitors: comparison of healthy infants with those at increased risk for SIDS, JAMA 285:2199–2207, 2001.

Schmidt B, Anderson PJ, Doyle LW, et al: Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity, JAMA 307:275–282,

2012.

Schmidt B, Roberts RS, Davis P, et al: Long term effects of caffeine for apnea of prematurity, N Engl J Med 357:1893–1902, 2007. Sreenan C, Lemke RP, Hudson-Mason A, et al: High-flow nasal cannulae in the management of apnea of prematurity: a comparison with conventional nasal continuous positive airway pressure, Pediatrics 107:1081–1083, 2001. Steer P, Flenady V, Shearman A, et al: High dose caffeine citrate for extubation of preterm infants: a randomized controlled trial, Arch Dis Child Fetal Neonatal Ed 89:F499–F503, 2004.

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Chapter 101   Respiratory   Tract  Disorders  851

Although rare, genetic disorders may contribute to respiratory dis- tress. Abnormalities in surfactant protein B and C genes as well as a gene responsible for transporting surfactant across membranes (ABC transporter 3 [ABCA3]) are associated with severe and often lethal familial respiratory disease. Other familial causes of neonatal respira- tory distress (not RDS) include alveolar capillary dysplasia, acinar dys- plasia, pulmonary lymphangiectasia, and mucopolysaccharidosis. Synthesis of surfactant depends in part on normal pH, temperature, and perfusion. Asphyxia, hypoxemia, and pulmonary ischemia, par- ticularly in association with hypovolemia, hypotension, and cold stress, may suppress surfactant synthesis. The epithelial lining of the lungs may also be injured by high oxygen concentrations and the effects of respirator management, thereby resulting in a further reduction in surfactant. Alveolar atelectasis, hyaline membrane formation, and interstitial edema make the lungs less compliant in RDS, so greater pressure is required to expand the alveoli and small airways. The chest wall of the preterm infant, which is highly compliant, offers less resistance than that of the mature infant to the natural tendency of the lungs to col- lapse. Thus, at end-expiration, the volume of the thorax and lungs tends to approach residual volume, and atelectasis may develop.

Neutral lipids SP-A SP-B SP-C 65% SP-D Other protein Phosphatidylinositol Phosphatidylethanolamine
Neutral lipids
SP-A
SP-B
SP-C
65%
SP-D
Other protein
Phosphatidylinositol
Phosphatidylethanolamine
Phosphatidylcholine
Phosphatidylglycerol

Figure 101-2 Composition  of surfactant recovered  by alveolar  wash. The quantities of the different components are similar for surfactant from the mature lungs of mammals. SP, surfactant protein. (From Jobe AH: Fetal lung development, tests for maturation, induction of matura- tion, and treatment. In Creasy RK, Resnick R, editors: Maternal-fetal medicine: principles and practice, ed 3, Philadelphia, 1994, WB Saunders.)

A
A

Deficient synthesis or release of surfactant, together with small respiratory units and a compliant chest wall, produces atelectasis and results in perfused but not ventilated alveoli, causing hypoxia. Decreased lung compliance, small tidal volumes, increased physiologic dead space, and insufficient alveolar ventilation eventually result in hypercapnia. The combination of hypercapnia, hypoxia, and acidosis produces pulmonary arterial vasoconstriction with increased right-to- left shunting through the foramen ovale and ductus arteriosus and within the lung itself. Progressive injury to epithelial and endothelial cells from atelectasis (atelectrauma), volutrauma, ischemic injury, and oxygen toxicity results in effusion of proteinaceous material into the alveolar spaces (Fig. 101-4).

CLINICAL MANIFESTATIONS

Signs of RDS usually appear within minutes of birth, although they may not be recognized for several hours in larger premature infants until rapid, shallow respirations become more obvious. A later onset of tachypnea should suggest other conditions. Some patients require resuscitation at birth because of intrapartum asphyxia or initial severe respiratory distress (especially with a birthweight < 1,000 g). Charac- teristically, tachypnea, prominent (often audible) grunting, intercostal and subcostal retractions, nasal flaring, and cyanosis are noted. Breath sounds may be normal or diminished with a harsh tubular quality, and on deep inspiration, fine crackles may be heard. The natural course of untreated RDS is characterized by progressive worsening of cyanosis and dyspnea. If the condition is inadequately treated, blood pressure may fall; cyanosis and pallor increase, and grunting decreases or disap- pears, as the condition worsens. Apnea and irregular respirations are ominous signs requiring immediate intervention. Untreated patients may also have a mixed respiratory-metabolic acidosis, edema, ileus, and oliguria. Respiratory failure may occur in infants with rapid pro- gression of the disease. In most cases, the signs reach a peak within 3 days, after which improvement is gradual. Improvement is often her- alded by spontaneous diuresis and improved blood gas values at lower inspired oxygen levels and/or lower ventilator support. Death can result from severe impairment of gas exchange, alveolar air leaks (inter- stitial emphysema, pneumothorax), pulmonary hemorrhage, or IVH. BPD is a form of chronic lung disease that often develops in infants with severe RDS.

DIAGNOSIS

The clinical course, chest x-ray findings, and blood gas and acid–base values help establish the clinical diagnosis. On x-ray, the lungs may have a characteristic but not pathognomonic appearance that includes

Air Water LMF MLB MLB MVB SLB GZ N ER B
Air
Water
LMF
MLB
MLB
MVB
SLB
GZ
N
ER
B

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

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852 Part  XII   The   Fetus  and  the  Neonatal  Infant

Prematurity C-section Familial predisposition Intrapartum asphyxia Acidosis Diminished surfactant Impaired
Prematurity
C-section
Familial predisposition
Intrapartum asphyxia
Acidosis
Diminished
surfactant
Impaired
Progressive
cellular
atelectasis
metabolism
Alveolar
Hypoventilation
hypoperfusion
(disturbed V/Q)
Transient tachypnea
Pulmonary
Neonatal asphyxia
pCO 2’
pO 2’
pH
vasoconstriction
Hypothermia
Apnea
Hypotension
“shock”

Hypovolemia

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

a fine reticular granularity of the parenchyma and air bronchograms,

which are often more prominent early in the left lower lobe because of superimposition of the cardiac shadow (Fig. 101-5). The initial x-ray appearance is occasionally normal, with the typical pattern developing during the first day. Considerable variation in radiographic findings may be seen, depending on the phase of respiration (inspiratory vs. expiratory radiograph) and the use of CPAP or positive end-expiratory pressure (PEEP); this variation often results in poor correlation between radiographic findings and the clinical course. Laboratory findings are characterized initially by hypoxemia and later by progres- sive hypoxemia, hypercapnia, and variable metabolic acidosis. In the differential diagnosis, early-onset sepsis may be indistin- guishable from RDS. In neonates with pneumonia, the chest radio- graph may be identical to that for RDS. Maternal group B streptococcal colonization, identification of organisms on Gram staining of gastric or tracheal aspirates or a buffy coat smear, and/or the presence of marked neutropenia may suggest the diagnosis of early-onset sepsis. Cyanotic heart disease (in particular, total anomalous pulmonary venous return) can also mimic RDS both clinically and radiographi- cally. Echocardiography with color-flow imaging should be performed in infants who show no response to surfactant replacement to rule out cyanotic congenital heart disease as well as ascertain patency of the ductus arteriosus and assess pulmonary vascular resistance (PVR). Persistent pulmonary hypertension, aspiration (meconium, amni- otic fluid) syndromes, spontaneous pneumothorax, pleural effu- sions, and congenital anomalies, such as cystic adenomatoid malformation, pulmonary lymphangiectasia, diaphragmatic hernia, and lobar emphysema, must be considered in patients with an atypical clinical course, but can generally be differentiated from RDS through radiographic and other evaluations. Transient tachypnea may be dis- tinguished by its shorter and milder clinical course and is characterized by low or no need for oxygen supplementation. Congenital alveolar proteinosis (congenital surfactant protein B deficiency) is a rare famil- ial disease that manifests as severe and lethal RDS in predominantly term and near-term infants (see Chapter 405). In atypical cases of RDS,

a lung profile (lecithin : sphingomyelin ratio and phosphatidylglycerol determination) performed on a tracheal aspirate can be helpful in establishing a diagnosis of surfactant deficiency.

PREVENTION

Avoidance of unnecessary or poorly timed early cesarean section

( <39 wk) or induction of labor, appropriate management of high-risk pregnancy and labor (including administration of antenatal corticoste- roids), and prediction of pulmonary immaturity with possible in utero acceleration of maturation (see Chapter 98) are important preventive strategies. Antenatal and intrapartum fetal monitoring may decrease the risk of fetal asphyxia; asphyxia is associated with an increased incidence and severity of RDS. Administration of antenatal corticosteroids to women before 34 wk of gestation significantly reduces the incidence and mortality of RDS as well as overall neonatal mortality. Antenatal steroids also reduce (1) overall mortality, (2) the need for and duration of ventilatory support and admission to a neonatal ICU, and (3) the incidence of severe IVH, necrotizing enterocolitis, and neurodevelopmental impair- ment. Postnatal growth is not adversely affected. Antenatal steroids do not increase the risk of maternal death, chorioamnionitis, or puerperal sepsis. Steroid administration is recommended for all women in preterm labor who are likely to deliver a fetus within 1 wk. Antenatal steroids act synergistically with postnatal exogenous surfactant therapy so they should be given even though surfactant therapy is effective. Betamethasone and dexamethasone have both been used antenatally. Betamethasone may reduce neonatal death to a greater extent as com- pared to dexamethasone. In the past administration of surfactant into the trachea of symp- tomatic premature infants immediately after birth (prophylactic) or during the 1st few hr of life (early rescue) showed reduced air leak and mortality from RDS. CPAP started at birth is as effective as prophylactic or early surfactant and is the approach of choice for the delivery room management of a preterm neonate at risk for RDS.

TREATMENT

The basic defect requiring treatment in RDS is inadequate pulmonary exchange of oxygen and carbon dioxide; metabolic acidosis and circu- latory insufficiency are secondary manifestations. Early supportive care of premature infants, especially in the treatment of acidosis, hypoxia, hypotension (see Chapter 98), and hypothermia, may lessen the severity of RDS. Therapy requires careful and frequent monitoring

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Chapter 101   Respiratory   Tract  Disorders  853

A A B B C C A B
A
A
B
B
C
C
A
B

Figure  101-5 Infant   with   respiratory  distress   syndrome. Note the granular lungs, air bronchogram, and air-filled esophagus. Anteroposterior ( A) and lateral (B) roentgenograms are needed to distinguish the umbilical artery from the vein catheter and to determine the appropriate level of insertion. The lateral view clearly shows that the catheter has been inserted into an umbilical vein and is lying in the portal system of the liver.

A

indicates endotracheal tube; B indicates the umbilical venous catheter at the junction of the umbilical vein, ductus venosus, and portal vein;

C

indicates the umbilical artery catheter passed up the aorta to T12. (Courtesy of Walter E. Berdon, Babies Hospital, New York City.)

of heart and respiratory rates, oxygen saturation, Pao 2 , Paco 2 , pH, serum bicarbonate, electrolytes, glucose, hematocrit, blood pressure, and temperature. Arterial catheterization is frequently necessary. Because most cases of RDS are self-limited, the goal of treatment is to minimize abnormal physiologic variations and superimposed iatro- genic problems. Treatment of infants with RDS is best carried out in the neonatal ICU. The general principles for supportive care of any premature infant should be adhered to, including developmental care and scheduled “touch times.” To avoid hypothermia and minimize oxygen consump- tion, the infant should be placed in an incubator or radiant warmer, and core temperature maintained between 36.5 and 37°C (97.7 and 98.6°F) (see Chapters 97 and 98). Use of an incubator is preferable in very-low birthweight (VLBW) infants owing to the high insensible water losses associated with radiant heat. Calories and fluids should initially be provided intravenously. For the 1st 24 hr, 10% glucose solution with additional amino acids in extremely premature infants, should be infused through a peripheral vein at a rate of 65-75 mL/ kg/24 hr. Electrolytes should be added on day 2 in the most mature infants and on days 3-7 in the more immature ones. Fluid volume is increased gradually over the 1st wk. Excessive fluids ( > 140 mL/kg/ day) contribute to the development of patent ductus arteriosus (PDA) and BPD. Warm humidified oxygen should be provided at a concentration initially sufficient to keep arterial oxygen pressure between 50 and 70 mm Hg (91-95% saturation) in order to maintain normal tissue oxygenation while minimizing the risk of oxygen toxicity. If oxygen saturation cannot be kept > 90% at inspired oxygen concentrations of 40-70% or greater, applying CPAP at a pressure of 5-10 cm H 2 O via nasal prongs is indicated and usually produces a rapid improvement in oxygenation. CPAP reduces collapse of surfactant-deficient alveoli and improves both FRC and ventilation–perfusion matching. Early use

of CPAP for stabilization of at-risk preterm infants beginning as early as in the delivery room reduces ventilatory needs. Another approach is to intubate the preterm infant, administer intratracheal surfactant and then extubate the infant and begin CPAP. The amount of CPAP required usually decreases after approximately 72 hr of age, and most infants can be weaned from CPAP shortly thereafter. If an infant with RDS undergoing CPAP cannot keep oxygen saturation >90% while breathing 40-70% oxygen, assisted ventilation and surfactant are indicated. Infants with respiratory failure or persistent apnea require assisted mechanical ventilation. Reasonable measures of respiratory failure are:

(1) arterial blood pH < 7.20, (2) arterial blood Pco 2 of 60 mm Hg or higher, and (3) oxygen saturation < 90% at oxygen concentrations of 40-70% and CPAP of 5-10 cm H 2 O. Infants with persistent apnea also need mechanical ventilation. Intermittent positive pressure ventilation delivered by time-cycled, pressure-limited, continuous flow ventilators is a common method of conventional ventilation for newborns. Other methods of conventional ventilation are synchronized intermittent mandatory ventilation (the set rate and pressure synchronized with the patient’s own breaths), pressure support (the patient triggers each breath and a set pressure is delivered), and volume ventilation (a mode in which a specific tidal volume is set and the delivered pressure varies), and combinations thereof. Assisted ventilation for infants with RDS should always include appropriate PEEP (see Chapter 71.1). High ventilatory rates ( 60/min) with lower tidal volumes result in fewer air leaks. With use of high ventilatory rates, sufficient expiratory time should be allowed to avoid the inadvertent PEEP. The goal of mechanical ventilation is to improve oxygenation and elimination of carbon dioxide without causing pulmonary injury or oxygen toxicity. Acceptable ranges of blood gas values, after the risks of hypoxia and acidosis are balanced against those of mechanical ven- tilation, vary among institutions: Pao 2 50-70 mm Hg, Paco 2 45-65 mm

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854Part  XII   The   Fetus   and   the   Neonatal  Infant

Hg (and higher after the first few days when the risk of IVH is less), and pH 7.20-7.35. During mechanical ventilation, oxygenation is

improved by increasing either the fraction of inspired oxygen (Fio 2 ) or the mean airway pressure. The latter can be increased by raising the peak inspiratory pressure, PEEP gas flow, or inspiratory-expiratory ratio. Pressure changes are usually most effective. However, excessive PEEP may impede venous return, thereby reducing cardiac output and decreasing oxygen delivery despite improvement in Pao 2 . PEEP levels of 4-6 cm H 2 O are usually safe and effective. Carbon dioxide elimina- tion is achieved by increasing the peak inspiratory pressure (tidal volume) or the rate of the ventilator.

