Chapter 50. Abnormalities of the Lungs

Respiratory distress syndrome in the newborn (discussed in detail in Chapter 54) is the most frequent problem that results in neonatal intensive care unit admission. It is essential to recognize, evaluate, and differentiate between the many possible causes of respiratory distress, including those that do not primarily involve the lung. The presenting symptoms and severity of these symptoms may alert the physician in a life-threatening situation.

One or more of the following may characterize respiratory distress in the newborn: tachypnea, grunting, nasal flaring, and chest retractions. A newborn normally breathes at a rate of 30 to 60 breaths per minute. A newborn with tachypnea may breathe at a faster rate to maintain adequate ventilation and may attempt to decrease airway resistance by flaring the nares. The infant may try to maintain lung volume by partially closing the glottis during expiration, thereby producing grunting sounds. Chest retractions may occur with parenchymal lung disease or an obstructed airway. Additional signs such as cyanosis, gasping, apnea, stridor, or choking should alert the physician of a more severe respiratory problem. Respiratory distress in the newborn is a common presentation for a wide variety of disorders shown in Table 50-1.

Transient tachypnea of the newborn (TTN) is a self-limited, usually benign disease, affecting the term infant and late-preterm infant soon after birth. Avery and coworkers described the clinical and radiographic features of this condition in 1966 and attributed it to a delayed absorption of fetal lung fluid.1 More recently, Bland2,3 described TTN as a persistent postnatal pulmonary edema, since some of the fluid may enter the lungs from the pulmonary circulation postnatally. TTN occurs in approximately 11 infants per 1000 live births and is more common in males. It is associated with cesarean section delivery,4 the use of maternal labor analgesia or anesthesia, gestational diabetes, and perinatal asphyxia.

Pathogenesis

Fetal lung fluid is essential for normal lung development, is a secretion intrinsic to the lung, and is not aspirated amniotic fluid.5 Fetal lung fluid is the result of active chloride secretion by the distal lung epithelia.6-8 The chloride ion draws fluid from the pulmonary circulation into the airways of the lung, where this fluid maintains expansion of the potential air spaces and allows for normal fetal lung growth and development.3,8

A few days before labor begins, secretion of lung fluid decreases in preparation for air breathing. The notion that during a vaginal delivery lung fluid is “squeezed” out accounts for only a fraction of the fluid cleared. The process of fetal lung fluid absorption is much more complicated, and labor plays an essential role.3 From the onset of labor to a few hours after birth, a large amount of extravascular lung fluid is actively absorbed by the lung epithelium. This occurs when the epithelium switches from predominant chloride secretion to predominant sodium absorption. Active transport of sodium across the lung epithelium via sodium channels at the apical membranes and sodium potassium exchange (Na+/K+-ATPase) at the basolateral membranes of epithelial cells drive the fluid from the lung lumen to the interstitium, with subsequent absorption into the vasculature and clearance by lymphatics (Fig. 50-1).8 In transgenic mice, the absence of functional epithelial sodium channels causes early neonatal death secondary to respiratory failure.9 The pulmonary expression and function of these sodium channels increase as birth approaches. With the onset of labor, the changes in ion transport by the fetal lung epithelium are “switched on” by catecholamines and other hormone surges and possibly maintained “on” by increased oxygenation after birth.8,10

Another factor that facilitates in the clearance of fetal lung fluid is the osmotic pressure gradient resulting from the large difference in protein content of the lung fluid (30 mg/dL) and plasma (5–6 g/dL). Infants with TTN are often hypoproteinemic, which may contribute to a decreased plasma oncotic pressure and delayed absorption of lung fluid. Elevated left atrial pressure may also affect the osmotic pressure gradient and inhibit lung fluid absorption.1

Inflation of the lungs at birth also helps clear fetal lung fluid by the increased transpulmonary pressure. Breathing also decreases hydraulic pressure in the pulmonary circulation, and with the differential in plasma protein osmotic pressure, the fluid is drawn from the interstitial space into the vasculature. Most of the lung fluid is cleared directly by the pulmonary circulation. A small amount of fluid is absorbed by the pulmonary lymphatics and extrapulmonary lymphatics.1,2,7 Under normal conditions, the physiologic process of fetal lung fluid clearance begins before birth and continues for 4 to 6 hours at birth. This process may be adversely affected by preterm delivery, delivery without labor, conditions in which left heart failure or hypoxia cause elevated pulmonary vascular pressure, and low plasma protein concentration.

Clinical Features and Diagnosis

The infant with transient tachypnea of the newborn (TTN) presents with tachypnea shortly after birth and mild to moderate signs of respiratory distress, such as nasal flaring, subcostal and intercostal retractions, and grunting during expiration. These infants have mild cyanosis and often require oxygen therapy but rarely need mechanical ventilation. On physical examination, diffuse crackles and rhonchi during the first few hours after birth result from residual fluid within the air spaces of the lungs. Blood gas analysis may be normal or may reveal mild alkalosis and hypoxemia. The characteristic radiographic findings are prominent pulmonary vascular markings especially around the hila, diffuse parenchymal infiltrates, widened interlobar fissures, and some degree of hyperinflation with flattening of the diaphragm. Pleural effusions may also be present, and the cardiac silhouette may appear enlarged (Fig. 50-2).

A diagnosis of TTN in a newborn infant with respiratory distress is made after other lung and cardiac disease have been excluded. Follow-up radiographs assist in differentiating TTN from other lung diseases such as pneumonia, meconium aspiration syndrome, and hyaline membrane disease, where abnormal radiographic findings may persist. Differential diagnoses also include air leaks, airway obstruction, diaphragmatic hernia, lung hypoplasia, and congestive heart failure, which can be excluded by chest radiograph and clinical progression.

