Respiratory Tract Disorders

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Chapter 95 Respiratory Tract Disorders

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 pulmonary, airway, cardiovascular, central nervous, and other disorders (Fig. 95-1).

Figure 95-1 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.)

It is occasionally difficult to distinguish respiratory from nonrespiratory etiologies on the basis of clinical signs alone. Any sign of respiratory distress is an indication for a physical examination and diagnostic evaluation, including a blood gas or pulse oximetry determination and radiograph of the chest. Timely and appropriate therapy is essential to prevent ongoing injury and improve outcome. As a result of important advances in treatment respiratory disease as well as in understanding of its pathophysiology, neonatal and infant deaths from early respiratory disease have declined markedly. The challenge is not only to continue to improve survival but also to reduce short- and long-term complications related to early lung disease.

95.1 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 respiratory 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 glucocorticoids 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 maintained in order to develop a ventilation-perfusion relationship that will provide optimal exchange of oxygen and carbon dioxide between alveoli and blood (Chapter 415).

The First Breath

During vaginal delivery, intermittent compression of the thorax facilitates removal of lung fluid. Surfactant lining the alveoli enhances the aeration of gas-free lungs by reducing surface tension, thereby lowering 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 H₂O and are more likely to establish FRC if they generate a spontaneous, negative pressure breath. Expiratory esophageal pressures associated with the 1st few spontaneous breaths in term newborns range from 45 to 90 cm H₂O. This high pressure, 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 respiration 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 1st 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 1st breath is due to a decline in PaO₂ and pH and a rise in PaCO₂ as a result of interruption of the placental circulation, 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, the low birthweight (LBW) infant who has a very compliant chest wall 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 LBW 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, which may resemble respiratory distress syndrome (RDS). However, even in healthy term infants, oxygenation is impaired soon after birth, and oxygen saturation improves to exceed 90% at around 5 minutes.

Breathing Patterns in Newborns

During sleep in the 1st months of life, 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 premature 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 it often stops without apparent reason. Periodic breathing, a normal characteristic of neonatal respiration, has no prognostic significance.

95.2 Apnea

Waldemar A. Carlo

Apnea is a common problem in preterm infants that may be due to prematurity or an associated illness. In term infants, apnea is always worrisome and demands immediate 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 95-1). 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, pneumonia, muscle weakness).

Table 95-1 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), 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

Idiopathic apnea of prematurity occurs in the absence of identifiable predisposing diseases. Apnea is a disorder of respiratory control and may be obstructive, central, or mixed. Obstructive apnea (pharyngeal 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 involved in maintaining airway patency. In central apnea, which is caused by decreased central nervous system (CNS) stimuli to respiratory muscles, airflow and chest wall motion are absent. Gestational 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 months 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 weeks after birth but is often delayed if there is RDS or other causes of respiratory distress. Apneic episodes have been noted to be as frequent on day 1 as throughout the 1st week 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 correlates 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 episodes noted with oxygen saturation monitoring are normal in neonates, and treatment is not necessary.

Treatment

Infants at risk for apnea should be started on cardiorespiratory monitoring. Gentle tactile stimulation is often adequate therapy for mild and intermittent episodes. The onset of apnea in a previously well premature neonate after the 2nd wk of life or in a term infant at any time is a critical event that warrants immediate investigation. Recurrent apnea of prematurity may be treated with theophylline or caffeine. Methylxanthines increase central respiratory drive by lowering the threshold of response to hypercapnia as well as enhancing contractility of the diaphragm and preventing diaphragmatic fatigue. Theophylline and caffeine are as effective, but caffeine has fewer side effects (tachycardia, feeding intolerance). Loading doses of 5-7 mg/kg of theophylline (orally) or aminophylline (intravenously) should be followed by doses of 1-2 mg/kg given every 6-12 hr by the oral or intravenous 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 determinations (therapeutic levels: theophylline, 6-10 µg/mL; caffeine, 8-20 µg/mL) are optional because important side effects of these agents are rare. Higher doses of methylxanthines are more effective, do not result in frequent side effects, and tend to reduce major neurodevelopmental disabilities. Withholding respiratory stimulants in infants with RDS may result in ventilator dependency, increased bronchopulmonary dysplasia (BPD), and death. Doxapram, known to be a potent respiratory stimulant, acts predominantly on peripheral chemoreceptors and is effective in neonates with apnea of prematurity that is unresponsive to methylxanthines. Transfusion 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 antireflux medications to reduce the frequency of apnea in preterm infants.

Nasal continuous positive airway pressure (continuous positive airway pressure [CPAP], 2-5 cm H₂O) and high-flow humidification using nasal cannula (1-2.5 L/min) are therapies for mixed or obstructive 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 prematurity are critical in determining the prognosis for apneic infants. Apnea of prematurity usually resolves by 36 wk of postconceptional age (PCA) and does not predict future episodes of sudden infant death syndrome (SIDS). Some infants with persistent apnea are discharged as long as cardiorespiratory monitoring can be performed at home. In the absence of significant events, home monitoring can be safely discontinued after 44 wk PCA.

Apnea and Sudden Infant Death Syndrome

Although preterm infants are at higher risk for SIDS, apnea of prematurity 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 smoking exposure and of overheating the infant are also important in the prevention of SIDS.

Bibliography

Arad-Cohen N, Cohen A, Tirosh E. The relationship between gastroesophageal reflux and apnea in infants. J Pediatr. 2000;137:321-326.

Committee on Fetus and Newborn, American Academy of Pediatrics. Apnea, sudden infant death syndrome, and home monitoring. Pediatrics. 2003;111:914-917.

Kimball AL, Carlton DP. Gastroesophageal reflux medications in the treatment of apnea in premature infants. J Pediatr. 2001;138:355-360.

Litmanovitz I, Carlo WA. Expectant management of pneumothorax in ventilated neonates. Pediatrics. 2008;122:e975-e979.

Martin RJ, Abu-Shaweesh JM, Baird TM. Apnoea of prematurity. Paediatr Respir Rev. 2004;5:S377-S382.

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. 2001;285:2199-2207.

Schmidt B, Roberts RS, Davis P, et al. Long term effects of caffeine for apnea of prematurity. N Engl J Med. 357, 2007. 1983–1902

Schmidt B, Roberts RS, Davis P, et al. Caffeine therapy for apnea of prematurity. N Engl J Med. 2006;354:2112-2120.

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. 2001;107:1081-1083.

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. 2004;89:F499-F503.

Tauman R, Sivan Y. Duration of home monitoring for infants discharged with apnea of prematurity. Biol Neonate. 2000;78:168-173.