A strategy to minimize ventilator-associated lung injury is the use

of CPAP instead of endotracheal intubation. The decreased need for ventilator support with the use of CPAP may allow lung inflation to be maintained but may prevent volutrauma from overdistention and/or atelectasis. Early nasal CPAP is beneficial as compared to intubation and prophylactic surfactant, including lower mortality or BPD with CPAP treatment. An effective strategy with conventional mechanical ventilation is the use of high rates and presumably small tidal volumes as Paco 2 levels were kept in comparable ranges. Meta-analyses of the randomized controlled trials comparing high ( > 60 breaths/min) and low (usually

30-40 breaths/min) rates (and presumed low vs. high tidal volumes,

respectively) revealed that the high ventilatory rate strategy led to fewer air leaks and a trend for increased survival.

If mechanical ventilation is needed, a ventilatory approach using

small tidal volumes and permissive hypercapnia can be employed. Permissive hypercapnia is a strategy for the management of patients receiving ventilatory support in which priority is given to the preven- tion or limitation of lung injury from the ventilator by tolerating rela- tively high levels of Paco 2 rather than maintenance of normal blood gas values. Permissive hypercapnia can be implemented during CPAP and mechanical ventilation. Volume-targeted ventilation allows the clinician to set a tidal volume that may prevent volutrauma. There are limited data on volume-targeted ventilation, but this mode of ventila- tion may decrease the rates of pneumothorax and BPD. Hyperoxia may also contribute to lung injury in preterm infants. However, a lower target range of oxygenation (85-89%), as compared with a higher range (91-95%) increases mortality, and does not alter rates of BPD, BPD/death, blindness, or neurodevelopmental impair- ment. Therefore, the currently recommended range of oxygen satu- ration targets is 91-95%. Many ventilated neonates receive sedation or pain relief with ben- zodiazepines or opiates (morphine, fentanyl), respectively. Midazolam is approved for use in neonates and has demonstrated sedative effects. Adverse hemodynamic effects and myoclonus have been associated with its use in neonates. If midazolam is used, a continuous infusion or administration of individual doses over at least 10 min is recom- mended to reduce these risks. Data are insufficient to assess the efficacy and safety of lorazepam. Diazepam is not recommended owing to its long half-life, its long-acting metabolites, and concern about the benzyl alcohol content of diazepam injection. Continuous infusion of mor- phine in VLBW neonates requiring mechanical ventilation does not reduce mortality rates, severe IVH, or periventricular leukomalacia. The need for additional doses of morphine is associated with poor outcome. High-frequency ventilation (HFV) achieves desired alveolar venti- lation by using smaller tidal volumes and higher rates (300-1,200 breaths/min or 5-20 Hz). HFV may improve elimination of carbon dioxide and improve oxygenation in patients who show no response to conventional ventilators and those who have severe RDS, interstitial emphysema, recurrent pneumothoraces, or meconium aspiration pneumonia. High-frequency oscillatory ventilation (HFOV) and high- frequency jet ventilation are the most frequently used methods of HFV. HFOV reduces BPD but may raise the risk for intracranial hem- orrhage. HFOV strategies that promote lung recruitment, combined with surfactant therapy, may improve gas exchange. High-frequency jet ventilation facilitates resolution of air leaks. Elective use of either method, in comparison with conventional ventilation, generally does

not offer advantages if used as the initial ventilation strategy to treat infants with RDS. Surfactant deficiency is the primary pathophysiology of RDS. Immediate effects of surfactant replacement therapy include improved alveolar-arterial oxygen gradients, reduced ventilatory support, increased pulmonary compliance, and improved chest radiograph appearance. In neonates with RDS who fail CPAP, treatment with endotracheal surfactant should be initiated immediately after intuba- tion. Repeated dosing is given every 6-12 hr for a total of 2 to 4 doses, depending on the preparation. Exogenous surfactant should be given by a physician who is qualified in neonatal resuscitation and respira- tory management. Additional onsite staff support required includes nurses and respiratory therapists experienced in the ventilatory man- agement of preterm infants. Appropriate monitoring equipment (radi- ology, blood gas laboratory, pulse oximetry) must also be available. Complications of surfactant therapy include transient hypoxia, hyper- capnia, bradycardia and hypotension, blockage of the endotracheal tube, and pulmonary hemorrhage (see Chapter 101.13). A number of surfactant preparations are available, including syn- thetic surfactants and natural surfactants derived from animal sources. The lack of reduction in BPD rates following surfactant replacement is probably, in part, a result of the survival of infants with severe RDS who would have died without surfactant administration. Infants requiring ventilator support after 1 wk of age may experience transient episodes of surfactant dysfunction associated with deficiencies of SP-B and SP-C, which are temporally associated with episodes of infection and respiratory deterioration. Surfactant treatment may be beneficial in these infants. Strategies for weaning infants from ventilators vary widely and are influenced by lung mechanics as well as the availability of ventilatory modes (pressure support). Once extubated, many infants are transi- tioned to nasal CPAP to avoid postextubation atelectasis and reduce re-intubation. Synchronized nasal intermittent ventilation decreases the need for re-intubation in premature infants. High flow (1-2 L/min) or warmed, humidified high-flow (2-8 L/min) nasal cannula oxygen is commonly used to support term and near-term infants following extu- bation and to wean premature infants from nasal CPAP. Preloading with methylxanthines may enhance the success of extubation.

Pharmacologic Therapies

Systemic corticosteroids have been used to treat infants with RDS, to selectively treat infants who continue to require respiratory support, and to treat those in whom BPD develops. Mortality and/or BPD at 36 wk decrease with moderately early (7-14 days) administration of corticosteroids. Early ( < 96 hr) and delayed ( > 2-3 wk) administration of systemic steroids has also been assessed with meta-analyses, and the results are qualitatively similar. However, there are short-term adverse effects, including hyperglycemia, hypertension, gastrointestinal bleed- ing, gastrointestinal perforation, hypertrophic obstructive cardiomy- opathy, poor weight gain, poor growth of the head, and a trend toward a higher incidence of periventricular leukomalacia. Furthermore, data showing an increased incidence of neurodevelopmental delay and cerebral palsy in infants randomly assigned to receive systemic corti- costeroids raise serious concerns about adverse long-term outcomes of this therapy. Thus, routine use of systemic corticosteroids for the pre- vention or treatment of BPD is not recommended by the Consensus Group of the American Academy of Pediatrics and the Canadian Pedi- atric Society. Administration of inhaled steroids to ventilated preterm infants during the 1st 2 wk after birth reduced the need for systemic steroids and tended to decrease rates of death and/or BPD at 36 wk without an increase in adverse effects. Inhaled nitric oxide has been evaluated in preterm infants follow- ing the observation of its effectiveness in term and near-term infants with hypoxemic respiratory failure. Inhaled nitric oxide (iNO) decreases the need for extracorporeal membrane oxygenation (ECMO) in term and near-term infants with hypoxic respiratory failure or persistent pulmonary hypertension of the neonate. Trials in preterm infants report heterogeneous effects on BPD, mortality, and other important outcomes. The most current data do not support the

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Chapter 101   Respiratory   Tract  Disorders  855

routine administration of iNO in preterm infants with hypoxemic respiratory failure. Prevention of extubation failure has been attempted with use of various pharmacologic approaches. Methylxanthines appear to have a large effect on reducing extubation failure. Similarly, use of systemic steroids before extubation reduces the need for reintubation (from 10% to 1%). In contrast, administration of racemic epinephrine after extu- bation does not improve pulmonary function or the rate of extubation failure. Metabolic acidosis in RDS may be a result of perinatal asphyxia and hypotension and is often encountered when an infant has required prolonged resuscitation (see Chapter 100). Sodium bicarbon- ate, 1-2 mEq/kg, may be administered over 15-20 min through a peripheral or umbilical vein, followed by an acid–base determination within 30 min, or it may be administered over several hours. Often, sodium bicarbonate is administered on an emergency basis through an umbilical venous catheter. Alkali therapy may result in skin slough- ing from infiltration, increased serum osmolarity, hypernatremia, hypocalcemia, hypokalemia, and liver injury when concentrated solu- tions are administered rapidly through an umbilical vein catheter wedged in the liver. Monitoring of aortic blood pressure through an umbilical or peripheral arterial catheter or by oscillometric technique is useful in managing the shock-like state that may occur during the 1st hr or so in premature infants who have been asphyxiated or have severe RDS (see Fig. 100-2 in Chapter 100). The position of a radiopaque umbilical catheter should be checked radiographically after insertion (see Fig. 101-5). The tip of an umbilical artery catheter should lie at L3-L5 just above the bifurcation of the aorta or at T6-T10. Preferred sites for peripheral catheters are the radial or posterior tibial arteries. The place- ment and supervision should be carried out by skilled and experienced personnel. Catheters should be removed as soon as patients no longer have any indication for their continued use—usually when an infant is stable and the Fio 2 is < 40%. Hypotension and low flow in the superior vena cava have been associated with higher rates of CNS morbidity and mortality and should be treated with cautious administration of volume (crystalloid) and early use of vasopressors. Dopamine is more effective in raising blood pressure than dobutamine. Hypotension may be refractory to pressors, but responsive to glucocorticoids, especially in neonates < 1,000 g. This hypotension may result from transient adrenal insufficiency in the ill premature infant, which may be treated with intravenous hydrocortisone at 1-2 mg/kg/dose q 6-12 hr (see Chapter 98). Periodic monitoring of Pao 2 , Paco 2 , and pH is an important part of the management; if assisted ventilation is being used, such monitor- ing is essential. Oxygenation may be assessed continuously from trans- cutaneous electrodes or pulse oximetry (oxygen saturation). Capillary blood samples are of limited value for determining Po 2 but may be useful for evaluating Pco 2 and pH. Because of the difficulty of distinguishing group B streptococcal or other bacterial infections from RDS, empirical antibiotic therapy is indicated until the results of blood cultures are available. Penicillin or ampicillin with an aminoglycoside is suggested, although the choice of antibiotics should be based on the recent pattern of bacterial sensitivity in the hospital where the infant is being treated (see Chapter 109).

COMPLICATIONS OF RESPIRATORY DISTRESS SYNDROME AND INTENSIVE CARE

The most serious complications of tracheal intubation are pneumo- thorax and other air leaks, asphyxia from obstruction or dislodgment of the tube, bradycardia during intubation or suctioning, and the subsequent development of subglottic stenosis. Other complications include bleeding from trauma during intubation, posterior pharyngeal pseudodiverticula, need for tracheostomy, ulceration of the nares caused by pressure from the tube, permanent narrowing of the nostril as a result of tissue damage and scarring from irritation or infection around the tube, erosion of the palate, avulsion of a vocal cord, laryn- geal ulcer, papilloma of a vocal cord, and persistent hoarseness, stridor, or edema of the larynx.