Management and Outcome

Supportive care and supplemental oxygen are all that may be required for infants with uncomplicated TTN. The need for mechanical ventilation or a prolonged course of oxygen is rare with TTN and may indicate another lung process. Most of these infants are also evaluated for sepsis, and empiric antibiotic therapy is given for 48 to 72 hours while awaiting blood culture results, clinical improvement, and radiographic evolution. The use of diuretics does not change the clinical course and may cause electrolyte problems. Infants with more moderate disease may respond well to nasal continuous positive airway pressure, which may increase the functional residual capacity and help clear lung fluid. For infants with uncomplicated disease, clinical improvement within 2 to 4 days is typical and prognosis is good without long-term pulmonary sequelae.

Congenital pneumonia is acquired from the mother and presents with clinical signs at or shortly after birth. It may occur in the setting of maternal infection (chorioamnionitis) that may or may not be symptomatic in the mother. The estimated incidence of this early-onset pneumonia ranges from 5 to 50 per 1000 live births, with higher rates occurring in preterm and low-birth-weight infants and in the presence of maternal chorioamnionitis.11 It is a difficult disease to identify prospectively, with nonspecific clinical manifestations that are often shared with noninfectious diseases such as transient tachypnea of the newborn, meconium aspiration, and hyaline membrane disease. (See Chapter 230.)

Etiology

Transmission of the infectious organism from the mother may occur via 3 possible routes.12 The first is via hematogenous transmission whereby the infectious organism is acquired from a maternal bloodstream infection, crossing into the fetal circulation, invading the lungs or causing a more disseminated infection. The second means of transmission is via ascending infection in which the infectious organism is believed to originate in the vagina and then ascend the birth canal and spread to the fetal membranes. Ascending transmission of organisms may be increased by amniocentesis, repeated pelvic examinations, and placement of intrauterine catheters, and it may occur with or without rupture of amniotic membranes. Finally, infectious organisms may be transmitted by aspiration, which is believed to occur in utero when the fetus develops gasping after an asphyxial event and aspirates amniotic fluid containing infectious organisms.13 Early-onset pneumonia may also occur secondary to intrapartum acquisition of infectious organisms during the passage of the newborn through the birth canal. Many pathogens may lead to neonatal pneumonia, but the most common are those also identified in cases of early-onset neonatal sepsis. The usual organisms include group B Streptococcus, Escherichia coli, Listeria, and sometimes Candida albicans or herpes simplex virus.12,13

Clinical Features and Diagnosis

The diagnosis of congenital pneumonia is based on a combination of historical, physical, and radiographic findings. Prenatal risk factors associated with congenital pneumonia in the newborn are the same as those associated with neonatal sepsis, including maternal fever and uterine tenderness, rupture of membranes for longer than 18 hours, foul-smelling amniotic fluid, maternal history of recurrent or recent untreated urinary tract infection, and previous infant with neonatal infection. Peripartum signs that may be associated with congenital pneumonia include fetal tachycardia, loss of beat-to-beat variability, meconium-stained amniotic fluid, and unexplained premature labor.

The clinical presentation of congenital pneumonia in the newborn is nonspecific, making the diagnosis difficult. It should be suspected in any newborn presenting with respiratory distress at or soon after birth and may include clinical signs that overlap with neonatal sepsis, such as temperature instability, hypoglycemia, hyperglycemia, lethargy, abdominal distention, and poor feeding. Some infants with congenital pneumonia may progress to septic shock and disseminated intravascular coagulation and develop pulmonary hemorrhage, air leaks, effusions, and pulmonary hypertension.

Radiographic and laboratory data are also nonspecific and share findings not only with neonatal sepsis but also with noninfectious processes such as transient tachypnea of the newborn, hyaline membrane disease, and meconium aspiration syndrome (eFig. 50.1). Blood cultures usually do not yield a pathogen (especially if maternal antimicrobial treatment was given during labor) but should always be obtained. Spinal fluid culture for the evaluation of congenital pneumonia is controversial because the yield is very low (< 1%), and a spinal tap may place a newborn with significant respiratory distress at risk. Culture and Gram stain of tracheal aspirate from a newly placed (within 8 hours of delivery) endotracheal tube may provide an early and specific diagnosis in some infants with congenital pulmonary infection.13 The use of inflammatory markers to support a diagnosis of infection, including pneumonia, is presently controversial.

Therapy and Prognosis

Supportive care should be provided, with a normothermic environment, adequate dextrose and fluid infusion, prompt correction of metabolic acidosis, supplemental oxygen, and mechanical ventilation if needed to maintain adequate oxygenation and ventilation. Antibiotic treatment with a broad-spectrum penicillin and an aminoglycoside is indicated until cultures are reported, and in many cases, it is continued for 7 to 10 days if a clinical diagnosis of congenital pneumonia is highly suspected even when cultures remain negative.

Prognosis is good for term infants with mild to moderate disease who have prompt treatment and no complications. Those infants with severe symptomatology and those who develop complications may have an increased risk of chronic lung disease, reactive airway disease, and childhood otitis media.

Massive pulmonary hemorrhage in the newborn infant is a catastrophic event that usually occurs between the second and fourth day of life. The incidence of pulmonary hemorrhage occurs at a rate of 1 to 12 per 1000 live births.14 Surprisingly, pulmonary hemorrhage was the principal cause of death in approximately 9% of neonatal autopsies.15 It occurs most commonly in preterm infants, usually associated with a patent ductus arteriosus.16 Other risk factors are perinatal conditions: preeclampsia, erythroblastosis fetalis, breech delivery, and maternal cocaine use; and neonatal factors: coagulopathies, infection, asphyxia, hypothermia, congenital heart disease, and aspiration.