95.3 Respiratory Distress Syndrome (Hyaline Membrane Disease)

Waldemar A. Carlo, 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, and rarely in those >37 wk. 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 (lecithin), phosphatidylglycerol, apoproteins (surfactant proteins SP-A, SP-B, SP-C, and SP-D), and cholesterol (Fig. 95-2). With advancing gestational age, increasing amounts of phospholipids are synthesized and stored in type II alveolar cells (Fig. 95-3). 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 produced 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. Mature levels of pulmonary surfactant are present usually after 35 wk. Though rare, genetic disorders may contribute to respiratory distress. 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 respiratory distress (not RDS) include alveolar capillary dysplasia, acinar dysplasia, pulmonary lymphangiectasia, and mucopolysaccharidosis.

Figure 95-2 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 maturation, and treatment. In Creasy RK, Resnick R, editors: Maternal-fetal medicine: principles and practice, ed 3, Philadelphia, 1994, WB Saunders.)

Figure 95-3 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.

(Courtesy of Mary Williams, MD, University of California, San Francisco.)

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.

(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.)

Synthesis of surfactant depends in part on normal pH, temperature, and perfusion. Asphyxia, hypoxemia, and pulmonary ischemia, particularly 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. In affected infants, the lower part of the chest wall is pulled in as the diaphragm descends, and intrathoracic pressure becomes negative, thus limiting the amount of intrathoracic pressure that can be produced; the result is the development of atelectasis. 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 collapse. Thus, at end-expiration, the volume of the thorax and lungs tends to approach residual volume, and atelectasis may develop.

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. Pulmonary blood flow is reduced and ischemic injury both to the cells producing surfactant and to the vascular bed results in an effusion of proteinaceous material into the alveolar spaces (Fig. 95-4).

Figure 95-4 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.)

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 have increased to 60 breaths/min or greater. A late 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). Characteristically, 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 rales 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 disappears, as the condition worsens. Apnea and irregular respirations are ominous signs requiring immediate intervention. Patients may also have a mixed respiratory-metabolic acidosis, edema, ileus, and oliguria. Respiratory failure may occur in infants with rapid progression of the disease. In most cases, the symptoms and signs reach a peak within 3 days, after which improvement is gradual. Improvement is often heralded by spontaneous diuresis and improved blood gas values at lower inspired oxygen levels and/or lower ventilator support. Death can be due to severe impairment of gas exchange, alveolar air leaks (interstitial emphysema, pneumothorax), pulmonary hemorrhage, or IVH. Death may be delayed by weeks or months if BPD develops in infants with severe RDS.

Diagnosis

The clinical course, chest radiographic findings, and blood gas and acid-base values help establish the clinical diagnosis. On radiographs, the lungs may have a characteristic but not pathognomonic appearance that includes 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. 95-5). The initial radiographic appearance is occasionally normal, with the typical pattern developing at 6-12 hr. Considerable variation in film 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 progressive hypoxemia, hypercapnia, and variable metabolic acidosis.

Figure 95-5 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.)

In the differential diagnosis, early-onset sepsis may be indistinguishable from RDS. In pneumonia manifested at birth, the chest roentgenogram 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 (total anomalous pulmonary venous return) can also mimic RDS both clinically and radiographically. 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, amniotic fluid) syndromes, spontaneous pneumothorax, pleural effusions, 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 evaluation. Transient tachypnea may be distinguished by its short and mild clinical course and is characterized by low or no need for oxygen supplementation. Congenital alveolar proteinosis (congenital surfactant protein B deficiency) is a rare familial disease that manifests as severe and lethal RDS in predominantly term and near-term infants (Chapter 399). 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 cesarean section, appropriate management of high-risk pregnancy and labor, and prediction of pulmonary immaturity with possible in utero acceleration of maturation (Chapter 90) are important preventive strategies. In timing of cesarean section or induction of labor, estimation of fetal head circumference by ultrasonography and determination of the lecithin concentration in amniotic fluid by the lecithin:sphingomyelin ratio (particularly useful with phosphatidylglycerol measurement in diabetic pregnancies) decrease the likelihood of delivering a premature infant. Antenatal and intrapartum fetal monitoring may similarly decrease the risk of fetal asphyxia; asphyxia is associated with an increased incidence and severity of RDS.

Administration of antenatal corticosteroids to women between 24 and 34 wk of gestation significantly reduces the incidence and mortality of RDS as well as overall neonatal mortality. Antenatal steroids also reduce (1) the need for and duration of ventilatory support and admission to a neonatal intensive care unit (NICU) and (2) the incidence of severe IVH, necrotizing enterocolitis, early-onset sepsis, and developmental delay. Postnatal growth is not adversely affected. Antenatal steroids do not increase the risk of maternal death, chorioamnionitis, or puerperal sepsis. Corticosteroid administration is recommended for all women in preterm labor (24-34 wk of gestation) who are likely to deliver a fetus within 1 wk. Repeated weekly doses of betamethasone until 32 wk may reduce neonatal morbidities and the duration of mechanical ventilation. Antenatal glucocorticoids act synergistically with postnatal exogenous surfactant therapy so they should be given even though surfactant therapy is so effective. Betamethasone and dexamethasone have been used antenatally. Dexamethasone may result in a lower incidence of IVH than betamethasone, but further research is needed to determine whether one of these steroids is superior for antenatal treatment.

Administration of a 1st dose of surfactant into the trachea of symptomatic premature infants immediately after birth (prophylactic) or during the 1st few hours of life (early rescue) reduces air leak and mortality from RDS but does not alter the incidence of BPD.

Treatment

The basic defect requiring treatment in RDS is inadequate pulmonary exchange of oxygen and carbon dioxide; metabolic acidosis and circulatory insufficiency are secondary manifestations. Early supportive care of premature infants, especially in the treatment of acidosis, hypoxia, hypotension (Chapter 92), and hypothermia, may lessen the severity of RDS. Therapy requires careful and frequent monitoring of heart and respiratory rates, oxygen saturation, PaO₂, PaCO₂, pH, serum bicarbonate, electrolytes, glucose, and 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 iatrogenic problems. Treatment of infants with RDS is best carried out in the NICU.