Measures to reduce the incidence of these complications include skillful intubation, adequate securing of the tube, use of polyvinyl endotracheal tubes, use of the smallest tube that will provide effective ventilation in order to reduce local pressure necrosis and ischemia, avoidance of frequent changes and motion of the tube in situ, avoid- ance of too frequent or too vigorous suctioning, and prevention of infection through meticulous cleanliness and frequent sterilization of all apparatus attached to or passed through the tube. The personnel inserting and caring for the endotracheal tube should be experienced and skilled in such care. Risks associated with umbilical arterial catheterization include vascular embolization, thrombosis, spasm, and vascular perforation; ischemic or chemical necrosis of abdominal viscera; infection; acciden- tal hemorrhage; hypertension; and impairment of circulation to a leg with subsequent gangrene. Aortography has demonstrated that clots form in or about the tips of 95% of catheters placed in an umbilical artery. Aortic ultrasonography can also be used to investigate for the presence of thrombosis. The risk of a serious clinical complication resulting from umbilical catheterization is probably between 2% and 5%. Transient blanching of the leg may occur during catheterization of the umbilical artery. It is usually caused by reflex arterial spasm, the incidence of which is lessened by using the smallest available catheter, particularly in very small infants. The catheter should be removed immediately; catheterization of the other artery may then be attempted. Persistent spasm after removal of the catheter may be relieved by a small amount of topical nitroglycerin paste applied to the affected area or by warming the other leg. Blood sampling from a radial artery may similarly result in spasm or thrombosis, and the same treatment is indicated. Intermittent severe spasm or unrelieved spasm may respond to the cautious use of topical nitroglycerin. Spasm or thrombosis unre- sponsive to treatment may result in gangrene of the organ or area supplied by the vessel. Serious hemorrhage upon removal of the catheter is rare. Thrombi may form in the artery or in the catheter, the incidence of which can be lowered by using a smooth-tipped catheter with a hole only at its end, by rinsing the catheter with a small amount of saline solution containing heparin, or by continuously infusing a solution containing 1-2 units/mL of heparin. The risk of thrombus formation with poten- tial vascular occlusion can also be reduced by removing the catheter when early signs of thrombosis, such as narrowing of pulse pressure and disappearance of the dicrotic notch, are noted. Some authorities prefer to use the umbilical artery for blood sampling only and to leave the catheter filled with heparinized saline between samplings. Reno- vascular hypertension may occur days to weeks after umbilical arterial catheterization in a small proportion of neonates. Umbilical vein catheterization is associated with many of the same risks as umbilical artery catheterization. Additional risks are cardiac perforation and pericardial tamponade; portal hypertension can develop from portal vein thrombosis, especially in the presence of omphalitis. Air leaks are a common complication of the management of infants with RDS (see Chapter 101.12). Some neonates with RDS may have clinically significant shunting through a PDA. Delayed closure of the PDA is associated with hypoxia, acidosis, increased pulmonary pressure secondary to vasoconstriction, systemic hypotension, immaturity, and local release of prostaglandins, which dilate the ductus. Shunting through the PDA may initially be bidirectional or right-to-left. As RDS resolves, PVR decreases, and left-to-right shunting may occur, leading to left ventricular volume overload and pulmonary edema. Manifestations of PDA may include (1) a hyperdynamic precordium, bounding peripheral pulses, wide pulse pressure, and a continuous or systolic murmur with or without extension into diastole or an apical diastolic murmur, or multiple clicks resembling the shaking of dice; (2) radiographic evidence of cardio- megaly and increased pulmonary vascular markings; (3) hepatomegaly; (4) increasing oxygen dependence; and (5) carbon dioxide retention. The diagnosis is confirmed by echocardiographic visualization of a PDA with Doppler flow imaging that demonstrates left-to-right or

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856 Part  XII   The   Fetus  and  the  Neonatal  Infant

bidirectional shunting. Prophylactic “closure” before signs of a PDA, closure of the asymptomatic but clinically detected PDA, and closure of the symptomatic PDA are 3 strategies to manage a PDA. Interven- tions include fluid restriction, the use of cyclooxygenase inhibitors (indomethacin or ibuprofen) to close the ductus, and surgical closure. Short-term benefits have to be balanced against adverse effects such as transient renal dysfunction and a possible increase in the risk of intes- tinal perforation with indomethacin. Much uncertainty about “best practice” in the management of a PDA remains. Many cases respond to general supportive measures, including fluid restriction. Medical and/or surgical ductal closure is indicated in the premature infant with a large PDA when there is a delay in clinical improvement or deteriora- tion after initial clinical improvement of RDS. Intravenous indometha- cin (0.1-0.2 mg/kg/dose) is given in 3 doses every 12-24 hr; treatment may be repeated once. A second course may be needed in a few symp- tomatic patients. If closure does not occur in a symptomatic patient, surgical ligation is usually the next step. Prophylactic low-dose indo- methacin given soon after birth reduces the incidence of both IVH and PDA and improves the rate of permanent ductus closure even in the most immature infants. Contraindications to indomethacin include thrombocytopenia ( < 50,000 platelets/mm 3 ), bleeding disorders, oligu- ria (urine output < 1 mL/kg/hr), necrotizing enterocolitis, isolated intestinal perforation, and an elevated plasma creatinine value

( >1.8 mg/dL). The infant whose symptomatic PDA fails to close with indomethacin or who has contraindications to indomethacin is a can- didate for surgical closure. Surgical mortality is very low even in the extremely low-birthweight infants. Complications of surgery include Horner syndrome, injury to the recurrent laryngeal nerve, chylothorax, transient hypertension, pneumothorax, and bleeding from the surgical site. Inadvertent ligation of the left pulmonary artery or the transverse aortic arch has rarely been reported. Intravenous ibuprofen may be an alternative to indomethacin; it can be as effective in closing a PDA without reducing cerebral, mesenteric, or renal blood flow velocity. Compared with indomethacin, therapeu- tic ibuprofen has a lower risk of oliguria. BPD is a result of lung injury in infants requiring mechanical ven- tilation and supplemental oxygen. The clinical, radiographic, and lung histology of classic BPD described in 1967, in an era before the wide- spread use of antenatal steroids and postnatal surfactant, was that of a disease of more mature preterm infants with RDS who were treated with positive-pressure ventilation and oxygen. The new BPD is a disease primarily of infants with birthweight < 1,000 g who were born at <28 wk of gestation, some of whom have little or no lung disease at birth but experience progressive respiratory failure over the 1st few wk of life. The lung histology currently found in infants with the new BPD include alveolar hypoplasia, variable saccular wall fibrosis, and minimal airway disease. Some specimens also have decreased pulmo- nary microvasculature development. The histopathology of BPD indi- cates interference with normal alveolar septation and microvascular maturation, which may prevent subsequent lung growth and develop- ment. The pathogenesis of BPD is multifactorial and affects both the lungs and the heart. RDS is a disease of progressive alveolar collapse. Alveolar collapse (atelectrauma) as a consequence of surfactant defi- ciency, together with ventilator-induced phasic overdistention of the lung (volutrauma), promotes injury. Oxygen induces injury by pro- ducing free radicals that cannot be metabolized by the immature anti- oxidant systems of VLBW neonates. Mechanical ventilation and oxygen injure the lung through their effect on alveolar and vascular development. Inflammation (detected with measurement of circulat- ing neutrophils, neutrophils and macrophages in alveolar fluid, and proinflammatory cytokines) contributes to the progression of lung injury. Several clinical factors, including immaturity, chorioamnion- itis, infection, symptomatic PDA, and malnutrition, contribute to the development of BPD. The occurrence of BPD is inversely related to gestational age. Addi- tional associations include the presence of interstitial emphysema, male sex, low Paco 2 during the treatment of RDS, PDA, high peak inspiratory pressure, increased airway resistance in the 1st wk of life,

increased pulmonary artery pressure, and, possibly, a family history of atopy or asthma. Genetic polymorphisms may increase the risk for development of BPD. In some VLBW infants without RDS who require mechanical ventilation for apnea or respiratory insufficiency, BPD that does not follow the classic pattern may develop. Overhydration during the 1st days of life may also contribute to the development of BPD. Vitamin A supplementation (5,000 IU intramuscularly 3 times/wk for 4 wk) in VLBW infants reduces the risk of BPD (1 case prevented for every 14-15 infants treated). Early use of nasal CPAP and rapid extuba- tion with transition to nasal CPAP are associated with a decreased risk of BPD. Instead of showing improvement on the 3rd or 4th day, which would be consistent with the natural course of RDS, some infants demonstrate an increased need for oxygen and ventilatory support. Respiratory distress persists or worsens and is characterized by hypoxia, hyper- capnia, oxygen dependence, and, in severe cases, the development of right-sided heart failure. The chest radiograph may reveal pulmonary interstitial emphysema, wandering atelectasis with concomitant hyper- inflation, and cyst formation (Fig. 101-6). Four distinct pathologic

stages of classic BPD have been identified: acute lung injury, exudative bronchiolitis, proliferative bronchiolitis, and obliterative fibroprolifera- tive bronchiolitis. Histologic study at this stage (10-20 days) shows residual hyaline membrane formation, progressive alveolar coales- cence with atelectasis of the surrounding alveoli, interstitial edema, coarse focal thickening of the basement membrane, and widespread bronchial and bronchiolar mucosal metaplasia and hyperplasia. These findings correspond to a severe maldistribution of ventilation. Patho- logic examination of infants who die later in the course of BPD reveals cardiac enlargement and pulmonary changes consisting of focal areas of emphysema with hypertrophy of the peribronchial smooth muscle of the tributary bronchioles, perimucosal fibrosis, widespread metapla- sia of the bronchiolar mucosa, thickening of basement membranes, and separation of the capillaries from the alveolar epithelial cells. BPD can be classified according to the need for oxygen supplemen- tation (Table 101-2). Neonates receiving positive pressure support or

30% supplemental oxygen at 36 wk or at discharge (whichever occurs first) are diagnosed as having severe BPD. Those needing supplementa- tion with 22-29% oxygen at this age are diagnosed as having moderate BPD. Those who need oxygen supplementation for > 28 days but are breathing room air at 36 wk or at discharge are diagnosed as having mild BPD. Those receiving < 30% oxygen should undergo a stepwise 2% reduction in supplemental oxygen to room air while under con- tinuous observation and with oxygen saturation monitoring to deter- mine whether they can be weaned off oxygen (physiologic definition of BPD). This test is highly reliable and correlated with discharge home on oxygen, length of hospital stay, and hospital readmissions in the 1st yr of life. Severe BPD requires prolonged mechanical ventilation. Gradual weaning should be attempted despite elevations in Paco 2 , because hypercapnia may be the result of gas trapping rather than inadequate minute ventilation. Acceptable blood gas concentrations include hypercapnia with pH >7.20 and a Pao 2 of 50-70 mm Hg with an oxygen saturation of 91-95%. Lower levels of Pao 2 may exacerbate pulmonary hypertension with resultant cor pulmonale, so the lower limit of oxygenation targets in neonates with BPD are higher than those in neonates with RDS. Airway obstruction in BPD may be due to mucus and edema production, bronchospasm, and airway collapse from acquired tracheobronchomalacia. These events may contribute to “blue spells.” Alternatively, blue spells may be the result of acute pul- monary vasospasm or right ventricular dysfunction. Treatment of BPD includes nutritional support, fluid restriction, drug therapy, maintenance of adequate oxygenation, and prompt treat- ment of infection. Growth must be monitored because recovery depends on the growth of lung tissue and remodeling of the pulmonary vascular bed. Nutritional supplementation to provide added calories (24-30 calories/30 mL formula), protein (3-3.5 g/kg/24 hr), and fat (3 g/kg/24 hr) is needed for growth. Diuretic therapy results in a short- term improvement in lung mechanics and may lead to decreased oxygen and ventilatory requirements. Furosemide (1 mg/kg/dose

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Chapter 101   Respiratory   Tract  Disorders  857

A B C D
A
B
C
D

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

Table 101-2

Definition of BPD: Diagnostic Criteria*

 

GESTATIONAL AGE

< 32 Wk

32 Wk

Time point of assessment

36 wk postmenstrual age or discharge home, whichever comes first Treatment with > 21% oxygen for at least 28 days plus

28 days but < 56 days postnatal age or discharge home, whichever comes first Treatment with > 21% oxygen for at least 28 days plus

>

Mild BPD

Breathing room air at 36 wk postmenstrual age or discharge home, whichever comes first

Breathing room air by 56 days postnatal age or discharge home, whichever comes first

Moderate BPD

Need for <30% oxygen at 36 wk postmenstrual age or discharge home, whichever comes first

Need for < 30% oxygen at 56 days postnatal age or discharge home, whichever comes first

Severe BPD

Need for 30% oxygen and/or positive pressure (PPV or NCPAP) at 36 wk postmenstrual age or discharge home, whichever comes first

Need for 30% oxygen and/or positive pressure (PPV or NCPAP) at 56 days postnatal age or discharge home, whichever comes first

*BPD usually develops in neonates being treated with oxygen and PPV for respiratory failure, most commonly respiratory distress syndrome. Persistence of the clinical features of respiratory disease (tachypnea, retractions, crackles) is considered common to the broad description of BPD and has not been included in the diagnostic criteria describing the severity of BPD. Infants treated with > 21% oxygen and/or PPV for nonrespiratory disease (e.g., central apnea or diaphragmatic paralysis) do not have BPD unless parenchymal lung disease also develops and they have clinical features of respiratory distress. A day of treatment with > 21% oxygen means that the infant received >21% oxygen for more than 12 hr on that day. Treatment with >21% oxygen and/or PPV at 36 wk postmenstrual age or at 56 days postnatal age or discharge should not reflect an “acute” event, but should rather reflect the infant’s usual daily therapy for several days preceding and after 36 wk postmenstrual age, 56 days postnatal age, or discharge. A physiologic test confirming that the oxygen requirement at the assessment time point remains to be defined. This assessment may include a pulse oximetry saturation range. BPD, bronchopulmonary dysplasia; NCPAP, nasal continuous positive airway pressure; PPV, positive-pressure ventilation. From Jobe AH, Bancalari E: Bronchopulmonary dysplasia, Am J Respir Crit Care Med 163:1723–1729, 2001.