Pathogenesis

The pathophysiology of pulmonary hemorrhage in newborn infants is still not clear. Cole and colleagues17 found that the fluid from the lungs of infants with pulmonary hemorrhage was a plasma filtrate with low hematocrit, characteristic of hemorrhagic edema. The most important precipitating factor was postulated to be acute left ventricular failure from hypoxia and severe acidosis, causing increased pressure in the pulmonary microcirculation and increased filtration of fluid into the lung. Alveolar overdistension and high pulmonary capillary pressures cause breaks in the epithelial-endothelial barrier leading to leakage of hemorrhagic edema fluid into the air spaces.14 Toxic products from sepsis increase microvascular permeability in the pulmonary circulation, which may contribute to pulmonary hemorrhage. Preterm infants with increased cord blood neutrophil chemotaxis and chemiluminescence were reported to be at high risk of pulmonary hemorrhage, possibly related to entrapment of neutrophils in the pulmonary microcirculation and injury to the alveolar-capillary barrier.18 In the preterm infant with a large patent ductus arteriosus, pulmonary hemorrhage may result from injury to the microvasculature from high pressure and high flow.16,19 Surfactant therapy has also been associated with pulmonary hemorrhage, perhaps from the rapid increase in pulmonary blood flow that occurs with the improvement in lung function after surfactant administration.20

Clinical Features and Diagnosis

The infant may present with increased respiratory distress, apnea, pallor, peripheral vasoconstriction, and bradycardia minutes before the onset of hemorrhage. Severe metabolic acidosis may precede the onset of hemorrhage. With massive hemorrhage, blood may be noted from the nose and mouth or from the endotracheal tube if the infant is intubated. The fluid may have a normal to low hematocrit. Chest radiographic findings are varied and nonspecific and may range from patchy infiltrates to complete opacification of the lung fields.

Management

A large pulmonary hemorrhage is a life-threatening event that requires immediate support and resuscitative measures. The airway must be cleared by suction to allow for adequate ventilation and oxygenation. Mechanical ventilation should provide sufficient mean airway pressure to maintain lung volume and sustain gas exchange. In a massive pulmonary hemorrhage, transfusion with packed red blood cells may be necessary to maintain adequate perfusion and blood volume. Caution should be used with excessive transfusion volumes which can increase left atrial pressure and cause pulmonary edema. Treatment of the underlying factor, such as sepsis, asphyxia, coagulopathy, or patent ductus arteriosus, should be undertaken promptly.

New treatment modalities being investigated include hemocoagulase and activated recombinant factor VII.15,21 Hemocoagulase is a substance prepared from the venom of the Brazilian snake B. Atrox and has been used clinically to control bleeding in abdominal surgery and human vitrectomy. Hemocoagulase, in addition to mechanical ventilation, decreased in duration of hemorrhage and a decreased number of ventilation days in the survivors for a group of infants with pulmonary hemorrhage in a small trial.14 The successful use of activated recombinant factor VII was described in 2 cases of newborns with pulmonary hemorrhage. Activated recombinant factor VII is a vitamin K–dependent glycoprotein structurally similar to plasma-derived human factor VII. It is used clinically in severe, life-threatening hemorrhages in patients with hemophilia and to treat nonhemophiliacs with severe hemorrhage where conventional therapies have failed.20 Further studies are needed before either hemocoagulase or activated recombinant factor VII can be recommended for newborns with pulmonary hemorrhage.

Outcomes

Mortality rates range from 30% to 60% in premature infants; approximately 60% of the survivors develop chronic lung disease.15,21 Mortality in term infants with pulmonary hemorrhage is related to the underlying precipitating disease process.

Meconium is present in the fetal intestine as early as 14 to 16 weeks of gestation. It is an odorless substance composed primarily of water and squamous cells, vernix, lanugo, blood, amniotic fluid, and intestinal secretions containing bile that imparts a black-green color. Passage of meconium in utero is rare before 32 weeks of gestation, making meconium aspiration syndrome (MAS) a disorder affecting near-term, term, and postterm infants.22-25

Incidence

Meconium staining of amniotic fluid occurs in approximately 10% to 15% of all live births, with 4% to 5% of these infants developing MAS.24 Respiratory failure is usually associated with the aspiration of thick or particulate meconium but may also occur in newborns in whom no meconium was recovered from below the vocal cords. Abnormalities of fetal heart tracings and low Apgar scores have been associated with the presence of meconium-stained fluid and MAS. Advanced gestation of 42 weeks or more increases the risk of meconium passage (30–50% of postterm infants), putting these infants at higher risk of MAS compared to term infants (7–22%) and preterm infants (< 2%).22,24

Pathogenesis

The passage of meconium in utero may be a response to fetal distress secondary to hypoxia, acidosis, or infection, which may cause relaxation of the anal sphincter and promote intestinal peristalsis. Ghidini and Spong26 hypothesized that severe meconium aspiration syndrome is not related to aspiration of meconium but to other pathologic processes occurring in utero, such as chronic asphyxia, infection, and pulmonary hypertension, with meconium in the lungs being an incidental finding. Oligohydramnios has also been associated with meconium passage, possibly resulting from compression of the umbilical cord or fetal head, thereby promoting a vagal response in the fetus. The timing of aspiration is still unclear in most infants. Fetal distress may cause the passage of meconium in utero; if the distress is ongoing and leads to fetal hypoxia, gasping may occur, explaining the aspiration prior to delivery. Stillborn infants and infants who die soon after birth can have lungs full of aspirated meconium. Aspiration of meconium may also occur during and soon after delivery. Meconium may be present in the infant’s mouth and upper airway and may be aspirated with the onset of breathing.

Aspiration of meconium-containing amniotic fluid can cause lung injury via a number of mechanisms. The meconium initially will partially obstruct the airways with air trapping and overdistension of the lungs, which may lead to air leaks. It may cause complete obstruction of some airways, atelectasis, and ventilation-perfusion mismatch. Meconium may induce inflammation and a chemical pneumonitis, and it may also inactivate surfactant. The most severe respiratory disease occurs in infants with aspiration of thick-particulate meconium, but respiratory comprise may also occur in infants who present with thin meconium-stained fluid. The hypoxia, hypercapnia, acidosis, and inflammatory reaction associated with meconium aspiration may result in the development of persistent pulmonary hypertension of the newborn (Fig. 50-3 and Chapter 61).

Clinical Features and Diagnosis

The predelivery course may indicate fetal distress with asphyxia, and after delivery, the infant often will have low Apgar scores and require resuscitation. The skin, nails, and umbilical cord may be stained with meconium. Meconium may be in the mouth and pharynx and may be suctioned from the trachea. The infant often will have signs of respiratory distress, such as tachypnea, retractions, and cyanosis. The chest may appear barrel-shaped on examination secondary to lung overinflation. Breath sounds may be obscured by coarse bronchial sounds, and expiration may be prolonged because of small airway obstruction. Occasionally, infants with meconium aspiration syndrome may have minimal symptomatology or even be asymptomatic.