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 consumption, the infant should be placed in an incubator or radiant warmer, and core temperature maintained between 36.5 and 37°C (Chapters 91 and 92). Use of an incubator is preferable in very LBW (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 and water 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 to 7 in the more immature ones. Fluid volume is increased gradually over the 1st week. 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 40 and 70 mm Hg (85-95% saturation) in order to maintain normal tissue oxygenation while minimizing the risk of oxygen toxicity. If oxygen saturation cannot be kept > 85% at inspired oxygen concentrations of 40-70% or greater, applying CPAP at a pressure of 5-10 cm H₂O via nasal prongs is indicated and usually produces a sharp improvement in oxygenation. CPAP prevents collapse of surfactant-deficient alveoli and improves both FRC and ventilation-perfusion matching. Early use of CPAP for stabilization of at-risk VLBW infants beginning as early as in the delivery room reduces ventilatory needs. Another approach is to intubate the VLBW infant, administer intratracheal surfactant, and then extubate the infant and begin CPAP. The amount of CPAP required usually decreases after about 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 > 85% 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 PCO₂ of 60 mmHg or higher, and (3) oxygen saturation <85% at oxygen concentrations of 40-70% and CPAP of 5-10 cm H₂O. 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 PEEP (Chapter 65.1). High ventilatory rates (60/min) result in fewer air leaks. With use of high ventilatory rates, sufficient expiratory time should be allowed to avoid the administration of 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 ventilation, vary among institutions: PaO₂ 40-70 mmHg, PaCO₂ 45-65 mmHg, and pH 7.20-7.35. During mechanical ventilation, oxygenation is improved by increasing either the fraction of inspired oxygen (FIO₂) 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 PaO₂. PEEP levels of 4-6 cm H₂O are usually safe and effective. Carbon dioxide elimination 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 due to overdistention and/or atelectasis. However, controlled trials do not report benefits of early CPAP. Interestingly, nasal intermittent mandatory ventilation (vs nasal CPAP) reduces extubation failure in small trials; this method could be an alternative by which to avoid intubation.

The strategy most evaluated with conventional mechanical ventilation is the use of high rates and presumably small tidal volumes as PaCO₂ levels were kept in comparable ranges. Meta-analyses of the randomized controlled trials comparing high (>60 per min) and low (usually 30-40 per 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 prevention or limitation of lung injury from the ventilator by tolerating relatively high levels of PaCO₂ rather than maintenance of normal blood gas values. A multicenter trial of infants ≤1,000 g reported that permissive hypercapnia (target PaCO₂ >50 mm Hg) during the 1st 10 days led to a trend for lower rates of BPD or death at 36 wk. Furthermore, the strategy of permissive hypercapnia reduced severity of BPD, as evidenced by a decreased need for ventilator support at 36 wk, from 16% to 1%. A large multi-center randomized controlled trial of permissive hypercapnia with emphasis on the use of CPAP revealed that this is an effective and maybe preferred approach to the standard strategy of intubation and surfactant administration to preterm infants with RDS. Volume-targeted ventilation allows the clinician to set a tidal volume that may prevent volutrama. There are limited data on volume-targeted ventilation, but this mode of ventilation may decrease the rates of pneumothorax and BPD.

Hyperoxia may also contribute to lung injury in preterm infants. Thus, permissive hypoxemia is another strategy that may reduce BPD. Trials to target different levels of oxygen saturation performed for treatment of retinopathy of prematurity or BPD revealed that the groups with lower saturation targets (89-94% or 91-94%, respectively) had less need for oxygen supplementation and lower rates of BPD or BPD exacerbation. Even lower oxygen saturation targets (85-89%) reduced retinopathy of prematurity significantly and tended to reduce BPD but increased mortality rates in a large multi-center randomized controlled trial. Thus, optimal target saturations are still not determined but some restriction of oxygen appears beneficial.

Many ventilated neonates receive sedation or pain relief with benzodiazepines 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 it is used, a continuous infusion or administration of individual doses over at least 10 min is recommended 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 morphine in VLBW neonates requiring mechanical ventilation does not reduce mortality rates, severe IVH, or periventricular leukomalacia (PVL). The need for additional doses of morphine is associated with poor outcome.

High-frequency ventilation (HFV) achieves desired alveolar ventilation by using smaller tidal volumes and higher rates (300-1,200 breaths/min or 5-20 Hz). HFV may improve the elimination of carbon dioxide and improve oxygenation in patients who show no response to conventional ventilators and who have severe RDS, interstitial emphysema, recurrent pneumothoraces, or meconium aspiration pneumonia. High-frequency oscillatory ventilation (HFOV) and high-frequency jet ventilation (HFJV) are the most frequently used methods of HFV. HFOV reduces BPD but increases air leaks and may raise the risk for IVH and PVL. HFOV strategies that promote lung recruitment, combined with surfactant therapy, may improve gas exchange. HFJV 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 . Treatment is initiated as soon as possible in the hours after birth. Repeated dosing is given via the endotracheal tube 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 respiratory management and who is able to care for the infant beyond the 1st hr of stabilization. Additional on-site staff support required includes nurses and respiratory therapists experienced in the ventilatory management of premature infants. Appropriate monitoring equipment (radiology, blood gas laboratory, pulse oximetry) must also be available. Complications of surfactant therapy include transient hypoxia, hypercapnia, bradycardia and hypotension, blockage of the endotracheal tube, and pulmonary hemorrhage (Chapter 95.13).

A number of surfactant preparations are available, including synthetic surfactants and natural surfactants derived from animal sources. Exosurf is a synthetic surfactant. Natural surfactants include Survanta (bovine), Infasurf (calf), and Curosurf (porcine). Surfactant replacement therapy is one of the major advances in the care of preterm infants. Prophylactic and rescue administrations of synthetic and natural surfactants have reduced adverse outcomes, including mortality. Specifically, neonatal mortality is lower with prophylactic (vs rescue) administration of both synthetic and natural surfactants. Prophylactic administration of both types of surfactants decreases the risk for pneumothorax and pulmonary interstitial emphysema. The lack of reduction in BPD rates following surfactant replacement is probably, in part, due to the survival of infants with severe RDS who would have died without surfactant administration.

In more mature preterm infants, a policy of prophylactic administration of surfactant may result in many infants’ receiving surfactant unnecessarily, and it is possible that early rather than prophylactic surfactant administration may be sufficiently effective. However, the time of rescue surfactant administration in the prophylactic trials varied widely. Early (< 2 hr) rather than delayed rescue surfactant administration resulted in decreased risk for neonatal mortality. Early rescue administration of surfactant reduced rates of both pneumothorax (from 14% to 12%) and pulmonary interstitial emphysema (from 15% to 10%). An alternative to early surfactant administration in many infants is to treat infants with surfactant before ventilation is needed. Temporary endotracheal intubation for surfactant administration in infants requiring only CPAP reduces the subsequent need for mechanical ventilation and may reduce mortality and/or BPD.

Head-to-head trials of natural and synthetic surfactants report superiority of the natural surfactants. Use of natural (vs synthetic) surfactants resulted in lower rates of pneumothorax (12% vs 7%) and mortality (18% vs. 16%) than use of synthetic surfactants. Natural surfactants are superior because of their surfactant-associated protein content, their more rapid onset, and their lower risk of pneumothorax and improved survival. Surfaxin, formerly known as KL4 surfactant, is a novel synthetic lung surfactant containing phospholipids and an engineered peptide, sinapultide, designed to mimic the actions of human SP-B. Use of Surfaxin for the prevention and treatment of RDS demonstrates equivalency to use of the natural surfactants Survanta and Curosurf. Initial protocols for surfactant administration used single-dose therapies. However, compared with a strategy of a single dose of surfactant, administration of multiple doses of surfactant when indicated according to the protocol resulted in lower pneumothorax risk (18% vs 9%) and a trend for lower mortality. A review of all the current evidence supports the use of prophylactic or early use of natural surfactants as early as when infants require CPAP. More than one dose of surfactant should be administered if indicated to optimize the benefits of this therapy.