intravenously twice daily [bid] or 2 mg/kg/dose orally bid) is the treat- ment of choice for acute fluid overload in infants with BPD. This loop diuretic has been demonstrated to decrease pulmonary interstitial emphysema and PVR, improve pulmonary function, and facilitate weaning from mechanical ventilation and oxygen. Adverse effects of long-term diuretic therapy are common and include hyponatremia,

hypokalemia, alkalosis, azotemia, hypocalcemia, hypercalciuria, cho- lelithiasis, renal stones, nephrocalcinosis, and ototoxicity. Potassium chloride supplementation is often necessary. Hyponatremia should be treated with fluid restriction and a decrease in the dose or frequency of furosemide. Thiazide diuretics have been used in infants with BPD. Several trials of thiazide diuretics combined with spironolactone have

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858Part  XII   The   Fetus   and   the   Neonatal  Infant

shown increased urine output with or without improvement in pulmo- nary mechanics in infants with BPD. Adverse effects include electrolyte imbalance. Inhaled bronchodilators improve lung mechanics by decreasing airway resistance. Albuterol is a specific β 2 -agonist used to treat bronchospasm in infants with BPD. Albuterol may improve lung com- pliance by decreasing airway resistance secondary to smooth muscle cell relaxation. Changes in pulmonary mechanics may last as long as 4-6 hr. Adverse effects include hypertension and tachycardia. Ipratro- pium bromide is a muscarinic antagonist related to atropine, but with more potent bronchodilator effects. Improvements in pulmonary mechanics have been demonstrated in BPD after ipratropium bromide inhalation. Combination therapy using albuterol and ipratropium bromide may be more effective than either agent alone. Few adverse effects have been noted. With current aerosol administration strategies, exactly how much medication is delivered to the airways and lungs of infants with BPD, especially if they are ventilator dependent, is unclear. Because significant smooth muscle relaxation does not appear to occur within the 1st few wk of life, aerosol therapy in the early stages of BPD is not indicated. Methylxanthines are used to increase respiratory drive, decrease apnea, and improve diaphragmatic contractility. Meth- ylxanthines may also decrease PVR and increase lung compliance in infants with BPD, probably through direct smooth muscle relaxation. They also exhibit diuretic effects. These effects may accelerate weaning from mechanical ventilation. Synergy between theophylline and diuretics has been demonstrated. Theophylline has a half-life of 30-40 hr, is metabolized primarily to caffeine in the liver and may have adverse effects, such as tachycardia, gastroesophageal reflux, agitation, and seizures. Caffeine has a longer half-life than theophylline. Both are available in intravenous and enteral formulations. Preventive therapy of BPD with postnatal dexamethasone may reduce the time to extubation and may decrease the risk of BPD but is associated with substantial short- and long-term risks, including hypertension, hyperglycemia, gastrointestinal bleeding and perfora- tion, hypertrophic cardiomyopathy, sepsis, and poor weight gain and head growth. Survival is not improved, and infants who have been treated with dexamethasone have an increased risk of neurodevelop- mental delay and cerebral palsy. The use of dexamethasone for the prevention of BPD is not recommended unless an infant has severe pulmonary disease, for example is ventilator dependent for at least 1 to 2 wk after birth. A rapid tapering course of therapy, starting at 0.25 mg/kg/day and lasting for 5-7 days, may be adequate. Inhaled beclomethasone does not prevent BPD but does decrease the need for systemic steroids. Inhaled corticosteroids facilitate earlier extubation of ventilated infants with BPD. Physiologic abnormalities of the pulmonary circulation in BPD include elevated PVR and abnormal vasoreactivity. Acute exposure to even modest levels of hypoxemia causes large elevations in pulmonary artery pressure in infants with BPD with pulmonary hypertension. Higher oxygen saturations are effective in lowering pulmonary artery pressure. The current recommendation for treatment of patients with BPD and pulmonary hypertension is to maintain oxygen saturation values in the 91-95% range. Low-dose iNO has no acute effects on lung function, cardiac func- tion, or oxygenation in evolving BPD. The use of low-dose iNO may improve oxygenation in some infants with severe BPD, allowing decreased Fio 2 and ventilator support.

PROGNOSIS

Early provision of intensive observation and care of high-risk newborn infants can significantly reduce the morbidity and mortality associated with RDS and other acute neonatal illnesses. Antenatal steroids, post- natal surfactant use, and improved modes of ventilation have resulted in low mortality from RDS ( 10%). Mortality increases with decreas- ing gestational age. Optimal results depend on the availability of expe- rienced and skilled personnel, care in specially designed and organized regional hospital units, proper equipment, and lack of complications such as severe asphyxia, intracranial hemorrhage, or irremediable con- genital malformation. Surfactant therapy has reduced mortality from

RDS by approximately 40%, but the incidence of BPD has not been measurably affected. Although 85-90% of all infants surviving RDS after requiring venti- latory support with respirators are normal, the outlook is much better for those weighing > 1,500 g. The long-term prognosis for normal pul- monary function in most infants surviving RDS is excellent. Survivors of severe neonatal respiratory failure may have significant pulmonary and neurodevelopmental impairment. Prolonged ventilation, IVH, pulmonary hypertension, cor pulmo- nale, and oxygen dependence beyond 1 yr of life are poor prognostic signs. Mortality in infants with BPD ranges from 10-25% and is highest in infants who remain ventilator dependent for longer than 6 mo. Cardiorespiratory failure associated with cor pulmonale and acquired infection (respiratory syncytial virus) are common causes of death. Survivors with BPD often go home on a regimen of oxygen, diuretics, and bronchodilator therapy. Pulmonary function slowly improves in most survivors owing to continued lung and airway growth and healing. Rehospitalization for impaired pulmonary function is most common during the 1st 2 yr of life. There is a gradual decrease in symptom frequency in children ages 6-9 yr from the frequency during the 1st 2 yr of life. Persistence of respiratory symptoms and abnormal pulmonary function test results are present in children ages 7-10 yr. Pulmonary function testing in children with a history of BPD shows persistent abnormalities in clini- cal moderate expiratory flow obstruction. Approximately 25-50% of very-low birthweight infants and more than 50% of children born at less than 26 wk of gestation continue to have abnormal spirometry as preadolescents. Many have asthma and respond to bronchodilators. Infants are at risk for severe respiratory syncytial virus infections and must receive prophylactic therapy (see Chapter 260). Airway obstruc- tion and hyperactivity and hyperinflation are noted in some adolescent and adult survivors of BPD. High-resolution chest CT scanning or MRI studies in children and adults with a history of BPD reveal lung abnor- malities that correlate directly with the degree of pulmonary function abnormality. Noncardiorespiratory complications of BPD include growth failure, psychomotor retardation, and parental stress, as well as sequelae of therapy, such as nephrolithiasis, osteopenia, and electrolyte imbalance. Airway problems, such as tonsillar and adenoidal hypertrophy, vocal cord paralysis, subglottic stenosis, and tracheomalacia, are common and may aggravate or cause pulmonary hypertension. Subglottic ste- nosis may require tracheotomy or an anterior cricoid split procedure to relieve upper airway obstruction. Cardiac complications of BPD include pulmonary hypertension, cor pulmonale, systemic hyperten- sion, left ventricular hypertrophy, and the development of aortopul- monary collateral vessels, which, if large, may cause heart failure.

Bibliography is available at Expert Consult.

101.4 Transient  Tachypnea  of  the  Newborn

Namasivayam Ambalavanan and Waldemar A. Carlo

Transient tachypnea is most common after term cesarean delivery. It is characterized by the early onset of tachypnea, sometimes with retrac- tions, or expiratory grunting and, occasionally, cyanosis that is relieved by minimal oxygen supplementation (< 40%). Most infants recover rapidly, usually within 3 days. The chest generally sounds clear without crackles or wheeze, and the chest radiograph shows prominent pulmo- nary vascular markings, fluid in the intralobar fissures, overaeration, flat diaphragms, and, rarely, small pleural effusions. Hypercapnia and acidosis are uncommon. Distinguishing the disease from RDS and other respiratory disorders (e.g., pneumonia) may be difficult, and transient tachypnea is frequently a diagnosis of exclusion; the distinc- tive features of transient tachypnea are rapid recovery of the infant and the absence of radiographic findings for RDS (hypoaeration, diffuse reticulogranular pattern, air bronchograms) and other lung disorders. The syndrome is believed to be secondary to slow absorption of fetal

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Chapter 101   Respiratory   Tract  Disorders  858.e1

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Ancora G, Lago P, Garetti E, et al: Efficacy and safety of continuous infusion of fentanyl for pain control in preterm newborns on mechanical ventilation, J Pediatr 163:645–651, 2013. Armangil D, Yurdakök M, Korkmaz A, et al: Inhaled beta-2 agonist salbutamol for the treatment of transient tachypnea of the newborn, J Pediatr 159:398–403,

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Askie LM: Optimal oxygen saturations in preterm infants: a moving target, Curr Opin Pediatr 25:188–192, 2013. Bancalari E, Claure N: Oxygen targets and outcomes in premature infants, JAMA 309:2161–2162, 2013. Batton B, Zhu X, Fanaroff J, et al: Blood pressure, anti-hypotensive therapy, and neurodevelopment in extremely preterm infants, J Pediatr 154:351–357, 2009. Been JV, Kornelisse RF, Rours IG, et al: Early postnatal blood pressure in preterm

infants: effects of chorioamnionitis and timing of antenatal steroids, Pediatr Res 66:571–576, 2009. Benders MJNL, Groenendaal F, Van Bel F, et al: Brain development of the preterm neonate after neonatal hydrocortisone treatment for chronic lung disease, Pediatr Res 66:555–559, 2009. Bidegain M, Greenberg R, Simmons C, et al: Vasopressin for refractory hypotension in extremely low birth weight infants, J Pediatr 157:502–504, 2010. Bishop NB, Stankiewicz P, Steinhorn RH: Alveolar capillary dysplasia, Am J Respir Crit Care Med 184:172–179, 2011. The Boost II United Kingdom, Australia, and New Zealand Collaborative Groups:

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Engle WA; American Academy of Pediatrics Committee on Fetus and Newborn:

Surfactant-replacement therapy for respiratory distress in the preterm and term neonate, Pediatrics 121:419–432, 2008. FischerHS:BührerC:Avoidingendotrachealventilationtopreventbronchopulmonary dysplasia: a meta-analysis, Pediatrics 132:e1351–e1360, 2013. Göpel W, Kribs A, Ziegler A, et al: Avoidance of mechanical ventilation by surfactant treatment of spontaneously breathing preterm infants (AMV): an open-label, randomized, controlled trial, Lancet 378:1627–1634, 2011. Greenough A, Dimitriou G, Prendergast M: Synchronized mechanical ventilation for respiratory support in newborn infants, Cochrane Database Syst Rev (1):CD000456, 2008. Hammerman C, Shchors I, Jacobson S, et al: Ibuprofen versus continuous indomethacin in premature neonates with patent ductus arteriosus: is the difference in the mode of administration?, Pediatr Res 64:291–297, 2008. Hamvas A, Cole FS, Nogee LM: Genetic disorders of surfactant proteins, Neonatology 91:311–317, 2007. Hibbs AM, Walsch MC, Martin RJ, et al: One-year respiratory outcomes of preterm infants enrolled in the nitric oxide (to prevent) chronic lung disease trial, J Pediatr 153:525–529, 2008.

Hitzert MM, Benders MJNL, Roescher AM, et al: Hydrocortisone vs. dexamethasone treatment for bronchopulmonary dysplasia and their effects on general movement in preterm infants, Pediatr Res 71:100–106, 2012. Hosono S, Mugishima H, Fujita H, et al: Blood pressure and urine output during

the first 120 h of life in infants born at less than 29 weeks’ gestation related to umbilical cord milking, Arch Dis Child Fetal Neonatal Ed 94:F328–F331, 2009. Inatomi T, Oue S, Ogihara T, et al: Antenatal exposure to urea plasma species exacerbates bronchopulmonary dysplasia synergistically with subsequent prolonged mechanical ventilation in preterm infants, Pediatr Res 71:267–273,

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Jegatheesan P, Ianus V, Buchh B, et al: Increased indomethacin dosing for persistent patent ductus arteriosus in preterm infants: a multicenter, randomized, controlled trial, J Pediatr 153:183–189, 2008. Kamlin COF, Davis PG: Long versus short inspiratory times in neonates receiving mechanical ventilation, Cochrane Database Syst Rev (4):CD004503, 2004. Kelly BA, Lewandowski AJ, Worton SA, et al: Antenatal glucocorticoid exposure and long-term alterations in aortic function and glucose metabolism, Pediatrics 129:e1282–e1290, 2012. Kinsella JP, Cutter GR, Walsh WF, et al: Early inhaled nitric oxide therapy in premature newborns with respiratory failure, N Engl J Med 355:354–364, 2006. Lavoie PM, Pham C, Jang KL: Heritability of bronchopulmonary dysplasia, defined according to the consensus statement of the National Institutes of Health, Pediatrics 122:479–485, 2008.