The radiographic findings of meconium aspiration syndrome (MAS) do not always correlate with the severity of the clinical disease. With severe aspiration, the chest radiograph may reveal areas of patchy infiltrates with regions of atelectasis and overinflation with flattened diaphragms (eFig. 50.2). Pneumomediastinum and pneumothorax occur in as many as 10% to 15% of infants with MAS23 and may be already present on initial radiograph or develop later in the course of the disease. Early in the clinical course of MAS, hypoxemia and some degree of metabolic acidosis may represent perinatal asphyxia. Later in the course of the disease, the partial pressure of carbon dioxide in arterial blood (PaCO2) may increase and the hypoxia may worsen, reflecting the effects of meconium in the smaller airways, the ongoing inflammatory process, and the surfactant inactivation.

Pulmonary Function

Partial small airway obstruction caused by aspiration of thick, particulate meconium will result in air trapping and alveolar overinflation (a ball valve effect), which will cause ventilation-perfusion mismatching and hypoxemia. Reduced lung compliance and increased airway resistance lead to an increased work of breathing and result in alveolar hypoventilation and CO2 retention.23 With complete small airway obstruction (a stop valve effect), distal alveolar gas is absorbed, resulting in collapse of the alveoli, which can then increase intrapulmonary shunting and lead to more severe arterial hypoxemia. The later stages of meconium aspiration syndrome are characterized by pulmonary inflammation, which causes microvascular endothelial damage, further increasing intrapulmonary shunt and alveolar collapse. Infants with severe meconium aspiration syndrome have a marked reduction in dynamic lung compliance,23 which may be secondary to the inflammation or inactivation of surfactant by meconium.27

Prevention

Antenatal Prevention

Ideally, management of meconium aspiration syndrome (MAS) should begin prior to delivery with the goal of preventing the aspiration. Fetal monitoring during labor can provide some insight into fetal well-being. However, fetal monitoring does not prevent meconium aspiration. Elective caesarean section delivery of infants born through meconium-stained fluid does not prevent MAS, yet, most studies indicate that infants with MAS are more likely to be delivered via cesarean section, often prompted by abnormalities detected during fetal monitoring.24,25,28

Amnioinfusion, the injection of hypotonic fluid into the amniotic cavity, has been evaluated for the prevention of MAS.25,28 The theory is that diluting the meconium in the amniotic fluid might reduce its toxicity and that aspiration of thinner meconium could potentially cause less injury. Amnioinfusion also was proposed to relieve compression of the umbilical cord or fetal head in the presence of oligohydramnios by increasing the amniotic fluid volume and thereby preventing fetal heart rate decelerations. Because oligohydramnios was associated with the passage of meconium in utero, prophylactic amnioinfusion in the presence of oligohydramnios has been advocated to prevent fetal hypoxia and gasping that would lead to in utero aspiration. Several small trials seemed to support the benefits of amnioinfusion in patients with meconium-stained fluid. However, a large, multicenter, randomized trial found no reduction in the rate of moderate or severe MAS with the use of prophylactic amnioinfusion.25 Furthermore, significant fetal and maternal complications have been reported with amnioinfusion.

Postnatal Prevention

Oropharyngeal and nasopharyngeal suctioning after delivery of the head but before delivery of the shoulders (intrapartum suctioning) had been recommended since early reports by Carson and colleagues demonstrated a decrease in the incidence of meconium aspiration syndrome following this procedure.26 Recent evidence from a large, multicenter, randomized trial revealed that the previous practice of routine intrapartum oropharyngeal and nasopharyngeal suctioning of term infants born through meconium-stained amniotic fluid does not prevent meconium aspiration syndrome or its complications.29

The previous recommendation was that infants with meconium-stained fluid have tracheal intubation immediately following birth, with the procedure repeated if meconium was suctioned from below the vocal cords and the infant’s heart rate remained stable. However, randomized controlled trials have shown that this practice offers no benefit for the vigorous infant.30 A vigorous infant is defined as one who has strong spontaneous respiratory effort, good muscle tone, and a heart rate of 100 or more beats per minute. Tracheal intubation and suction now is recommended immediately after birth and before stimulation only for infants who are not vigorous. If no meconium is recovered, then normal resuscitation procedures should proceed. If meconium is recovered with suctioning, then this procedure may be repeated if no bradycardia has occurred. Infants born through meconium-stained fluid who experience apnea or respiratory distress should have tracheal suctioning before positive pressure ventilation, even if they were initially vigorous. Controversy remains whether to suction a vigorous infant born through thick meconium fluid.30,31 The incidence of meconium aspiration syndrome has decreased in recent years, probably because of better fetal surveillance with aggressive intervention for fetal distress and the avoidance of postmaturity.

Management

The infant with meconium aspiration syndrome (MAS) should have pulse oximetry monitoring of oxygenation, blood gas analysis, and radiographic evaluation. High concentrations of oxygen may be required to maintain partial pressure of arterial oxygen (PaO2) above 70 to 80 mm Hg or oxygen saturation above 95%. Some degree of metabolic acidosis is usually present and should be corrected to decrease the risk of pulmonary vasoconstriction and hypertension. Infants with MAS may initially tolerate spontaneous breathing, but as the disease progresses, mechanical ventilation may be required. High-peak inspiratory pressures may be necessary to overcome reduced lung compliance and increased airway resistance associated with meconium plugging or injured lungs, which may increase the risk of air leak and further lung injury. The use of high-frequency ventilation in MAS may be necessary to avoid excessive peak inspiratory pressures or if pulmonary hypertension complicates the clinical course of MAS. However, hyperventilation to low PCO2 values should be avoided because of the associations with lung and brain injury. Animal studies31 have shown enhanced CO2 elimination, increased lung compliance, and diminished right-to-left shunts with the use of high-frequency ventilation compared to conventional ventilation in MAS models. Sedation may be necessary during the first 24 to 48 hours in those infants who fight mechanical ventilation and whose agitation may worsen their clinical course and pulmonary hypertension.