Premature infants requiring ventilator support after 1 wk of age 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.

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. The response to iNO is equivalent to that to HFOV in term or near-term infants with hypoxic respiratory failure. A positive response to combined therapy suggests that alveolar recruitment by HFOV may allow iNO gas to reach the pulmonary resistance vessels. A reduction in the rate of death or BPD in infants <1,000 g treated with iNO was observed in one study but not in others.

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 transitioned 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 extubation and to wean premature infants from nasal CPAP. Preloading with methylxanthines may enhance the success of extubation.

Pharmacologic Therapies

Several pharmacologic options are available to the clinician for the treatment of RDS and prevention of its complications. Selected treatments are reviewed here.

Vitamin A supplementation given largely to infants < 1,000 g resulted in a decrease in death and/or BPD at 36 wk (from 66% to 60%) and trends for less nosocomial sepsis and retinopathy of prematurity.

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 (from 72% to 45%) 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 bleeding, gastrointestinal perforation, hypertrophic obstructive cardiomyopathy, poor weight gain, poor growth of the head, and a trend toward a higher incidence of PVL. Furthermore, data showing an increased incidence of neurodevelopmental delay and cerebral palsy in infants randomly assigned to receive systemic corticosteroids raise serious concerns about adverse long-term outcomes of this therapy. Thus, routine use of systemic corticosteroids for the prevention or treatment of BPD is not recommended by the Consensus Group of the American Academy of Pediatrics and the Canadian Pediatric Society. Administration of inhaled steroids to ventilated preterm infants during the 1st 2 wk after birth reduced the need for systemic steroids (from 45% to 35%) and tended to decrease rates of death and/or BPD at 36 wk without an increase in adverse effects.

Inhaled NO has been evaluated in preterm infants following the observation of its effectiveness in term and near-term infants with hypoxemic respiratory failure. Despite optimistic results from a large randomized controlled trial, trials in preterm infants report heterogeneous effects on BPD, mortality, and other important outcomes. The most current data do not support the routine administration of iNO in preterm infants with hypoxemic respiratory failure.

Prevention of extubation failure has been attempted with use of various pharmacologic approaches. Methylaxanthines appear to have a large effect on reducing extubation (from 51% to 25%). Similarly, use of systemic steroids before extubation reduces the need for re-intubation (from 10% to 1%). In contrast, administration of racemic epinephrine after extubation 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 resuscitation (Chapter 94). Sodium bicarbonate, 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 from infiltration, increased serum osmolarity, hypernatremia, hypocalcemia, hypokalemia, and liver injury when concentrated solutions 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. 94-2). The position of a radiopaque umbilical catheter should be checked roentgenographically after insertion (see Fig. 95-5). The tip of an umbilical artery catheter should lie just above the bifurcation of the aorta (L3-L5) or above the celiac axis (T6-T10). Preferred sites for peripheral catheters are the radial or posterior tibial arteries. The placement 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 FIO₂ is < 40%. Hypotension and low flow in the superior vena cava (SVC) 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 be due to transient adrenal insufficiency in the ill premature infant. It should be treated with intravenous hydrocortisone (Solu-Cortef) at 1-2 mg/kg/dose q6-12 hr (Chapter 92).

Periodic monitoring of PaO₂, PaCO₂, and pH is an important part of the management; if assisted ventilation is being used, such monitoring is essential. Oxygenation may be assessed continuously from transcutaneous electrodes or pulse oximetry (oxygen saturation). Capillary blood samples are of limited value for determining PO₂ but may be useful for evaluating PCO₂ 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 (Chapter 103).

Complications of Respiratory Distress Syndrome and Intensive Care

The most serious complications of tracheal intubation are pneumothorax 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 due to 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, laryngeal 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, avoidance 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; accidental 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 due to 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 topical nitroglycerin paste applied to the affected area or, rarely, 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 unresponsive 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 potential 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. Renovascular 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, which can occur if the catheter is incorrectly placed in the right atrium; 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 (Chapter 95.12).

Some neonates with RDS may have clinically significant shunting through a patent ductus arteriosus. 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 cardiomegaly 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 bidirectional shunting. Prophylactic “closure” before symptoms or signs of a PDA, closure of the asymptomatic but clinically detected PDA, and closure of the symptomatic PDA are three strategies to manage a PDA. Interventions include fluid restriction, the use of cyclo-oxygenase 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 intestinal 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 deterioration after initial clinical improvement of RDS. Intravenous indomethacin (0.1-0.2 mg/kg/dose) is given in three doses every 12-24 hr; treatment may be repeated once. A second course may be needed in a few symptomatic patients. If closure does not occur in a symptomatic patient, surgical ligation is usually the next step. Prophylactic low-dose indomethacin 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/mm³), bleeding disorders, oliguria (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 candidate for surgical closure. Surgical mortality is very low even in the extremely LBW 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 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, therapeutic ibuprofen has a lower risk of oliguria.

Bronchopulmonary dysplasia is a result of lung injury in infants requiring mechanical ventilation and supplemental oxygen. The clinical, radiographic, and lung histology of classic BPD described in 1967, in an era before the widespread use of antenatal steroids and postnatal surfactant, was 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 born at less than 28 wk gestation, some of whom have little or no lung disease at birth but experience progressive respiratory failure over the 1st few weeks of life.

The morphometric features currently found in infants with the new BPD include alveolar hypoplasia, variable saccular wall fibrosis, and minimal airway disease. Some specimens also have decreased pulmonary microvasculature development. The histopathology of BPD indicates interference with normal lung anatomic maturation, which may prevent subsequent lung growth and development. The pathogenesis of BPD is multifactorial and affects both the lungs and the heart. RDS is a disease of progressive alveolar collapse. Alveolar collapse (atelectotrauma) due to surfactant deficiency, together with ventilator-induced phasic overdistention of the lung (volutrauma), promotes injury. Oxygen induces injury by producing free radicals that cannot be metabolized by the immature antioxidant systems of VLBW neonates. Mechanical ventilation and oxygen injure the lung through their effect on alveolar and vascular development. Inflammation (detected with measurement of circulating neutrophils, neutrophils and macrophages in alveolar fluid, and pro-inflammatory cytokines) contributes to the progression of lung injury. Several clinical factors, including immaturity, chorioamnionitis, infection, symptomatic PDA, and malnutrition, contribute to the development of BPD.