Levit O, Jiang Y, Bizzarro MJ, et al: The genetic susceptibility to respiratory distress syndrome, Pediatr Res 66:693–697, 2009. Machado LU, Fiori HH, Baldisserotto M, et al: Surfactant deficiency in transient tachypnea of the newborn, J Pediatr 159:750–754, 2011. Manley BJ, Owen LS, Doyle LW, et al: High-flow nasal cannulae in very preterm infants after extubation, N Engl J Med 369:1425–1433, 2013. Meneses J, Bhandari V, Alves JG, et al: Noninvasive ventilation for respiratory distress syndrome: a randomized controlled trial, Pediatrics 127:300–307,

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Mercier JC, Hummler H, Durrmeyer X, et al: Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomized controlled trial, Lancet 376:346–352, 2010. Morley CJ, Davis PG, Doyle LW, et al: Nasal CPAP or intubation at birth for very preterm infants, N Engl J Med 358:700–708, 2008. Ng PC, Lee CH, Bnur FL, et al: A double-blind, randomized, controlled study of a “stress dose” of hydrocortisone for rescue treatment of refractory hypotension in preterm infants, Pediatrics 117:367–375, 2006. Polin RA, Bateman D: Oxygen-saturation targets in preterm infants, N Engl J Med 368:2141–2142, 2013. Roberts D, Dalziel S: Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth, Cochrane Database Syst Rev (3):CD004454, 2006. Schmidt B, Whyte RK, Asztalos EV, et al: Effects of targeting higher vs lower arterial oxygen saturations on death or disability in extremely preterm infants, JAMA 309:2111–2120, 2013. Schmölzer GM, Kuma M, Pichler G, et al: Non-invasive versus respiratory support in preterm infants in the delivery room; systematic review and meta-analysis, BMJ 342:d1696, 2011. Schmölzer GM, Te Pas AB, Davis PG, et al: Reducing lung injury during neonatal

resuscitation of preterm infants, J Pediatr 153:741–745, 2008.

Shah SS, Ohlsson A, Halliday H, et al: Inhaled versus systemic corticosteroids for the treatment of chronic lung disease in ventilated very low birth weight preterm infants (review), Cochrane Database Syst Rev (4):CD002057, 2012. Shah PS, Shah VS: Continuous heparin infusion to prevent thrombosis and catheter occlusion in neonates with peripherally placed percutaneous central venous catheters, Cochrane Database Syst Rev (2):CD002772, 2008. Sosenko IRS, Bancalari E: NO for preterm infants at risk of bronchopulmonary dysplasia, Lancet 376:308–310, 2010. Sosenko IRS, Fajardo F, Claure N, et al: Timing of patent ductus arterious treatment and respiratory outcome in premature infants: a double-blind randomized controlled trial, J Pediatr 160:929–935, 2012. Stälnacke J, Heijtz RD, Norberg H, et al: Cognitive outcome in adolescents and young adults after repeat courses of antenatal corticosteroids, J Pediatr 163:441–446, 2013. Stark AR, Carlo WA, Tyson JE, et al: Adverse effects of early dexamethasone treatment in extremely-low-birth-weight infants, N Engl J Med 344:95–101,

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Stevens TP, Blennow M, Myers EH, et al: Early surfactant administration with brief ventilation vs. selective surfactant and continued mechanical ventilation for preterm infants with or at risk for respiratory distress syndrome, Cochrane Database Syst Rev (4):CD003063, 2007.

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858.e2Chapter  101   Respiratory   Tract   Disorders

for preterm infants with or at risk for respiratory distress syndrome (review), Cochrane Database Syst Rev (4):CD003063, 2007. Stewart A, Brion LP, Primhak RA: Intravenous or enteral loop diuretics for preterm infants with (or developing) chronic lung disease, Cochrane Database Syst Rev (4):CD001453, 2011. Subramaniam P, Henderson-Smart DJ, Davis PG: Prophylactic nasal continuous positive airways pressure for preventing morbidity and mortality in very preterm infants, Cochrane Database Syst Rev (3):CD001243, 2005. SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network: Early CPAP versus surfactant in extremely preterm infants, N Engl J Med 362:1970–1978, 2010. SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Carlo WA, Finer NN, et al: Target ranges of oxygen saturation in extremely preterm infants, N Engl J Med 362:1959–1969, 2010. Tan A, Schulze AA, O’Donnell CPF, et al: Air versus oxygen for resuscitation of infants at birth, Cochrane Database Syst Rev (2):CD002273, 2005. Trembath A, Hornik CP, Clark R, et al: Comparative effectiveness of surfactant preparations in premature infants, J Pediatr 163:955–960, 2013. Vaucher YE, Peralta-Carcelen M, Finer NN, et al: Neurodevelopmental outcomes in the early CPAP and pulse oximetry trial, N Engl J Med 367:2495–2504, 2012.

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a pilot study, Pediatrics 121:e1310–e1318, 2008. Yoder BA, Stoddard RA, Li M, et al: Heated, humidified high-flow nasal cannula versus nasal CPAP for respiratory support in neonates, Pediatrics 131:e1482– e1490, 2013.

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Chapter 101   Respiratory   Tract  Disorders  859

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

Bibliography is available at Expert Consult.

101.5 Aspiration  of Foreign  Material  (Fetal Aspiration  Syndrome,  Aspiration  Pneumonia)

Waldemar A. Carlo

With fetal distress, infants often initiate vigorous respiratory move- ments in utero because of interference with the supply of oxygen through the placenta. Under such circumstances, the infant may aspi- rate amniotic fluid containing vernix caseosa, epithelial cells, meco- nium, blood, or material from the birth canal, which may block the smallest airways and interfere with alveolar exchange of oxygen and carbon dioxide. Pathogenic bacteria may accompany the aspirated material, and pneumonia may ensue, but even in noninfected cases, respiratory distress accompanied by radiographic evidence of aspira- tion is seen (Fig. 101-7). Postnatal pulmonary aspiration may also occur in newborn infants as a result of prematurity, tracheoesophageal fistula, esophageal and duodenal obstruction, gastroesophageal reflux, improper feeding prac- tices, and administration of depressant medicines. To avoid aspiration of gastric contents, the stomach should be aspirated using a soft cath- eter just before surgery or other major procedures that require anes- thesia or conscious sedation. The treatment of aspiration pneumonia is symptomatic and may include respiratory support and systemic anti- biotics (see Chapters 109.8 and 397). Gradual improvement generally occurs over 3-4 days.

101.6 Meconium  Aspiration

Namasivayam Ambalavanan and Waldemar A. Carlo

Meconium-stained amniotic fluid is found in 10-15% of births and usually occurs in term or postterm infants. Meconium aspiration syn- drome (MAS) develops in 5% of such infants; 30% require mechanical ventilation and 3-5% die. Usually, but not invariably, fetal distress and hypoxia occur before the passage of meconium into amniotic fluid. The infants are meconium stained and may be depressed and require resus- citation at birth. Figure 101-8 shows the pathophysiology of the MAS. Infants with MAS are at increased risk of persistent pulmonary hyper- tension (see Chapter 101.7).

CLINICAL MANIFESTATIONS

Either in utero or with the first breath, thick, particulate meconium is aspirated into the lungs. The resulting small airway obstruction may produce respiratory distress within the first hours, with tachypnea, retractions, grunting, and cyanosis observed in severely affected infants. Partial obstruction of some airways may lead to pneumome- diastinum, pneumothorax, or both. Overdistention of the chest may

pneumothorax, or both. Overdistention of the chest may Figure  101-7 Fetal  aspiration   syndrome  

Figure  101-7 Fetal  aspiration   syndrome   (aspiration   pneumonia). Note the coarse granular pattern with irregular aeration typical of fetal distress from the aspiration of material contained in amniotic fluid, such as vernix caseosa, epithelial cells, and meconium. (From Goodwin SR, Grave SA, Haberkern CM: Aspiration in intubated premature infants, Pediatrics 75:85–88, 1985.)

be prominent. The condition usually improves within 72 hr, but when its course requires assisted ventilation, it may be severe with a high risk for mortality. Tachypnea may persist for many days or even several weeks. The typical chest radiograph is characterized by patchy infil- trates, coarse streaking of both lung fields, increased anteroposterior diameter, and flattening of the diaphragm. A normal chest roentgeno- gram in an infant with severe hypoxemia and no cardiac malformation suggests the diagnosis of pulmonary hypertension (see Chapter 101.7).

PREVENTION

The risk of meconium aspiration may be decreased by rapid identifica- tion of fetal distress and initiation of prompt delivery in the presence of late fetal heart rate deceleration or poor beat-to-beat fetal heart rate variability. Despite initial enthusiasm for amnioinfusion, it does not reduce the risk of MAS, cesarean delivery, or other major indicators of maternal or neonatal morbidity. Intrapartum nasopharyngeal suction- ing in infants with meconium-stained amniotic fluid does not reduce the risk for MAS.

TREATMENT

Routine intubation to aspirate the lungs of vigorous infants born through meconium-stained fluid is not effective in reducing the MAS or other major adverse outcomes. Depressed infants (those with hypo- tonia, bradycardia, or decreased respiratory effort) are at higher risk of MAS and may benefit from endotracheal intubation and suction to remove meconium from the airway before the first breath in the deliv- ery room, but the data are inconclusive. Treatment of the MAS includes supportive care and standard man- agement for respiratory distress. The beneficial effect of mean airway pressure on oxygenation must be weighed against the risk of

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Chapter 101   Respiratory   Tract  Disorders  859.e1

Bibliography

Armangil D, Yurdakök M, Korkmaz A, et al: Inhaled beta-2 agonist salbutamol for the treatment of transient tachypnea of the newborn, J Pediatr 159:398–403,

2011.

Liem JJ, Huq SI, Ekuma O, et al: Transient tachypnea of the newborn may be an early clinical manifestation of wheezing symptoms, J Pediatr 151:29–33, 2007. Machado LU, Holmer H, Baldisserotto M, et al: Surfactant deficiency in transient tachypnea of the newborn, J Pediatr 159:750–754, 2011.

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860 Part  XII   The   Fetus  and  the  Neonatal  Infant

Physiologic meconium passage (particularly if postdates) Fetal compromise (hypoxia, cord compression, etc.) meconium
Physiologic meconium passage
(particularly if postdates)
Fetal compromise (hypoxia, cord
compression, etc.)
meconium passage
Meconium-stained amniotic fluid
Post-partum
In-utero
Continued
aspiration
gasping
compromise
Meconium aspiration
Peripheral
Proximal
Inflammatory
airway
airway
and chemical
obstruction
obstruction
pneumonitis
Remodeling of
pulmonary
vasculature
Partial
Complete
Acidosis
Hypoxemia
Ball-valve effect
Persistent
Hypercapnea
Atelectasis
pulmonary
hypertension
Air-trapping
V/Q mismatch
Air leaks

Figure 101-8 Pathophysiology   of   meconium  passage  and   the   meconium  aspiration   syndrome. V/Q , ventilation-perfusion ratio. (From Wiswell TE, Bent RC: Meconium staining and the meconium aspiration syndrome: unresolved issues, Pediatr Clin North Am 40:955– 981, 1993.)

pneumothorax. Administration of exogenous surfactant and/or iNO to infants with MAS and hypoxemic respiratory failure, or pulmonary hypertension requiring mechanical ventilation, decreases the need for ECMO, which is needed by the most severely affected infants who show no response to therapy. Severe meconium aspiration may be complicated by persistent pulmonary hypertension. Patients with MAS that is refractory to conventional mechanical ventilation may benefit from HFV or ECMO (see Chapter 101.7).

PROGNOSIS

The mortality rate of meconium-stained infants is considerably higher than that of nonstained infants. The decline in neonatal deaths caused by MAS during the last decades is related to improvements in obstetric and neonatal care. Residual lung problems are rare, but include symp- tomatic cough, wheezing, and persistent hyperinflation for up to 5-10 yr. The ultimate prognosis depends on the extent of CNS injury from asphyxia and the presence of associated problems such as pulmo- nary hypertension.

Bibliography is available at Expert Consult.

101.7 Persistent  Pulmonary Hypertension  of  the  Newborn  (Persistent  Fetal  Circulation)

Namasivayam Ambalavanan and Waldemar A. Carlo

Persistent pulmonary hypertension of the newborn (PPHN) occurs mostly in in term and postterm infants. Predisposing factors include birth asphyxia, MAS, early-onset sepsis, RDS, hypoglycemia, polycy- themia, maternal use of nonsteroidal antiinflammatory drugs with in

↑ PVR SVR ↓ Pulmonay Vascular (structural changes; altered reactivity to dilator and constrictor stimuli)
↑ PVR
SVR ↓
Pulmonay Vascular
(structural changes;
altered reactivity to
dilator and constrictor
stimuli)
Heart
↑ right to left shunting
at PDA and FO
(RV pressure
overload,
hypotension, and
LV dysfunction)
Hypoxia,
hypercarbia,
acidosis
Lung
↓ lung volume
↓ compliance
↑ intrapulmonary shunt

Figure  101-9 Cardiopulmonary   interactions   in  PPHN. FO, foramen ovale; LV, left ventricular; PDA, patent ductus arteriosus; PVR, pulmo- nary vascular resistance; RV, right ventricular; SVR, systemic vascular resistance. (From Kinsella JP, Abman SH: Recent developments in the pathophysiology and treatment of persistent pulmonary hypertension of the newborn, J Pediatr 126:853–864, 1995.)

utero constriction of the ductus arteriosus, maternal late trimester use of selective serotonin reuptake inhibitors, and pulmonary hypoplasia caused by diaphragmatic hernia, amniotic fluid leak, oligohydramnios, or pleural effusions. PPHN is often idiopathic. Some patients with PPHN have low plasma arginine and NO metabolite concentrations and polymorphisms of the carbamoyl phosphate synthase gene, find- ings suggestive of a possible subtle defect in NO production. The inci- dence is 1/500-1,500 live births with a wide variation among clinical centers.