MAS may inactivate endogenous surfactant. Multiple small trials33,34 demonstrated improved outcome and reduced need for extracorporeal membrane oxygenation when exogenous surfactant is used early in the course of the disease. Clinical trials32,34 have reported better outcomes in infants with MAS treated with surfactant therapy and high-frequency ventilation, suggesting stabilization of alveoli and small airways with surfactant and high mean airway pressures improve lung function. Preliminary studies33 suggest lavage of the MAS lung with dilute surfactant may improve gas exchange, decrease air leaks, and improve clearance of meconium from the lungs but this approach remains experimental.

MAS may cause chemical pneumonitis and inflammation and increase the risk of bacterial invasion and infection. Clinical infection with MAS cannot be distinguished from MAS alone. In addition, maternal infection may be the trigger for fetal distress, leading to meconium passage in utero and MAS. Therefore, infants with MAS born to mothers with chorioamnionitis, fever during labor, or history of untreated urinary tract or other infection should have a sepsis evaluation and antibiotic therapy.

Inhaled nitric oxide (iNO) is effective treatment for pulmonary hypertension in term newborns. The use of iNO in MAS complicated by pulmonary hypertension may improve oxygenation and prevent the need for extracorporeal membrane oxygenation (see Chapter 61).

Outcomes and Complications

Infants with severe meconium aspiration syndrome (MAS) may develop life-threatening complications. Air leaks occur in 10% to 15% of newborns with MAS24 and may complicate ventilation and oxygenation. Air leaks result from obstruction of the small airways, leading to gas trapping and maldistribution of inspired air in the terminal air sacs and rupture of the alveoli. Prolonged intubation and ventilation in infants with severe MAS may lead to airway injury, subglottic stenosis, reactive airway disease, and feeding problems.22-24 Most infants with mild to moderate MAS survive without major sequelae, with overall survival rates greater than 95%. However, neurological and developmental sequelae are prevalent in infants with severe MAS associated with perinatal asphyxia and postnatal hyperventilation. Despite new therapeutic strategies and modes of ventilation, MAS remains a challenging condition with significant risks.

Pulmonary air leaks are a common complication in the newborn with lung disease. Air leaks may present as extrapulmonary gas collections within lung tissue, causing pulmonary interstitial emphysema; the mediastinum, causing pneumomediastinum; the pericardial sac, causing pneumopericardium; the intrapleural space, causing pneumothorax; and may extend into the peritoneal cavity, causing pneumoperitoneum. Prompt diagnosis and aggressive intervention are essential to minimize morbidity and mortality with air leaks.

Incidence

Spontaneous pneumothorax occurs in approximately 1% of infants born vaginally at term and in approximately 2% of those born via cesarean section.35 Small air leaks in asymptomatic infants may go undetected and resolve spontaneously. The incidence of air leaks in newborns is more common in infants with lung disease and is significantly higher in infants who require respiratory interventions at the time of birth. The use of more cautious ventilation strategies and surfactant therapy in the preterm infant is associated with a decline in air leaks.

Pathogenesis

Air leaks often begin with some degree of pulmonary interstitial emphysema. Air that has leaked may track through the perivascular and peribronchial cuffs to the hilum of the lung and rupture into the mediastinum (to produce a pneumomediastinum), into the pleural space (to produce a pneumothorax), and, more rarely, into the track from the mediastinum to the pericardial space (producing a pneumopericardium) and peritoneal cavity (producing a pneumoperitoneum).

Clinical Features and Diagnosis

Clinical signs and symptoms of air leaks depend on the location and size of the air accumulated. A small pneumothorax or the presence of a small degree of pulmonary interstitial emphysema may be asymptomatic and resolve spontaneously. However, an infant with a large air leak, either into the interstitium or the pleural space, may present with respiratory distress or a sudden deterioration in clinical status. Tachypnea is a universal finding and may be accompanied by grunting, pallor, or cyanosis. When a pneumothorax is present, chest asymmetry and/or abdominal distention may be noted if air is displaced to one side of the chest or into the abdomen. Breath sounds may be decreased on the affected side, and heart sounds may be displaced or muffled by the air. With a large air leak, particularly one involving the pericardial sac, compression of the great veins can decrease stroke volume, cardiac output, and systemic blood pressure.36 Pneumomediastinum alone is rarely symptomatic, but if the tension increases, air can dissect into the soft tissues of the neck, producing subcutaneous emphysema, or can rupture into the intrapleural space. A pneumoperitoneum, if large, may cause respiratory compromise and require drainage. To differentiate it from a gastric or bowel perforation needle aspiration of the abdomen may be necessary. If it reveals green or brown peritoneal fluid, then a primary bowel perforation is more likely.37

Pulmonary interstitial emphysema most often presents in a preterm infant with significant lung disease requiring ventilatory support. The clinical picture is often one of respiratory deterioration, requiring increased ventilator settings. The diagnosis requires a chest radiograph because pulmonary interstitial emphysema cannot be diagnosed by transillumination of the chest. A small pneumothorax or the presence of pulmonary interstitial emphysema may be an incidental finding on chest radiograph of a newborn with mild distress. In the infant with severe respiratory distress or sudden worsening of clinical status, translumination of the chest38 may be a very useful and life-saving technique to diagnose a large pneumothorax at the bedside. The technique is best performed using a fiber optic light probe placed on the infant’s chest wall in a darkened room. The hemithorax on the affected side will light up when a large pneumothorax is present. The contralateral side will have diminished translumination secondary to lung compression. Immediate decompression is necessary and need not await radiographic confirmation if the infant is unstable. If translumination is questionable and the infant is stable, radiographic evaluation is appropriate. A radiograph will allow for better localization and quantification of the pneumothorax and differentiation from pulmonary interstitial emphysema, pneumomediastinum, or pneumopericardium.