The occurrence of BPD is inversely related to gestational age. Additional associations include the presence of interstitial emphysema, male sex, low PaCO₂ 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 extubation 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, hypercapnia, oxygen dependence, and, in severe cases, the development of right-sided heart failure. The chest roentgenogram may reveal pulmonary interstitial emphysema, wandering atelectasis with concomitant hyperinflation, and cyst formation (Fig. 95-6). Four distinct pathologic stages of classic BPD have been identified: acute lung injury, exudative bronchiolitis, proliferative bronchiolitis, and obliterative fibroproliferative bronchiolitis. Histologic study at this stage (10-20 days) shows residual hyaline membrane formation, progressive alveolar coalescence 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. Pathologic 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 metaplasia of the bronchiolar mucosa, thickening of basement membranes, and separation of the capillaries from the alveolar epithelial cells.

Figure 95-6 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 opacification 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 patent ductus arteriosus.

(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.)

BPD can be classified according to the need for oxygen supplementation (Table 95-2). Neonates receiving positive pressure support or ≥30% supplemental oxygen at 36 wk or at discharge (whichever occurs 1st) are diagnosed as having severe BPD. Those needing supplementation 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 continuous observation and with oxygen saturation monitoring to determine whether they can be weaned off oxygen. 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.

Table 95-2 DEFINITION OF BRONCHOPULMONARY DYSPLASIA: DIAGNOSTIC CRITERIA *

	GESTATIONAL AGE
	<32 Wk	≥32 Wk
Time point of assessment	36 wk postmenstrual age or discharge home, whichever comes 1st Treatment with >21% oxygen for at least 28 days plus

>28 days but <56 days postnatal age or discharge home, whichever comes 1st

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 1st Breathing room air by 56 days postnatal age or discharge home, whichever comes 1st Moderate BPD Need^† for <30% oxygen at 36 wk postmenstrual age or discharge home, whichever comes 1st Need^† for <30% oxygen at 56 days postnatal age or discharge home, whichever comes 1st Severe BPD Need^† for ≥30% oxygen and/or positive pressure (PPV or NCPAP) at 36 wk postmenstrual age or discharge home, whichever comes 1st Need^† for ≥30% oxygen and/or positive pressure (PPV or NCPAP) at 56 days postnatal age or discharge home, whichever comes 1st

BPD, bronchopulmonary dysplasia; NCPAP, nasal continuous positive airway pressure; PPV, positive pressure ventilation.

* 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.

From Jobe AH, Bancalari E: Bronchopulmonary dysplasia, Am J Respir Crit Care Med 163:1723–1729, 2001.

Severe BPD requires prolonged mechanical ventilation. Gradual weaning should be attempted despite elevations in PaCO₂, 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 PaO₂ of 50-70 mm Hg with an oxygen saturation of 88-95%. Lower levels of PaO₂ 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 due to acute pulmonary vasospasm or right ventricular dysfunction.

Treatment of BPD includes nutritional support, fluid restriction, drug therapy, maintenance of adequate oxygenation, and prompt treatment 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 intravenously twice daily [bid] or 2 mg/kg/dose orally bid) is the treatment of choice for acute fluid overload in infants with BPD. This loop diuretic has been demonstrated to decrease pulmonary interstitial emphysema (PIE) 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, cholelithiasis, 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. Sodium chloride supplementation should be avoided. Thiazide diuretics with inhibitors of aldosterone have been used in infants with BPD. Several trials of thiazide diuretics combined with spironolactone have shown increased urine output with or without improvement in pulmonary mechanics in infants with BPD. Adverse effects include electrolyte imbalance.

Inhaled bronchodilators improve lung mechanics by decreasing airway resistance. Albuterol is a specific β2-agonist used to treat bronchospasm in infants with BPD. Albuterol may improve lung compliance 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. Ipratropium 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 weeks 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. Methylxanthines 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 perforation, 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 neurodevelopmental 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 avoid oxygen saturation values <88% and, in those with established pulmonary hypertension, to maintain oxygen saturation values in the 90-95% range.

Low-dose iNO has no acute effects on lung function, cardiac function, or oxygenation in evolving BPD. The use of low-dose iNO may improve oxygenation in some infants with severe BPD, allowing decreased FIO₂ 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, postnatal surfactant use, and improved modes of ventilation have resulted in low mortality from RDS (≈10%). Mortality increases with decreasing gestational age. Optimal results depend on the availability of experienced 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 congenital malformation. Surfactant therapy has reduced mortality from RDS approximately 40%, but the incidence of BPD has not been measurably affected.

Although 85-90% of all infants surviving RDS after requiring ventilatory support with respirators are normal, the outlook is much better for those weighing > 1,500 g. The long-term prognosis for normal pulmonary 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 pulmonale, and oxygen dependence beyond 1 yr of life are poor prognostic signs. Mortality in infants with BPD ranges from 10% to 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.

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 stenosis may require tracheotomy or an anterior cricoid split procedure to relieve upper airway obstruction. Cardiac complications of BPD include pulmonary hypertension, cor pulmonale, systemic hypertension, left ventricular hypertrophy, and the development of aortopulmonary collateral vessels, which, if large, may cause heart failure. 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 aged 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 aged 7-10 yr. Airway obstruction 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 abnormalities that correlate directly with the degree of pulmonary function abnormality.

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95.4 Transient Tachypnea of the Newborn

Namasivayam Ambalavanan, Waldemar A. Carlo

Transient tachypnea usually follows uneventful preterm or term vaginal delivery or cesarean delivery. It is characterized by the early onset of tachypnea, sometimes with retractions, or expiratory grunting and, occasionally, cyanosis that is relieved by minimal oxygen supplementation (<40%). Most infants recover rapidly, within 3 days. The chest generally sounds clear without rales or rhonchi, and the chest radiograph shows prominent pulmonary 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 distinctive 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 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. Treatment is supportive. There is no evidence supporting the use of oral furosemide in this disorder.

Severe respiratory morbidity and mortality have been reported in infants born by elective cesarean section who initially present with signs and symptoms of transient tachypnea. These infants demonstrate refractory hypoxemia due to pulmonary hypertension and require ECMO support. The term “malignant TTN” has been used to describe this condition.

Bibliography

Liem JJ, Huq SI, Ekuma O, et al. Transient tachypnea of the newborn may be an early clinical manifestation of wheezing symptoms. J Pediatr. 2007;151:29-33.

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

Waldemar A. Carlo

During prolonged labor and difficult deliveries, infants often initiate vigorous respiratory movements in utero because of interference with the supply of oxygen through the placenta. Under such circumstances, the infant may aspirate amniotic fluid containing vernix caseosa, epithelial cells, meconium, 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 roentgenographic evidence of aspiration is seen (Fig. 95-7).