PATHOPHYSIOLOGY

Persistence of the fetal circulatory pattern of right-to-left shunting through the PDA and foramen ovale after birth is a result of excessively high PVR. Fetal PVR is usually elevated relative to fetal systemic or postnatal pulmonary pressure. This fetal state normally permits shunt- ing of oxygenated umbilical venous blood to the left atrium (and brain) through the foramen ovale, from which it bypasses the lungs through the ductus arteriosus and passes to the descending aorta. After birth, PVR normally declines rapidly as a consequence of vasodilation sec- ondary to lung inflation, a rise in postnatal Pao 2 , a reduction in Paco 2 , increased pH, and release of vasoactive substances. Increased neonatal PVR may be (1) maladaptive from an acute injury (not demonstrating normal vasodilation in response to increased oxygen and other changes after birth); (2) the result of increased pulmonary artery medial muscle thickness and extension of smooth muscle layers into the usually non- muscular, more peripheral pulmonary arterioles in response to chronic fetal hypoxia; (3) a consequence of pulmonary hypoplasia (diaphrag- matic hernia, Potter syndrome); or (4) obstructive as a result of poly- cythemia or total anomalous pulmonary venous return, or of alveolar capillary dysplasia, which is a lethal autosomal recessive disorder char- acterized by thickened alveolar septa, increased muscularization of the pulmonary arterioles, a reduced number of capillaries, and misalign- ment of the intrapulmonary veins. Regardless of etiology, profound hypoxemia from right-to-left shunting and normal or elevated Paco 2 are present (Fig. 101-9).

CLINICAL MANIFESTATIONS

Infants with PPHN usually become ill in the delivery room or within the 1st 12 hr after birth. PPHN related to polycythemia, idiopathic

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Chapter 101   Respiratory   Tract  Disorders  860.e1

Bibliography

Vain NE, Szyld EG, Prudent LM: Oropharyngeal and nasopharyngeal suctioning of meconium-stained neonates before delivery of their shoulders: multicentre, randomized controlled trial, Lancet 364:597–602, 2004.

Wiswell TE, Gannon CM, Jacob J, et al: Delivery room management of the apparently vigorous meconium-stained neonate: results of the multicenter, international collaborative trial, Pediatrics 105:1–7, 2000.

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Chapter 101   Respiratory   Tract  Disorders  861

causes, hypoglycemia, hypothermia, or asphyxia may result in severe cyanosis with tachypnea, although initial signs of respiratory distress may be minimal. Infants who have PPHN associated with meconium aspiration, group B streptococcal pneumonia, diaphragmatic hernia, or pulmonary hypoplasia usually exhibit cyanosis, grunting, flaring, retractions, tachycardia, and shock. Multiorgan involvement may be present (see Table 98-1 in Chapter 98). Myocardial ischemia, papillary muscle dysfunction with mitral and tricuspid regurgitation, and biven- tricular dysfunction produce cardiogenic shock with decreases in pulmonary blood flow, tissue perfusion, and oxygen delivery. The hypoxemia is often labile and out of proportion to the findings on chest radiographs.

DIAGNOSIS

PPHN should be suspected in all term infants who have cyanosis independent of a history of fetal distress, intrauterine growth restric- tion, meconium-stained amniotic fluid, hypoglycemia, polycythemia, diaphragmatic hernia, pleural effusions, or birth asphyxia. Hypoxemia is universal and is at least intermittently unresponsive to 100% oxygen given by oxygen hood, but it may respond transiently to hyperoxic hyperventilation administered after endotracheal intubation or to the application of a bag and mask. A Pao 2 or oxygen saturation gradient between a preductal (right radial artery) and a postductal (umbilical artery) site of blood sampling suggests right-to-left shunting through the ductus arteriosus. Foramen ovale shunting does not lead to a Pao 2 or oxygen saturation gradient. Real-time echocardiography combined with Doppler flow imaging is very helpful in evaluating PPHN. Systolic flattening of the interven- tricular septum as the right ventricular systolic pressure approaches the left ventricular systolic pressure can be used to estimate the degree of pulmonary hypertension. The peak velocity of the tricuspid valve regurgitation jet, when present, yields a quantitative estimate of the right ventricular systolic pressure. Likewise, the direction and velocity of a shunt across the PDA provides a quantitative comparison between the aortic and pulmonary artery pressures. In advanced cases, right- to-left or bidirectional shunting across a PDA and/or a patent foramen ovale can be observed. In asphyxia-associated and idiopathic PPHN, chest x-ray findings are normal, whereas in PPHN associated with pneumonia and diaphragmatic hernia, parenchymal opacification and bowel and/or liver in the chest, respectively, are seen. The differential diagnosis of PPHN includes cyanotic heart disease (especially obstructed total anomalous pulmonary venous return) congenital surfactant deficiency syndromes, alveolar-capillary dysplasia, and the associated etiologic entities that predispose to PPHN (hypoglycemia, polycythemia, sepsis, hypothermia).

TREATMENT

Therapy is directed toward correcting any predisposing condition (hypoglycemia, polycythemia, others) and improving poor tissue oxy- genation. The response to therapy is often unpredictable, transient, and complicated by the adverse effects of drugs or mechanical ventilation. Initial management includes oxygen administration and correction of acidosis, hypotension, and hypercapnia. Persistent hypoxemia should be managed with intubation and mechanical ventilation. The optimal approach to mechanical ventilation has evolved. In the pre-iNO era, treatment of severe PPHN consisted of instituting mechanical ventilation with 1 or more of the following: muscle relax- ants, hyperventilation, and alkalinization with sodium bicarbonate. These therapies may lead to complications associated with hypocarbia including reduced cerebral blood flow, cerebral palsy, and deafness; volutrauma; and impaired cardiac function which have resulted in less use of these practices. Currently, infants with PPHN are usually managed without hyperventilation and/or alkalinization. In skilled hands, “gentle ventilation” with normocarbia or permissive hypercar- bia and avoidance of hypoxemia result in excellent outcomes and a low incidence of chronic lung disease and ECMO use. Because of their instability and ability to fight the ventilator, new- borns with PPHN usually require sedation. The use of paralytic agents

is controversial and reserved for the newborn that cannot be treated with sedatives alone. Muscle relaxants may promote atelectasis of dependent lung regions and ventilation–perfusion mismatch and may be associated with an increased risk of death. Inotropic therapy is frequently needed to support blood pressure and perfusion. Whereas dopamine is frequently used as a first-line agent, other agents, such as dobutamine, epinephrine, and milrinone may be helpful when myocardial contractility is poor. Some of the sickest newborns with PPHN demonstrate hypotension refractory to vasopressor administration. This results from desensitization of the cardiovascular system to catecholamines by overwhelming illness and relative adrenal insufficiency. Hydrocortisone rapidly upregulates car- diovascular adrenergic receptor expression and serves as a hormone substitute in cases of adrenal insufficiency. NO is an endothelium-derived signaling molecule that relaxes vas- cular smooth muscle and can be delivered to the lung by inhalation. Use of iNO reduces the need for ECMO support by approximately 40%. The optimal starting dose is 20 ppm. Higher doses have not been shown to be more effective and are associated with side effects includ- ing methemoglobinemia and increased levels of nitrogen dioxide, a pulmonary irritant. Most newborns require iNO for <5 days. Although NO has been used as long-term therapy in children and adults with primary pulmonary hypertension, prolonged dependency is rare in neonates and suggests the presence of lung hypoplasia, congenital heart disease, or alveolar capillary dysplasia. The maximal safe dura- tion of iNO therapy is unknown. The dose can be weaned to 5 ppm after 6-24 hr of therapy. The dose can then be weaned slowly and dis- continued when the Fio 2 is <0.6 and the iNO dose is 1 ppm. Abrupt discontinuation should be avoided as it may cause rebound pulmonary hypertension. iNO should be used only at institutions that offer ECMO support or have the capability of transporting an infant on iNO therapy if a referral for ECMO is necessary. Some infants with PPHN do not respond adequately to iNO. Therapy with continuous inhaled or intra- venous prostacyclin (prostaglandin I 2 ) has improved oxygenation and outcome in infants with PPHN. The safety and efficacy of sildenafil (a type 5 phosphodiesterase inhibitor) in newborns with PPHN is under investigation; initial results are promising.

Extracorporeal Membrane Oxygenation

In 5-10% of patients with PPHN, the response to 100% oxygen, mechanical ventilation, and drugs is poor. In such patients, two param- eters have been used to predict mortality, the alveolar-arterial oxygen

gradient (Pao 2 Pao 2 ), and the oxygenation index, which is calculated as follows: Fio 2 (as %) × MAP/Pao 2. An alveolar–arterial gradient > 620 for 8-12 hr and an oxygenation index > 40 that is unresponsive to iNO predict a high mortality rate

( >80%) and are indications for ECMO. ECMO is used to treat carefully

selected, severely ill infants with hypoxemic respiratory failure caused

by RDS, meconium aspiration pneumonia, congenital diaphragmatic hernia, PPHN, or sepsis. ECMO is a form of cardiopulmonary bypass that augments systemic perfusion and provides gas exchange. Most experience has been with venoarterial bypass, which requires carotid artery ligation and the placement of large catheters in the right internal jugular vein and carotid artery. Venovenous bypass avoids carotid artery ligation and provides gas exchange, but it does not support cardiac output. Blood is initially pumped through the ECMO circuit at a rate that approxi- mates 80% of the estimated cardiac output, 150-200 mL/kg/min. Venous return passes through a membrane oxygenator, is rewarmed, and returns to the aortic arch in venoarterial ECMO and to the right atrium in venovenous ECMO. Venous oxygen saturation values are used to monitor tissue oxygen delivery and subsequent extraction for infants undergoing venoarterial ECMO, whereas arterial oxygen satu- ration values are used to monitor oxygenation for infants receiving venovenous ECMO. Because ECMO requires complete heparinization to prevent clot- ting in the circuit, it cannot be used in patients with or at high risk for IVH (weight <2 kg, gestational age < 34 wk). In addition, infants for whom ECMO is being considered should have reversible lung

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862 Part  XII   The   Fetus  and  the  Neonatal  Infant

disease, no signs of systemic bleeding, an absence of severe asphyxia or lethal malformations, and they should have been ventilated for less than 10 days. Complications of ECMO include thromboembo- lism, air embolization, bleeding, stroke, seizures, atelectasis, choles- tatic jaundice, thrombocytopenia, neutropenia, hemolysis, infectious complications of blood transfusions, edema formation, and systemic hypertension.

PROGNOSIS

Survival in patients with PPHN varies with the underlying diagnosis. The long-term outcome for infants with PPHN is related to the associ- ated hypoxic-ischemic encephalopathy and the ability to reduce PVR. The long-term prognosis for infants who have PPHN and who survive after treatment with hyperventilation is comparable to that for infants who have underlying illnesses of equivalent severity (birth asphyxia, hypoglycemia, polycythemia). The outcome for infants with PPHN who are treated with ECMO is also favorable; > 80-90% survive, and 60-75% of survivors appear normal at 1-3.5 yr of age. Survival of infants born with congenital diaphragmatic hernia (CDH) has increased over the past 10 yr to 67%; benchmark institutions are reporting survival rates > 80%. Those infants with CDH who require ECMO continue to have a lower survival than the general neonatal population undergoing ECMO (~50%).

Bibliography is available at Expert Consult.

101.8 Diaphragmatic  Hernia

Akhil Maheshwari and Waldemar A. Carlo

A diaphragmatic hernia is defined as a communication between the

abdominal and thoracic cavities with or without abdominal contents

highly variable, ranging from a small hole to complete agenesis of this area of the diaphragm.

CONGENITAL DIAPHRAGMATIC HERNIA (BOCHDALEK) Pathology and Etiology

Although CDH is characterized by a structural diaphragmatic defect, a major limiting factor for survival is the associated pulmonary hypo- plasia. Lung hypoplasia was initially thought to be solely caused by the compression of the lung from the herniated abdominal contents, which impaired lung growth. However, emerging evidence indicates that pul- monary hypoplasia, at least in some cases, may precede the develop- ment of the diaphragmatic defect. Pulmonary hypoplasia is characterized by a reduction in pulmonary mass and the number of bronchial divisions, respiratory bronchioles, and alveoli. The pathology of pulmonary hypoplasia and CDH includes abnormal septa in the terminal saccules, thickened alveoli, and thick- ened pulmonary arterioles. Biochemical abnormalities include relative surfactant deficiencies, increased glycogen in the alveoli, and decreased levels of phosphatidylcholine, total DNA, and total lung protein, all of which contribute to limited gas exchange.

Epidemiology

The incidence of CDH is between 1/2,000 and 1/5,000 live births, with females affected twice as often as males. Defects are more common on the left (85%) and are occasionally (< 5%) bilateral. Pulmonary hypo- plasia and malrotation of the intestine are part of the lesion, not associ- ated anomalies. Most cases of CDH are sporadic, but familial cases have been reported. Associated anomalies have been reported in up to 30% of cases; these include CNS lesions, esophageal atresia, omphalo- cele, and cardiovascular lesions. CDH is recognized as part of several chromosomal syndromes: trisomy 21, trisomy 13, trisomy 18, Fryns, Brachmann-de Lange, Pallister-Killian, and Turner.

in

the thorax (Fig. 101-10). The etiology is usually congenital but may

be

traumatic. The symptoms and prognosis depend on the location of

Diagnosis and Clinical Presentation

the defect and associated anomalies. The defect may be at the esopha- geal hiatus (hiatal), paraesophageal (adjacent to the hiatus), retroster- nal (Morgagni), or at the posterolateral (Bochdalek) portion of the diaphragm. The term congenital diaphragmatic hernia typically refers

to the Bochdalek form. These lesions may cause significant respiratory

distress at birth, can be associated with other congenital anomalies, and have significant mortality and long-term morbidity. The overall survival from the CDH Study Group is 67%. The Bochdalek hernia accounts for up to 90% of the hernias seen in the newborn period, with 80-90% occurring on the left side. The Morgagni hernia accounts for 2-6% of congenital diaphragmatic defects. The size of the defect is

congenital diaphragmatic defects. The size of the defect is Normal diaphragm A Bochdalek diaphragmatic defect with

Normal diaphragm

A

Bochdalek diaphragmatic defect with herniation of small lung

B

Figure101-10 A, A normal diaphragm separating the abdominal and thoracic cavity. B, Diaphragmatic hernia with a small lung and abdomi- nal contents in the thoracic cavity.