A large pneumothorax will be easily identified by chest radiograph. Air will be present in the pleural cavity separating the lung parietal and visceral pleura. The ipsilateral lobes will be collapsed, the mediastinum may be displaced to the contralateral side, and the diaphragm may be displaced downward (Fig. 50-4). In bilateral tension pneumothoraces, the heart will appear small on chest radiograph. The chest radiograph of an isolated pneumomediastinum may demonstrate a hyperlucent area lateral to the heart borders, elevating the thymus away from the pericardium in the characteristic “spinnaker sail” sign shown in eFigure 50.3. The classic radiographic finding in a pneumopericardium will demonstrate air completely surrounding the heart on all borders.

Management

A small pneumothorax in an asymptomatic infant may not require any intervention. Close monitoring of vital signs is essential, and repeat chest radiographs may be necessary if respiratory symptoms occur. The use of 100% oxygen to help accelerate resorption of the pneumothorax, although sometimes used, is not recommended in the newborn because the high oxygen tension in arterial blood may cause retinopathy of prematurity, and high concentrations of inspired oxygen may cause lung damage.

Infants with pulmonary interstitial emphysema require close clinical and radiographic monitoring as well as ventilation with lower peak pressures. High-frequency oscillatory ventilation may be preferable to conventional mechanical ventilation in the presence of pulmonary interstitial emphysema and other types of air leaks.

The infant with a symptomatic pneumothorax requires immediate intervention. If the infant presents with severe respiratory distress, hypoxemia, hypercarbia, and hypotension, immediate chest tube insertion is the recommended treatment. If this is not possible, then emergency needle decompression may be performed, preferably using a 22- or 20-gauge Stylette/catheter combination connected to a 3-way stopcock and 10-ml syringe. The needle is inserted through the second intercostal space (above the rib) at the midclavicular line until it enters the pleural space while maintaining negative pressure in the syringe. The catheter then is advanced, and the needle is removed. When the air is removed from the pleural space, the plastic catheter is withdrawn, and a chest radiograph is obtained to evaluate for persistent air leak or reaccumulation of air. Needle aspiration of a pneumothorax may be life-saving by restoring venous return and improving stability of the infant, but it is not the definitive treatment for persistent pneumothorax.

Chest tube placement39 is done in a controlled environment under sterile conditions. The infant is positioned with the affected side up. The area of the third to fifth intercostal space in the midaxillary line is cleaned and draped, and local anesthesia is applied. A small incision is made directly over the rib, below the desired intercostal space (avoiding any breast tissue). A track over the superior margin of the rib through the intercostal muscles is bluntly dissected using a hemostat until the pleural membrane is reached. With the closed hemostat grasping the chest tube, the pleural cavity is entered and the chest tube is angled anteriorly and superiorly to the desired distance based on the infant’s weight. The chest tube is attached to an underwater seal at a suction pressure of 10 to 20 cm water and is secured in place by suturing and occlusive dressing. Chest radiographs should be obtained to confirm adequate placement of the chest tube and removal of air from the pleural space. The chest tube should be maintained until bubbling has ceased and no air leak is observed on radiograph.

The newborn cardiopulmonary system must undergo a rapid transition at birth for infant survival. Extrauterine life demands that the newborn lungs become gas exchange organs and that the circulation perfuse the lungs. If these changes do not occur at birth, the newborn will remain hypoxic, and pulmonary vascular resistance will not decrease, leading to persistent pulmonary hypertension of the newborn (PPHN). Meconium aspiration syndrome (MAS) is the most common cause of PPHN, with PPHN occurring in 40% to 75% of severe cases of MAS.26,40 PPHN is also associated with abnormalities of pulmonary vasculature structure, as seen with congenital diaphragmatic hernia, and with certain congenital heart anomalies. PPHN occurs in 1 to 2 infants per 1000 live births, most commonly in near-term or term infants.39 Maternal asthma, diabetes, and obesity may be associated with an increased risk for PPHN.41 Other perinatal risk factors include fetal distress, malpresentation at delivery, cesarean section delivery, postmaturity, neonatal infection, pneumonia, polycythemia and hyperviscosity, and maternal exposure to nonsteroidal anti-inflammatory drugs. When PPHN occurs with no obvious clinical association, it is considered to be idiopathic PPHN.40

Fetal Pulmonary Vascular Development

Understanding the complex pathogenesis of PPHN and possible therapies requires knowledge of the developmental changes of the fetal pulmonary circulation in transition to a newborn pulmonary circulation. Because of the high pulmonary vascular resistance in utero, pulmonary blood flow is about 10% of the combined ventricular output, with most of the blood shunted right to left across the ductus arteriosus and foramen ovale.41,42 The mechanisms contributing to high pulmonary vascular resistance in utero are not completely understood but include low oxygen tension, low basal production of the vasodilators nitric oxide and prostacyclin, production of vasoconstrictors endothelin-1 and thromboxane A2, and alterations of smooth muscle cell reactivity.41-43

A rapid drop in pulmonary vascular resistance at birth accommodates an 8-fold to 10-fold rise in pulmonary blood flow.41 Pulmonary vascular transition is initiated by sheer stress, ventilation and rhythmic breathing, clearance of lung fluid, and increased oxygen tension, all contributing to a reduction in pulmonary vascular resistance and increased pulmonary blood flow as the lungs establish gas exchange. Pulmonary vascular tone decreases in part by increased production of the pulmonary endothelial cell mediators nitric oxide and prostacyclin that vasodilate smooth muscle.

Endothelial nitric oxide synthesis is regulated during lung development.41,42 Pulmonary expression of endothelial nitric oxide synthase and its target, soluble guanylate cyclase, increases in the last trimester of gestation and increases further with birth. The increased nitric oxide production and soluble guanylate cyclase activity increase concentrations of cyclic guanosine monophosphate in vascular smooth muscle cells and increase vessel relaxation through regulation of extracellular calcium mobilization. Another vasodilator, prostacyclin, is generated in the fetal lung from arachidonic acid by cyclooxygenase, which also increases in late gestation.43 Prostacyclin interacts with adenylate cyclase to increase intracellular cyclic adenosine monophosphate levels, causing vasorelaxation. Oxygen also stimulates the activity of endothelial nitric oxide synthase and cyclooxygenases-1 and 2, with increased levels of the vasodilators nitric oxide and prostacyclin.39,41-45 The pulmonary vessels undergo rapid structural adaptation from birth with arterial dilatation and recruitment to accommodate the increased pulmonary blood flow and allow for gas exchange. The pulmonary vessels become less muscular over subsequent weeks.