Figure 95-7 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.)

Postnatal pulmonary aspiration may also occur in newborn infants as a result of prematurity, tracheoesophageal fistula, esophageal and duodenal obstruction, gastroesophageal reflux, improper feeding practices, and administration of depressant medicines. To avoid aspiration of gastric contents, the stomach should be aspirated using a soft catheter just before surgery or other major procedures that require anesthesia or conscious sedation. The treatment of aspiration pneumonia is symptomatic and may include respiratory support and systemic antibiotics (Chapters 103.8 and 389). Gradual improvement generally occurs over 3-4 days.

95.6 Meconium Aspiration

Namasivayam Ambalavanan, Waldemar A. Carlo

Meconium-stained amniotic fluid is found in 10-15% of births and usually occurs in term or post-term infants. Meconium aspiration syndrome (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 resuscitation at birth. The pathophysiology is shown in Figure 95-8. Infants with MAS are at increased risk of persistent pulmonary hypertension (Chapter 95.7).

Figure 95-8 Pathophysiology of meconium passage and the meconium aspiration syndrome. , 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.)

Clinical Manifestations

Either in utero or with the 1st breath, thick, particulate meconium is aspirated into the lungs. The resulting small airway obstruction may produce respiratory distress within the 1st hours, with tachypnea, retractions, grunting, and cyanosis observed in severely affected infants. Partial obstruction of some airways may lead to pneumomediastinum, pneumothorax, or both. Overdistention of the chest may 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 roentgenogram is characterized by patchy infiltrates, coarse streaking of both lung fields, increased anteroposterior diameter, and flattening of the diaphragm. A normal chest roentgenogram in an infant with severe hypoxemia and no cardiac malformation suggests the diagnosis of pulmonary hypertension (Chapter 95.7).

Prevention

The risk of meconium aspiration may be decreased by rapid identification of fetal distress and initiation of prompt delivery in the presence of late fetal heart rate (FHR) deceleration or poor beat-to-beat FHR 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. Nasopharyngeal suctioning of a meconium-stained infant after delivery of the head was once considered a low-risk method of reducing the incidence of MAS. However, routine intrapartum nasopharyngeal suctioning 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 MAS or other major adverse outcomes. Depressed infants (those with hypotonia, 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 1st breath in the delivery room. The risk associated with laryngoscopy and endotracheal intubation (bradycardia, laryngospasm, hypoxia) is less than the risk of MAS in meconium-stained infants who are depressed at birth.

Treatment of MAS includes supportive care and standard management for respiratory distress. The beneficial effect of mean airway pressure on oxygenation must be weighed against the risk of 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 support, 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 (Chapter 95.7).

Prognosis

The mortality rate of meconium-stained infants is considerably higher than that of non-stained infants. The decline in neonatal deaths due to MAS during the last decades is related to improvements in obstetric and neonatal care. Residual lung problems are rare but include symptomatic 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 pulmonary hypertension.

Bibliography

Fraser WD, Hofmeyr J, Lede R, et al. Amnioinfusion for prevention of the meconium aspiration syndrome. N Engl J Med. 2005;353:909-917.

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

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. 2000;105:1-7.

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

Namasivayam Ambalavanan, Waldemar A. Carlo

Persistent pulmonary hypertension of the newborn (PPHN) occurs in term and post-term infants. Predisposing factors include birth asphyxia, MAS, early-onset sepsis, RDS, hypoglycemia, polycythemia, maternal use of nonsteroidal anti-inflammatory drugs with in utero constriction of the ductus arteriosus, maternal late trimester use of selective serotonin reuptake inhibitors, and pulmonary hypoplasia due to 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, findings suggestive of a possible subtle defect in NO production. The incidence 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 due to excessively high PVR. Fetal PVR is usually elevated relative to fetal systemic or postnatal pulmonary pressure. This fetal state normally permits shunting 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 secondary to filling of the lungs with gas, a rise in postnatal PaO₂, a reduction in PaCO₂, 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 nonmuscular, more peripheral pulmonary arterioles in response to chronic fetal hypoxia; (3) due to pulmonary hypoplasia (diaphragmatic hernia, Potter syndrome); or (4) obstructive as a result of polycythemia or total anomalous pulmonary venous return, or of alveolar capillary dysplasia, which is a lethal autosomal recessive disorder characterized by thickened alveolar septa, increased muscularization of the pulmonary arterioles, a reduced number of capillaries, and misalignment of the intrapulmonary veins. Regardless of etiology, profound hypoxemia from right-to-left shunting and normal or elevated PaCO₂ are present (Fig. 95-9).

Figure 95-9 Cardiopulmonary interactions in persistent pulmonary hypertension of the newborn (PPHN). FO, foramen ovale; LV, left ventricular; PDA, patent ductus arteriosus; PVR, pulmonary 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.)

Clinical Manifestations

Infants with PPHN become ill in the delivery room or within the 1st 12 hr of life. PPHN related to polycythemia, idiopathic causes, hypoglycemia, 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 92-1). Myocardial ischemia, papillary muscle dysfunction with mitral and tricuspid regurgitation, and biventricular 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 roentgenograms.

Diagnosis

PPHN should be suspected in all term infants who have cyanosis with or without a history of fetal distress, intrauterine growth restriction, meconium-stained amniotic fluid, hypoglycemia, polycythemia, diaphragmatic hernia, pleural effusions, and birth asphyxia. Hypoxemia is universal and is 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 PaO₂ gradient between a preductal (right radial artery) and a postductal (umbilical artery) site of blood sampling >20 mm Hg suggests right-to-left shunting through the ductus arteriosus, as does an oxygenation saturation gradient >5% between preductal and postductal sites on pulse oximetry. Real-time echocardiography combined with Doppler flow imaging studies demonstrates right-to-left or bidirectional shunting across a patent foramen ovale and a ductus arteriosus. Deviation of the intra-atrial septum into the left atrium is seen in severe PPHN. Tricuspid or mitral insufficiency may be noted on auscultation as a holosystolic murmur and can be visualized echocardiographically together with poor contractility when PPHN is associated with myocardial ischemia. The degree of tricuspid regurgitation can be used to estimate pulmonary artery pressure. The 2nd heart sound is accentuated and not split. In asphyxia-associated and idiopathic PPHN, chest roentgenogram 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) and the associated etiologic entities that predispose to PPHN (hypoglycemia, polycythemia, sepsis).