CDH can be diagnosed on prenatal ultrasonography (between 16 and 24 wk of gestation) in > 50% of cases. High-speed fetal MRI can further define the lesion. Findings on ultrasonography may include polyhy- dramnios, chest mass, mediastinal shift, gastric bubble or a liver in the thoracic cavity, and fetal hydrops. Certain imaging features may predict outcome; these include lung : head size ratio. Nonetheless, no definitive characteristic reliably predicts outcome. After delivery, a chest radio- graph is needed to confirm the diagnosis (Fig. 101-11). In some infants with an echogenic chest mass, further imaging is required. The dif- ferential diagnosis may include other diaphragm disorders such as eventration, a cystic lung lesion (pulmonary sequestration, cystic ade- nomatoid malformation), and others. Arriving at the diagnosis early in pregnancy allows for prenatal counseling, possible fetal interventions, and planning for postnatal care. A referral to a center providing high-risk obstetrics, pediatric surgery, and tertiary care neonatology is advised. Careful evaluation for other anomalies should include echocardiography and amniocen- tesis. To avoid unnecessary pregnancy termination and unrealistic expectations, an experienced multidisciplinary group must carefully counsel the parents of a child diagnosed with a diaphragmatic hernia. Respiratory distress is a cardinal sign in babies with CDH. It may occur immediately after birth or there may be a “honeymoon” period of up to 48 hr during which the baby is relatively stable. Early respira- tory distress, within 6 hr after birth, is thought to be a poor prognostic sign. Respiratory distress is characterized clinically by tachypnea, grunting, use of accessory muscles, and cyanosis. Children with CDH may also have a scaphoid abdomen and increased chest wall diameter. Bowel sounds may also be heard in the chest with decreased breath sounds bilaterally. The point of maximal cardiac impulse may be dis- placed away from the side of the hernia if mediastinal shift has occurred. A chest x-ray and passage of a nasal gastric tube are all that is usually required to confirm the diagnosis. A small group of infants with CDH present beyond the neonatal period. Patients with a delayed presentation may experience vomiting

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Chapter 101   Respiratory   Tract  Disorders  862.e1

Bibliography

Baquero H, Soliz A, Neira F, et al: Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study, Pediatrics 117:1077–1083, 2006. Barrington KJ, Finer N: Inhaled nitric oxide for respiratory failure in preterm infants, Cochrane Database Syst Rev (3):CD000509, 2007. Finer N, Barrington KJ: Nitric oxide for respiratory failure in infants born at or near term, Cochrane Database Syst Rev (4):CD000399, 2006. Ibrahim YI, Ninnis JR, Hopper AO, et al: Inhaled nitric oxide therapy increases blood nitrite, nitrate, and S-nitrosohemoglobin concentrations in infants with pulmonary hypertension, J Pediatr 160:245–251, 2012. Kieler H, Artama M, Engeland A, et al: Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the

newborn: population based cohort study from the five Nordic countries, BMJ 344:d8012, 2012.

Kulik TJ, Rhein LM, Mullen MP: Pulmonary arterial hypertension in infants with chronic lung disease: will we ever understand it?, J Pediatr 157(2):186–190,

2010.

Mugford M, Elbourne D, Field D: Extracorporeal membrane oxygenation for severe respiratory failure in newborn infants, Cochrane Database Syst Rev (16):CD001340, 2008. Sen P, Thakur N, Stockton DW, et al: Expanding the phenotype of alveolar capillary dysplasia (ACD), J Pediatr 145:646–651, 2004.

Steinhorn RH, Kinsella JP, Pierce C, et al: Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension, J Pediatr 155:841–847,

2009.

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Chapter 101   Respiratory   Tract  Disorders  863

  ◆   Respiratory   Tract  Disorders  863 Figure  101-11 This   chest   radiograph

Figure  101-11 This   chest   radiograph   shows   a   stomach,   nasogastric   tube,   and   small  bowel   contents   in  the   thoracic   cavity,   consistent   with   a  CDH.

as a result of intestinal obstruction or mild respiratory symptoms. Occasionally, incarceration of the intestine proceeds to ischemia with sepsis and shock. Unrecognized diaphragmatic hernia is a rare cause of sudden death in infants and toddlers. Group B streptococcal sepsis has been associated with delayed onset of symptoms and a CDH (often right side).

Treatment Initial  Management

Aggressive respiratory support is often needed in children with CDH. This includes rapid endotracheal intubation, sedation, and possibly paralysis. Arterial (preductal and postductal) and central venous (umbilical) lines are mandated, as are a urinary catheter and naso- gastric tube. A preductal arterial oxygen saturation (Spo 2 ) value 85% should be the minimum goal. Prolonged mask ventilation in the deliv- ery room, which enlarges the stomach and small bowel and thus makes oxygenation more difficult, must be avoided. Volutrauma is a significant problem. Gentle ventilation with permissive hypercapnia reduces lung injury, need for ECMO, and mortality. Factors that con- tribute to pulmonary hypertension (hypoxia, acidosis, hypothermia) should be avoided. Echocardiography is important to guide therapeu- tic decisions by measuring pulmonary and system vascular pressures and defining the presence of cardiac dysfunction. Routine use of ino- tropes is indicated in the presence of left ventricular dysfunction. Babies with CDH may be surfactant deficient. Although surfactant is commonly used, no study has proven that it is beneficial in treatment of CDH.

Ventilation  Strategies

Conventional mechanical ventilation, HFOV, and ECMO are the 3 main strategies to support respiratory failure in the newborn with CDH. The goal is to maintain oxygenation and carbon dioxide elimina- tion without inducing volutrauma. The first modality to be used is conventional ventilation. Hyperventilation to induce alkalosis and decrease ductal shunting has not proved effective and should be avoided. Permissive hypercapnia has reduced lung injury and mortality rates in several studies. HFOV can be used early to prevent lung injury by using lower airway pressures.

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

Extracorporeal  Membrane  Oxygenation

The availability of ECMO and the utility of preoperative stabilization have improved survival of babies with CDH. ECMO is the therapeutic option in children in whom conventional ventilation or conventional ventilation and HFOV fail. ECMO is most commonly used before repair of the defect. Several objective criteria for ECMO have been developed (see Chapter 101.7). Birthweight and the 5-min Apgar score may be the best predictors of outcome in patients treated with ECMO. The lower limit of weight for ECMO is 2,000 g. The duration of ECMO for neonates with diaphragmatic hernia is longer (7-14 days) than for those with persistent fetal circulation or meconium aspiration, and may last up to 2-4 wk. Timing of repair of the diaphragm while the infant receives ECMO is controversial; some experts prefer early repair to allow a greater duration of ECMO after the repair, whereas many defer repair until the infant has demonstrated the ability to tolerate weaning from ECMO. The recurrence of pulmo- nary hypertension is associated with a high mortality, and weaning from ECMO support should be cautious. If the patient cannot be weaned from ECMO after repair of CDH, options include discontinu- ing support and, in rare cases, lung transplantation.

Novel  Strategies for Infants  with  Congenital  Diaphragmatic  Hernia

The most reliable prenatal prognosticators of outcomes in children with CDH studied is fetal ultrasonography. A prospective study using this modality at 24-26 wk compared fetal lung : head size ratio. There were no survivors when the lung : head size ratio was < 1, and all babies with lung : head size ratio > 1.4 survived. A second important consid- eration was the presence of liver in the thoracic cavity, which is a poor prognostic feature. Human studies have shown no benefit for in utero repair of CDH. Tracheal occlusion in utero is based on the observation that in utero fetal lung fluid plays a critical role in lung growth and maturity. A deficiency of lung fluid results in pulmonary hypoplasia. Initial studies in affected fetuses have not demonstrated success, but new preliminary reports are showing some efficacy. Partial liquid ventilation after birth is an experimental therapy under investigation in adults and children with severe respiratory failure. Partial liquid ventilation increases FRC by recruiting collapsed alveoli, thereby improving ventilation– perfusion mismatches and compliance. It also may reduce lung injury and increase surfactant production.

Surgical  Repair

The ideal time to repair the diaphragmatic defect is under debate. Most experts wait at least 48 hr after stabilization and resolution of the pulmonary hypertension. Good relative indicators of stability are the requirement for conventional ventilation only, a low peak inspira- tory pressure, and a Fio 2 <50. If the newborn is on ECMO, an ability to be weaned from this support should be a consideration before surgical repair. In some centers, the repair is done with the cannulas in place; in other centers, the cannulas are removed. A subcostal approach is the most frequently used (Fig. 101-12). This allows for good visualization of the defect and, if the abdominal cavity cannot accommodate the herniated contents, a polymeric silicone (Silastic) patch can be placed. Both laparoscopic and thoracoscopic repairs have been reported, but these should be reserved for only the most stable infants. The defect size and amount of native diaphragm present are variable. Whenever possible, a primary repair using native tissue is performed. If the defect is too large, a porous polytetrafluoroethylene (Gore-Tex) patch is used.

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864 Part  XII   The   Fetus  and  the  Neonatal  Infant

A B
A
B

Diaphragm

defect

and  the  Neonatal  Infant A B Diaphragm defect Diaphragm with patch repair Figure 101-12 A, An

Diaphragm with

patch repair

Figure 101-12 A, An intraoperative picture of a CDH before repair. B, An intraoperative picture of a patch repair of a CDH.

There is a higher recurrence rate of CDH among children with patches (the patch does not grow as the child grows) than among those with repairs with native tissue. A loosely fitted patch may reduce the recurrence rates. Pulmonary hypertension must be monitored care- fully, and in some instances, a postoperative course of ECMO is needed. Other recognized complications include bleeding, chylotho- rax, and bowel obstruction.

Outcome and Long-Term Survival

Overall survival of liveborn infants with CDH is 67%. The incidence of spontaneous fetal demise is 7-10%. Relative predictors of a poor prognosis include an associated major anomaly, symptoms before 24 hr of age, severe pulmonary hypoplasia, herniation to the contra- lateral lung, and the need for ECMO. Pulmonary problems continue to be a source of morbidity for long- term survivors of CDH. Children receiving CDH repair who were studied at 6-11 yr of age demonstrated significant decreases in forced expiratory flow at 50% of vital capacity and decreased peak expiratory flow. Both obstructive and restrictive patterns can occur. Those without severe pulmonary hypertension and barotrauma do the best. Those at highest risk include children who required ECMO and patch repair, but the data clearly show that CDH survivors who did not require ECMO also need frequent attention to pulmonary issues. At discharge, up to 20% of infants require oxygen, but only 1-2% require oxygen past 1 yr of age. BPD is frequently documented radiographically but will improve as more alveoli develop and the child ages. Gastroesophageal reflux disease is reported in more than 50% of children with CDH. It is more common in those children whose dia- phragmatic defect involves the esophageal hiatus. Intestinal obstruc- tion is reported in up to 20% of children and may result from a midgut volvulus, adhesions, or a recurrent hernia that became incarcerated. Recurrent diaphragmatic hernia is reported in 5-20% in most series. Children with patch repairs are at highest risk. Children with CDH typically have delayed growth in the 1st 2 yr of life. Contributing factors include poor intake, gastroesophageal reflux disease, and a caloric requirement that may be higher because of the

and a caloric requirement that may be higher because of the Figure  101-13 A  

Figure  101-13 A   chest   radiograph  demonstrating   a   Morgagni   hernia.

energy required to breathe. Many children normalize and “catch up” in growth by the time they are 2 yr old. Neurocognitive defects are common and may result from the disease or the interventions. The incidence of neurologic abnormalities is higher in infants who require ECMO (67% vs. 24% of those who do not). The abnormalities are similar to those seen in neonates treated with ECMO for other diagnoses and include transient and permanent developmental delay, abnormal hearing or vision, and seizures. Serious hearing loss may occur in up to 28% of children who underwent ECMO. The majority of neurologic abnormalities are classified as mild to moderate. Other long-term problems occurring in this population include pectus excavatum and scoliosis. Survivors of CDH repair, particularly those requiring ECMO support, have a variety of long-term abnor- malities that appear to improve with time but require close monitoring and multidisciplinary support.

Bibliography is available at Expert Consult.