Pathogenesis

Persistent pulmonary hypertension of the newborn (PPHN) occurs when the normal pulmonary vascular transition does not occur (see Chapter 43).

Infants born with parenchymal lung disease caused by such processes as meconium aspiration, pneumonia, sepsis, or surfactant deficiency may develop PPHN. These conditions may interfere with the normal ventilation and oxygenation of the lungs and lead to acidosis, hypoxia, hypercarbia, and inflammation. These conditions will then affect pulmonary vascular tone with decreased vasodilators (nitric oxide, cyclic guanosine monophosphate, prostacyclin) and increased vasoconstrictors (endothelin-1, thromboxane), resulting in pulmonary vascular constriction (eFig. 50.4).40,42,43

Some infants may develop PPHN without parenchymal lung disease, termed idiopathic PPHN.40 The pulmonary hypertension of idiopathic PPHN appears to be caused by significant remodeling of the pulmonary vasculature, possibly secondary to in utero asphyxia. At autopsy, the pulmonary vessel walls are thickened with extension of muscle into nonmuscular pulmonary arteries. As a result, infants with PPHN do not dilate their pulmonary vasculature adequately at birth and have severe hypoxemia and acidosis. The chest radiograph typically has clear, hyperlucent, underperfused lung fields, and because of these radiographic findings, idiopathic PPHN has been termed “black lung” PPHN.40 Constriction of the ductus arteriosus in utero from exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) during the last trimester of pregnancy is one of the proposed causes of idiopathic PPHN40 (see Chapter 55).39,41,42 Surgical ligation of the ductus arteriosus in fetal lambs results in pulmonary vascular remodeling, elevated pulmonary artery pressures, and profound hypoxemia. NSAIDs are frequently found in meconium from infants with PPHN, and the concentration of these drugs in the meconium correlated with the incidence and severity of the PPHN.39

Disruptions of the nitric oxide–cyclic guanosine monophosphate, prostacyclin–cyclic adenosine monophosphate, and endothelin pathways may also contribute to idiopathic PPHN. Decreased expression and activity of endothelial nitric oxide synthase resulted from ductal ligation in animal models and in newborns with idiopathic PPHN. The role of cyclic guanosine monophosphate, an important vasodilator of vascular smooth muscle, was also demonstrated in ductal ligation models of PPHN. Cyclic guanosine monophosphate production may be reduced by decreased production of nitric oxide and soluble guanylate cyclase, and its destruction may be enhanced by the increased activity of phosphodiesterase type 5.40The reactive oxygen species superoxide and hydrogen peroxide may also promote vasoconstriction and vessel remodeling in PPHN.47,48 Reactive oxygen species originate from endothelial cells, smooth muscle cells, adventitial fibroblasts, and inflammatory cells. Besides the effect on vascular tone, excess reactive oxygen species can stimulate growth of vascular smooth muscle cells and react with nitric oxide, disrupting its physiological signaling and possibly producing toxic and reactive molecules. Endothelin may also increase the production of superoxide and hydrogen peroxide.

Persistent pulmonary hypertension of the newborn frequently occurs in infants with congenital diaphragmatic hernia and lung hypoplasia. Because the pulmonary vasculature develops in parallel with the conducting airways, hypoplasia of the pulmonary vascular bed occurs in conjunction with the lung hypoplasia. In addition to the reduction in total cross-sectional area of the pulmonary vascular bed, there is increased muscularization of the intra-acinar pulmonary arteries, which will decrease pulmonary blood flow.40,42,43 This may be further decreased by abnormal pulmonary vasodilation via the pathways outlined previously.

Clinical Features and Diagnosis

The infant with persistent pulmonary hypertension of the newborn (PPHN) may have a history of fetal distress, meconium passage in utero, or risk factors for infection and pneumonia. The infant with PPHN may be normal at birth and then progress to cyanosis, tachypnea, and signs of respiratory distress within hours or may have cyanosis and distress at birth.

On physical examination, a systolic murmur may be appreciated secondary to tricuspid insufficiency, and the second heart sound may be louder than usual as a result of a more forceful pulmonic valve closure. Differential cyanosis may be observed, with greater preductal oxygen saturation (right upper extremity) when a large right-to-left shunt exists at the level of the ductus arteriosus. Arterial blood gas analysis may reveal severe arterial oxygen desaturation with relatively normal CO2 tensions, depending on the associated lung disease, and marked acidosis reflecting poor tissue perfusion. Chest radiographs will reflect the underlying lung disease process in infants with MAS, congenital diaphragmatic hernia, and pneumonia. The infant with idiopathic PPHN will have clear, hyperlucent, or undervascularized lung fields and possibly an enlarged cardiac silhouette.

Echocardiography with Doppler flow studies are the most useful diagnostic tools for PPHN. Cyanotic congenital heart disease must be excluded. The right-to-left shunts across the foramen ovale and ductus arteriosus and tricuspid valve regurgitation consistent with elevated pulmonary pressures are diagnosed with flow Doppler. The persistently elevated pulmonary vascular resistance also increases right ventricular afterload and oxygen demand and impairs oxygen delivery to the right ventricle, the posterior wall of the left ventricle, and the subendocardial regions of the right ventricle. The ischemia can cause right and left ventricular failure, papillary muscle necrosis, and tricuspid insufficiency. The increased right ventricular afterload causes displacement of the septum into the left ventricle, impairs left ventricular filling, and reduces cardiac output.