Treatment

Therapy is directed toward correcting any predisposing condition (hypoglycemia, polycythemia) and improving poor tissue oxygenation. 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 is controversial. In the pre-NO era, one approach to the treatment of severe PPHN consisted of instituting mechanical ventilation with or without the use of muscle relaxants; ventilator settings were adjusted to achieve a PaO₂ of 50-70 mm Hg and a PaCO₂ of 50-60 mm Hg. Tolazoline (1 mg/kg), a nonselective α-adrenergic antagonist, was sometimes used as an adjunct to nonselectively vasodilate the pulmonary arterial system, but its use also usually resulted in systemic hypotension, which was treated with volume expansion and dopamine. Another approach incorporated hyperventilation to reduce pulmonary vasoconstriction by lowering the PaCO₂ (≈25 mm Hg) and increasing the pH (7.50-7.55). This strategy required high peak inspiratory pressures and rapid respiratory rates, often necessitating the use of muscle relaxants for control of ventilation. Ventilator settings were adjusted to achieve a PaO₂ between 90 and 100 mm Hg. Alkalinization with sodium bicarbonate was also used to elevate serum pH.

Forced alkalosis using sodium bicarbonate and hyperventilation were popular therapies because of their ability to produce acute pulmonary vasodilation and rapid increases in PaO₂. Hypocarbia constricts the cerebral vasculature and reduces cerebral blood flow. Extreme alkalosis and hypocarbia are associated with later neurodevelopmental deficits, including cerebral palsy and neurosensory hearing loss. Other complications of hyperventilation included air trapping, reduced cardiac output due to decreased venous return, barotrauma, pneumothorax, increased fluid requirements, and edema. Sodium bicarbonate and tromethamine (Tham) infusions, on the other hand, require careful monitoring of serum electrolytes and blood gases to ensure that ventilation is adequate to allow carbon dioxide clearance. The use of alkali infusions is associated with an increased need for ECMO and an increased rate of chronic lung disease. Currently, infants with PPHN are often managed without hyperventilation and/or alkalinization. In skilled hands, “gentle ventilation” with normocarbia or permissive hypercarbia results in excellent outcomes and a low incidence of chronic lung disease.

Because of their lability and ability to fight the ventilator, newborns with PPHN usually require sedation. Fentanyl may decrease sympathetic tone during stressful interventions and maintain a more relaxed pulmonary vascular bed. The use of paralytic agents is controversial and reserved for the newborn who cannot be treated with sedatives alone. Muscle relaxants may promote atelectasis of dependent lung regions and ventilation-perfusion mismatch. Paralysis may be associated with an increased risk of death. In survivors of congenital diaphragmatic hernia (CDH), prolonged administration of pancuronium during the neonatal period is associated with sensorineural hearing loss as well as an acute myopathy.

Inotropic therapy is frequently needed to support blood pressure and perfusion. Whereas dopamine is frequently used as a 1st-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 cardiovascular adrenergic receptor expression and serves as a hormone substitute in cases of adrenal insufficiency.

NO gas is an endothelium-derived signaling molecule that relaxes vascular 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 including 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 duration 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 discontinued when the FiO₂ is < 0.6 and the iNO dose is 1 ppm. Abrupt discontinuation should be avoided as it may cause rebound pulmonary hypertension. Inhaled NO 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 cases of PPHN do not respond adequately to iNO. Therapy with continuous inhaled or intravenous prostacyclin (prostaglandin I₂) has improved oxygenation and outcome in infants with PPHN. Intravenous continuous prostacyclin is also effective in treating older children with primary pulmonary hypertension. Oral sildenafil (a type 5 phosphodiesterase inhibitor) improves exercise tolerance in adults with moderately severe pulmonary artery hypertension. The safety and efficacy of intravenous sildenafil in newborns with PPHN is under investigation; initial results are promising.

Extracorporeal Membrane Oxygenation

In 5-10% of patients with PPHN (approximately 1/4,000 births), the response to 100% oxygen, mechanical ventilation, and drugs is poor. In such patients, two parameters have been used to predict mortality, the alveolar-arterial oxygen gradient (PAO₂ − PaO₂), which is roughly, at sea level, 760 − 47, and the oxygenation index (OI), which is calculated as follows:

An alveolar-arterial gradient >620 for 8-12 hr and an OI >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 approximates 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 saturation values are used to monitor oxygenation for infants receiving venovenous ECMO. The rate of ECMO flow is adjusted to achieve satisfactory venous oxygen saturation (>65%) and cardiovascular stability with venoarterial ECMO and an arterial saturation of 85-95% with venovenous ECMO. When ECMO is started in an infant, the FiO₂ is gradually changed over to room air and ventilatory settings are minimized to reduce the risk of oxygen toxicity and barotrauma, thus permitting time for the lungs to rest and heal.

Because ECMO requires complete heparinization to prevent clotting 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 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 thromboembolism, air embolization, bleeding, stroke, seizures, atelectasis, cholestatic jaundice, thrombocytopenia, neutropenia, hemolysis, infectious complications of blood transfusions, edema formation, and systemic hypertension.

The number of neonatal respiratory ECMO cases has shown a progressive decline from a high of 1,500/year in 1992 to 750/year in 2004. The probable reasons for this decline are improved perinatal management and neonatal care, including the use of lung-protective ventilation and iNO.

Prognosis

Survival in patients with PPHN varies with the underlying diagnosis. The long-term outcome for infants with PPHN is related to the associated 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; 70-80% survive, and 60-75% of survivors appear normal at 1-3.5 yr of age. Survival of infants born with 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 (52%).

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. 2006;117:1077-1083.

Barrington KJ, Finer N: Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev (3):CD000509, 2007.

Chambers CD, Hernandez-Díaz S, van Marter LJ, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med. 2006;354:579-587.

Finer N, Barrington KJ: Nitric oxide for respiratory failure in infants born at or near term, Cochrane Database Syst Rev (4):CD000399, 2006.

Kulik TJ, Rhein LM, Mullen MP. Pulmonary arterial hypertension in infants with chronic lung disease: will we ever understand it? J Pediatr. 2010;157(2):186-190.

Mugford M, Elbourne D, Field D: Extracorporeal membrane oxygenation for severe respiratory failure in newborn infants, Cochrane Database Syst Rev (16):CD001340, 2008.

Nakajima W, Ishida A, Arai H, et al. Methaemoglobinaemia after inhalation of nitric oxide in infants with pulmonary hypertension. Lancet. 1997;350:1002-1003.

Sen P, Thakur N, Stockton DW, et al. Expanding the phenotype of alveolar capillary dysplasia (ACD). J Pediatr. 2004;145:646-651.

Steinhorn RH, Kinsella JP, Pierce C, et al. Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension. J Pediatr. 2009;155:841-847.

Wiswell TE, Knight GR, Finer NN, et al. A multicenter, randomized, controlled trial comparing Surfaxin (lucinactant) lavage with standard care for treatment of meconium aspiration syndrome. Pediatrics. 2002;109:1081-1087.