101.9 Foramen of Morgagni  Hernia

Akhil Maheshwari and Waldemar A. Carlo

The anteromedial diaphragmatic defect through the foramen of Morgagni accounts for 2-6% of diaphragmatic hernias. Failure of the sternal and crural portions of the diaphragm to meet and fuse produces this defect. These defects are usually small, with a greater transverse than anteroposterior diameter, and are more commonly right-sided (90%) but may be bilateral (Fig. 101-13). The transverse colon or small intestine or liver is usually contained in the hernial sac. The majorities of children with these defects are asymptomatic and are diagnosed beyond the neonatal period. The diagnosis is usually made on chest radiograph when a child is evaluated for another reason. The antero- posterior radiograph shows a structure behind the heart, and a lateral film localizes the mass to the retrosternal area. Chest CT or MRI will confirm the diagnosis. When symptoms occur, they can be recurrent respiratory infections, cough, vomiting, or reflux; in rare instances, incarceration may occur. Repair is recommended for all patients, in view of the risk of bowel strangulation, and can be accomplished lapa- roscopically or by an open approach. Prosthetic material is rarely required.

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Chapter 101   Respiratory   Tract  Disorders  864.e1

Bibliography

Congenital Diaphragmatic Hernia Study Group: Surfactant replacement therapy on ECMO does not improve outcomes in neonates with congenital diaphragmatic hernia, J Pediatr Surg 39:1632–1637, 2004. Harrison MR, Keller RL, Hawgood SB, et al: A randomized trial of fetal endoscopic tracheal occlusion for severe congenital diaphragmatic hernia, N Engl J Med 349:1916–1924, 2003. Jaillard SM, Pierrat V, Dubois A, et al: Outcome at two years of infants with congenital diaphragmatic hernia: a population based study, Ann Thorac Surg 75:250–256, 2003. Keszler M: Congenital diaphragmatic hernia: not quite there yet, J Pediatr 163:15–16, 2013.

Konduri GG, Vohr B, Robertson C, et al: Early inhaled nitric oxide therapy for term and near-term newborn infants with hypoxic respiratory failure:

neurodevelopmental follow-up, J Pediatr 150:235–240, 2007. Morini F, Goldman A, Pierro A: Extracorporeal membrane oxygenation in infants with congenital diaphragmatic hernia: a systematic review of the evidence, Eur J Pediatr Surg 16:385–391, 2006. Rollins MD: Recent advances in the management of congenital diaphragmatic hernia, Curr Opin Pediatr 24:379–385, 2012. Van Meures K, Congenital Diaphragmatic Hernia Study Group: Is surfactant therapy beneficial in the treatment of the term newborn infant with congenital diaphragmatic hernia?, J Pediatr 145:312–316, 2004.

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Chapter 101   Respiratory   Tract  Disorders  865

101.10 Paraesophageal  Hernia

Akhil Maheshwari and Waldemar A. Carlo

Paraesophageal hernia is differentiated from hiatal hernia in that the gastroesophageal junction is in the normal location. The herniation of the stomach alongside or adjacent to the gastroesophageal junction is prone to incarceration with strangulation and perforation. A previous Nissen fundoplication and other diaphragmatic procedures are risk factors. This unusual diaphragmatic hernia should be repaired promptly after identification.

101.11 Eventration

Akhil Maheshwari and Waldemar A. Carlo

Eventration of the diaphragm is an abnormal elevation, consisting of a thinned diaphragmatic muscle that causes elevation of the entire hemidiaphragm or, more commonly, the anterior aspect of the hemi- diaphragm. This elevation produces a paradoxical motion of the affected hemidiaphragm. Most eventrations are asymptomatic and do not require repair. A congenital form is the result of either incomplete development of the muscular portion or central tendon or abnormal development of the phrenic nerves. Congenital eventration may affect lung development, but it has not been associated with pulmonary hypoplasia. The differential diagnosis includes diaphragmatic paraly- sis, diaphragmatic hernia, traction injury, and iatrogenic injury after heart surgery. Eventration is also associated with pulmonary sequestra- tion, congenital heart disease, and chromosomal trisomies. Most even- trations are asymptomatic and do not require repair. The indications for surgery include continued need for mechanical ventilation, recur- rent infections, and failure to thrive. Large or symptomatic eventra- tions can be repaired by plication through an abdominal or thoracic approach that is minimally invasive.

Bibliography is available at Expert Consult.

101.12 Extrapulmonary  Air  Leaks  (Pneumothorax,  Pneumomediastinum,  Pulmonary  Interstitial  Emphysema,  Pneumopericardium)

Waldemar A. Carlo

Asymptomatic pneumothorax, usually unilateral, is estimated to occur in 1-2% of all newborn infants; symptomatic pneumothorax and pneu- momediastinum are less common (see Chapter 94). The incidence of pneumothorax is increased in infants with lung diseases such as meco- nium aspiration and RDS; in those who receive assisted ventilation, especially if high ventilator support is necessary; and in infants with urinary tract anomalies or oligohydramnios.

ETIOLOGY AND PATHOPHYSIOLOGY

The most common cause of pneumothorax is overinflation resulting in alveolar rupture. It may be “spontaneous” or caused by underlying pulmonary disease, such as lobar emphysema or rupture of a congeni- tal lung cyst or pneumatocele, to trauma, or to a “ball-valve” type of bronchial or bronchiolar obstruction resulting from aspiration. Pneumothorax associated with pulmonary hypoplasia is common, tends to occur during the 1st few hr after birth, and is caused by reduced alveolar surface area and poorly compliant lungs. It is associ- ated with disorders of decreased amniotic fluid volume (Potter syn- drome, renal agenesis, renal dysplasia, chronic amniotic fluid leak), decreased fetal breathing movement (oligohydramnios, neuromus- cular disease), pulmonary space-occupying lesions (diaphragmatic

hernia, pleural effusion, chylothorax), and thoracic abnormalities (thoracic dystrophies). Gas from a ruptured alveolus escapes into the interstitial spaces of the lung, where it may cause interstitial emphysema or dissect along the peribronchial and perivascular connective tissue sheaths to the hilum of the lung. If the volume of escaped air is great enough, it may collect in the mediastinal space (pneumomediastinum) or rupture into the pleural space (pneumothorax), subcutaneous tissue (subcutane- ous emphysema), peritoneal cavity (pneumoperitoneum), and/or pericardial sac (pneumopericardium). Rarely, increased mediastinal pressure may compress the pulmonary veins at the hilum and thereby interfere with pulmonary venous return to the heart and cardiac output. On occasion, air may embolize into the circulation (pulmonary air embolism) and produce cutaneous blanching, air in intravascular cath- eters, an air-filled heart and vessels on chest roentgenograms, and death. Tension pneumothorax occurs if an accumulation of air within the pleural space is sufficient to elevate intrapleural pressure above atmo- spheric pressure. Unilateral tension pneumothorax results in impaired ventilation not only in the ipsilateral lung but also in the contralateral lung owing to a shift in the mediastinum toward the contralateral side. Compression of the vena cava and torsion of the great vessels may interfere with venous return.

CLINICAL MANIFESTATIONS

The physical findings of a clinically asymptomatic pneumothorax are hyperresonance and diminished breath sounds over the involved side of the chest with or without tachypnea. Symptomatic pneumothorax is characterized by respiratory distress, which varies from merely high respiratory rate to severe dyspnea, tachypnea, and cyanosis. Irritability and restlessness or apnea may be the earliest signs. The onset is usually sudden but may be gradual; an infant may rapidly become critically ill. The chest may appear asym- metric with an increased anteroposterior diameter and bulging of the intercostal spaces on the affected side; other signs may be hyperreso- nance and diminished or absence of breath sounds. The heart is displaced toward the unaffected side, resulting in displacement of the cardiac apex and point of maximal impulse of the heart. The diaphragm is displaced downward, as is the liver with right-sided pneu- mothorax, and may result in abdominal distention. Because pneumo- thorax may be bilateral in approximately 10% of patients, symmetry of findings does not rule it out. In tension pneumothorax, signs of shock may be noted. Pneumomediastinum can occur in patients with pneumothorax and is usually asymptomatic. The degree of respiratory distress depends on the amount of trapped gas. If it is great, bulging of the midthoracic area is observed, the neck veins are distended, and blood pressure is low. The last 2 findings are a result of tamponade of the systemic and pulmonary veins. Although often asymptomatic, subcu- taneous emphysema in newborn infants is almost pathognomonic of pneumomediastinum. Pulmonary interstitial emphysema may precede the development of a pneumothorax or may occur independently and lead to increasing respiratory distress as a result of decreased compliance, hypercapnia, and hypoxemia. Hypoxemia is caused by an increased alveolar–arterial oxygen gradient and intrapulmonary shunting. Progressive enlarge- ment of blebs of gas may result in cystic dilation and respiratory deterioration resembling pneumothorax. In severe cases, pulmonary interstitial emphysema precedes the development of BPD. Avoidance of high inspiratory or mean airway pressures may prevent the develop- ment of pulmonary interstitial emphysema. Treatment may include bronchoscopy in patients with evidence of mucous plugging, selective intubation and ventilation of the uninvolved bronchus, oxygen, general respiratory care, and HFV.

DIAGNOSIS

Pneumothorax and other air leaks should be suspected in newborn infants who show signs of respiratory distress, are restless or irritable, or have a sudden change in condition. The diagnosis of pneumothorax is established by radiography, with the edge of the collapsed

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Chapter 101   Respiratory   Tract  Disorders  865.e1

Bibliography

Boloker J, Bateman DA, Wung JT, et al: Congenital diaphragmatic hernia in 120 infants treated consecutively with permissive hypercapnia/ spontaneous respiration/elective repair, J Pediatr Surg 37:357–366,

2002.

Congenital Diaphragmatic Hernia Study Group: Estimating disease severity of congenital diaphragmatic hernia in the first 5 minutes of life, J Pediatr Surg 36:141–145, 2001.

Congenital Diaphragmatic Hernia Study Group: Surfactant replacement therapy on ECMO does not improve outcomes in neonates with congenital diaphragmatic hernia, J Pediatr Surg 39:1632–1637, 2004. Harrison MR, Keller RL, Hawgood SB, et al: A randomized trial of fetal endoscopic tracheal occlusion for severe congenital diaphragmatic hernia, N Engl J Med 349:1916–1924, 2003. Hutcheon JA, Butler B, Lisonkova S, et al: Timing of delivery for pregnancies with congenital diaphragmatic hernia, BJOG 117:1658–1662, 2010.

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866 Part  XII   The   Fetus  and  the  Neonatal  Infant

lung standing out in relief against the pneumothorax (Fig. 101-14); pneumomediastinum is signified by hyperlucency around the heart border and between the sternum and the heart border (Fig. 101-15). Transillumination of the thorax is often helpful in the emergency diag- nosis of pneumothorax; the affected side transmits excessive light. Associated renal anomalies are identified by ultrasonography. Pulmo- nary hypoplasia is suggested by signs of uterine compression (extrem- ity contractures), a small thorax on chest roentgenograms, severe hypoxia with hypercapnia, and signs of the primary disease (hypoto- nia, diaphragmatic hernia, Potter syndrome).

Pneumopericardium may be asymptomatic, requiring only general supportive treatment, but it usually manifests as sudden shock with tachycardia, muffled heart sounds, and poor pulses suggesting tam- ponade. Pneumoperitoneum from air dissecting through the dia- phragmatic apertures during mechanical ventilation may be confused with intestinal perforation. Abdominal paracentesis can be helpful in differentiating the two conditions. The presence of organisms on Gram stain of intestinal contents suggests the latter. Occasionally, pneumo- peritoneum can result in an abdominal compartment syndrome requiring decompression.

A B
A
B

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

interpretation, Philadelphia, 1994, WB Saunders, p. 73.) Figure 101-15 Pneumomediastinum   in   a 

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

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TREATMENT

Without a continued air leak, asymptomatic and mildly symptomatic small pneumothoraces require only close observation. Conservative management of a pneumothorax is effective even in selected infants requiring ventilatory support. Frequent small feedings may prevent gastric dilation and minimize crying, which can further compromise ventilation and worsen the pneumothorax. Breathing 100% oxygen in term infants may accelerate the resorption of free pleural air into blood by reducing the nitrogen tension in blood and producing a resultant nitrogen pressure gradient from the trapped gas in the blood, but the clinical effectiveness is not proven and the benefit must be weighed against the risks of oxygen toxicity. With severe respiratory or circula- tory embarrassment, emergency aspiration using a soft small catheter introduced with a needle is indicated. Either immediately or after catheter aspiration, a chest tube should be inserted and attached to underwater seal drainage (see Fig. 101-14). If the air leak is ongoing, continuous suction ( 5 to 20 cm H 2 O) may be needed to evacuate the pneumothorax completely. A pneumopericardium requires prompt evacuation of entrapped air. Severe localized interstitial emphysema may respond to selective bronchial intubation. Judicious use of sedation in an infant fighting a ventilator may reduce the risk of pneumothorax. Surfactant therapy for RDS reduces the incidence of pneumothorax.

Bibliography is available at Expert Consult.

101.13 Pulmonary  Hemorrhage

Namasivayam Ambalavanan and Waldemar A. Carlo

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

improve lung compliance, because the presence of intra-alveolar blood and protein can inactivate surfactant. Acute pulmonary hemorrhage may rarely occur in previously healthy full-term infants. The cause is unknown. Pulmonary hemor- rhage may manifest as hemoptysis or blood in the nasopharynx or airway with no evidence of upper respiratory or gastrointestinal bleed- ing. Patients present with acute, severe respiratory failure requiring mechanical ventilation. Chest radiographs usually demonstrate bilat- eral alveolar infiltrates. The condition usually responds to intensive supportive treatment (see Chapter 407).

Bibliography is available at Expert Consult.

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Chapter 101   Respiratory   Tract  Disorders  867.e1

Bibliography

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

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867.e2Chapter  101   Respiratory   Tract   Disorders

Bibliography

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

e233–e238, 2008.

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