95.8 Diaphragmatic Hernia

Akhil Maheshwari, Waldemar A. Carlo

A diaphragmatic hernia is defined as a communication between the abdominal and thoracic cavities with or without abdominal contents in the thorax (Fig. 95-10). The etiology may be congenital or traumatic. The symptoms and prognosis depend on the location of the defect and associated anomalies. The defect may be at the esophageal hiatus (hiatal), paraesophageal (adjacent to the hiatus), retrosternal (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 highly variable, ranging from a small hole to complete agenesis of this area of the diaphragm.

Figure 95-10 A, A normal diaphragm separating the abdominal and thoracic cavity. B, Diaphragmatic hernia with a small lung and abdominal contents in the thoracic cavity.

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 hypoplasia. Lung hypoplasia was initially thought to be due solely to the compression of the lung from the herniated abdominal contents, which impaired lung growth. However, emerging evidence indicates that pulmonary hypoplasia, at least in some cases, may precede the development 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 thickened 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 hypoplasia and malrotation of the intestine are part of the lesion, not associated anomalies. Most cases of CDH are sporadic, but familial cases have been reported. In one study, complete agenesis of the diaphragm had an autosomal recessive pattern of inheritance; in the majority of cases, genetic factors are multifactorial. Associated anomalies have been reported in up to 30% of cases; these include CNS lesions, esophageal atresia, omphalocele, 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.

Diagnosis and Clinical Presentation

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 polyhydramnios, 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 to head size ratio (LHR). Nonetheless, no definitive characteristic reliably predicts outcome. After delivery, a chest radiograph is needed to confirm the diagnosis (Fig. 95-11). In some infants with an echogenic chest mass, further imaging is required. The differential diagnosis may include a cystic lung lesion (pulmonary sequestration, cystic adenomatoid malformation) requiring a CT scan or an upper gastrointestinal radiographic series to confirm the diagnosis.

Figure 95-11 This chest radiograph shows a stomach, nasogastric tube, and small bowel contents in the thoracic cavity, consistent with a congenital diaphragmatic hernia (CDH).

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 amniocentesis. 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 respiratory distress, within 6 hr of life, 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 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 displaced away from the side of the hernia if mediastinal shift has occurred. A chest radiograph 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 as a result of intestinal obstruction or mild respiratory symptoms. Delayed presentation of a diaphragmatic hernia (often right-sided) after a documented episode of group B streptococcal sepsis is well described. 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.

Treatment

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 contralateral 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 (GERD) is reported in more than 50% of children with CDH. It is more common in those children whose diaphragmatic defect involves the esophageal hiatus. Approximately 25% of cases of GERD in children with CDH are refractory to medical management and require an antireflux procedure. Intestinal obstruction is reported in up to 20% of children. This condition could be due to 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, GERD, and a caloric requirement that may be higher because of the 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 be due to 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 abnormalities that appear to improve with time but require close monitoring and multidisciplinary support.

Bibliography

Congenital Diaphragmatic Hernia Study Group. Surfactant replacement therapy on ECMO does not improve outcomes in neonates with congenital diaphragmatic hernia. J Pediatr Surg. 2004;39:1632-1637.

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. 2003;349:1916-1924.

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. 2003;75:250-256.

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. 2007;150:235-240.

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. 2006;16:385-391.

Smith NP, Jesudason EC, Featherstone NC, et al. Recent advances in congenital diaphragmatic hernia. Arch Dis Child. 2005;90:426-428.

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. 2004;145:312-316.

95.9 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. 95-13). 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. Theanteroposterior radiograph shows a structure behind the heart, and a lateral film localizes the mass to the retrosternal area. Chest CT 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 laparoscopically or by an open approach. Prosthetic material is rarely required.

Figure 95-13 A chest radiograph demonstrating a Morgagni hernia.

95.10 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.

95.11 Eventration

Akhil Maheshwari, 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 hemidiaphragm. 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 paralysis, diaphragmatic hernia, traction injury, and iatrogenic injury after heart surgery. Eventration is also associated with pulmonary sequestration, congenital heart disease, and chromosomal trisomies. Most eventrations are asymptomatic and do not require repair. The indications for surgery include continued need for mechanical ventilation, recurrent infections, and failure to thrive. Large or symptomatic eventrations can be repaired by plication through an abdominal or thoracic approach that is minimally invasive.

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. 2002;37:357-366.

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

Congenital Diaphragmatic Hernia Study Group. Surfactant replacement therapy on ECMO does not improve outcomes in neonates with congenital diaphragmatic hernia. J Pediatr Surg. 2004;39:1632-1637.

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. 2003;349:1916-1924.

Hutcheon JA, Butler B, Lisonkova S, et al. Timing of delivery for pregnancies with congenital diaphragmatic hernia. BJOG. 2010;117:1658-1662.

95.12 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 pneumomediastinum are less common (Chapter 94). The incidence of pneumothorax is increased in infants with lung diseases such as meconium aspiration and RDS; in those who have undergone vigorous resuscitation or are receiving 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 may be due to underlying pulmonary disease, such as lobar emphysema or rupture of a congenital 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 hours after birth, and is due to reduced alveolar surface area and poorly compliant lungs. It is associated with disorders of decreased amniotic fluid volume (Potter syndrome, renal agenesis, renal dysplasia, chronic amniotic fluid leak), decreased fetal breathing movement (oligohydramnios, neuromuscular disease), pulmonary space-occupying lesions (diaphragmatic hernia, pleural effusion, chylothorax), and thoracic abnormalities (asphyxiating 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 (subcutaneous 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 catheters, 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 atmospheric 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 asymmetric with an increased anteroposterior diameter and bulging of the intercostal spaces on the affected side; other signs may be hyperresonance 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 (PMI) of the heart. The diaphragm is displaced downward, as is the liver with right-sided pneumothorax, and may result in abdominal distention. Because pneumothorax 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 occurs in at least 25% of 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 two findings are a result of tamponade of the systemic and pulmonary veins. Although often asymptomatic, subcutaneous 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 hypoxia. The last is due to an increased alveolar-arterial oxygen gradient and intrapulmonary shunting. Progressive enlargement of blebs of gas may result in cystic dilatation and respiratory deterioration resembling pneumothorax. In severe cases, PIE precedes the development of BPD. Avoidance of high inspiratory or mean airway pressures may prevent the development of PIE. 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 lung standing out in relief against the pneumothorax (Fig. 95-14); pneumomediastinum is signified by hyperlucency around the heart border and between the sternum and the heart border (Fig. 95-15). Transillumination of the thorax is often helpful in the emergency diagnosis of pneumothorax; the affected side transmits excessive light. Associated renal anomalies are identified by ultrasonography. Pulmonary hypoplasia is suggested by signs of uterine compression (extremity contractures), a small thorax on chest roentgenograms, severe hypoxia with hypercapnia, and signs of the primary disease (hypotonia, diaphragmatic hernia, Potter syndrome).