Management

The goals for management of infants with persistent pulmonary hypertension of the newborn are to lower pulmonary vascular resistance, reverse right-to-left shunting, improve oxygenation and tissue perfusion, and maintain systemic blood pressure while reducing oxygen demand. These infants should be cared for in a normothermic environment. Metabolic derangements such as hypoglycemia, hypocalcemia, and acidosis should be corrected promptly. Cardiac evaluation should be of the highest priority, and once congenital heart disease is excluded, cardiac function and systemic arterial pressure should be optimized using low-dose pressors such as dopamine and/or dobutamine and careful use of volume expansion. If the central hematocrit is greater than 60% to 65%, a partial exchange transfusion should be performed to lower the hematocrit and reduce the effects of hyperviscosity on pulmonary artery pressure. Intravenous antibiotics should be started immediately in cases where infection is suspected.

Oxygen should be provided to maintain adequate PaO2. This may be attempted via an oxygen hood if the infant is breathing spontaneously and maintaining a normal or low PaCO2. The use of high concentrations of oxygen can be life-saving in persistent pulmonary hypertension of the newborn, but oxygen is also toxic to the developing lung with formation of reactive oxygen species.47,48 Reactive oxygen species can react with arachidonic acid to form potent vasoconstrictors. Superoxide also inactivates nitric oxide, and the resulting peroxynitrite can cause vasoconstriction, cytotoxicity, and damage to surfactant proteins and lipids.47,48

If supplemental oxygen fails to maintain adequate oxygenation, then mechanical ventilation may be required. The goal of mechanical ventilation is to achieve optimal lung volumes that allow for alveolar recruitment while minimizing lung injury. Infants with parenchymal lung disease and hypoplastic lungs may have a better response to high-frequency oscillatory ventilation, which may allow adequate gas exchange with smaller tidal volumes and lower airway pressures with effective recruitment of the lung. Caution is advised when these infants are mechanically ventilated because excessive pressures and hyperventilation can further promote lung injury, causing inflammation, pulmonary edema, and decreased lung compliance. Overexpansion of the lung may also worsen pulmonary hypertension because the overdistended alveoli can compress the small arterioles and capillaries. Alkali infusions for the treatment of persistent pulmonary hypertension of the newborn (PPHN) do not reduce mortality and were associated with an increased risk for the use of extracorporeal membrane oxygenation (ECMO) and prolonged oxygen dependency.49 Hyperventilation strategies and hypocarbia are of no benefit for PPHN. Gentle ventilation strategies that allow for normal PaCO2 or even permissive hypercarbia are equally effective and potentially less damaging to the lung. Infants with PPHN may be very sensitive to stimulation; therefore, sedation may be necessary to avoid fluctuations in oxygen saturation. However, the use of paralytic agents has been associated with an increased risk for mortality. Surfactant therapy may improve ventilation and oxygenation in infants with MAS and, with sepsis associated PPHN, reduce the need for ECMO.40

Inhaled nitric oxide (iNO) therapy has decreased the need for ECMO in infants with severe PPHN but not in infants with PPHN secondary to congenital diaphragmatic hernia.40,45,50 Inhaled nitric oxide is a potent vasodilator that can be delivered directly to the lungs with minimal systemic effects. Low-dose iNO reduces pulmonary vascular resistance, improves pulmonary blood flow, and improves ventilation-perfusion mismatch in the treatment of severe parenchymal lung diseases.50Sildenafil, a potent and highly specific phosphodiesterase type 5 inhibitor, is presently used for the treatment of pulmonary hypertension in adults.40,45,50 Sildenafil can improve oxygenation in infants with PPHN when iNO is not readily available, and it also attenuates rebound pulmonary hypertension after withdrawal of iNO.40,45,50 Kinsella and coworkers50 found that therapy with iNO and high-frequency ventilation was more successful than either one alone in severe PPHN. Some infants may not respond to iNO therapy and may require ECMO. The use of iNO, high-frequency oscillatory ventilation, and surfactant prior to ECMO has not been associated with any adverse outcomes during ECMO therapy.

Newer therapies are presently being investigated for the treatment of PPHN. For example, scavengers of reactive oxygen species, such as superoxide dismutase, when given via the trachea to newborn lambs with PPHN, alone or in combination with iNO, rapidly increased oxygenation and reduced both vasoconstriction and oxidation.46,47 Understanding the mechanisms involved in the pathogenesis of PPHN has provided information for possible interventions at the level of the endothelial and vascular smooth muscle cells. These new therapies may be effective in the treatment of PPHN associated with congenital diaphragmatic hernia, lung hypoplasia, and idiopathic PPHN.

Outcomes

Persistent pulmonary hypertension of the newborn is fatal in approximately 10% to 20% of cases despite therapies with inhaled nitric oxide, extracorporeal membrane oxygenation, and advanced modes of ventilation.50,51 The survivors of severe persistent pulmonary hypertension of the newborn are at increased risk for serious, long-term sequelae as a result of the hypoxemia associated with this condition and the therapies used for treatment.

Congenital diaphragmatic hernia (CDH) occurs once in every 2000 to 3000 live births and accounts for 8% of all major congenital anomalies.52 CDH is more common in male infants and occurs mostly on the left side (85%). CDH can be associated with chromosomal disorders, such as trisomy 13, 18, and 21; tetraploidy; Pallister-Killian syndrome; and Turner syndrome, as well as in single gene disorders, such as Fryns syndrome. However, most cases of CDH occur as isolated events in nonsyndromic infants. Recurrence in future siblings is approximately 2%, and familial CDH is rare (< 2% of all cases).52,53

Diaphragm Development and CDH Pathogenesis

The diaphragm is a dome-shaped, musculotendinous partition that separates the chest and abdomen. The diaphragm develops by the end of the sixth week of embryogenesis from fusion of 4 structures: the septum transversum, pleuroperitoneal membranes, dorsal mesentery of the esophagus, and the body wall. The posterior portion of the diaphragm is the last to close, and closure occurs from right to left. If closure fails to occur, the most common type of diaphragmatic hernia (a Bochdalek hernia) occurs. Defects in the central and lateral portions of the diaphragm result in a less common anterior retrosternal (Morgagni) hernia. Herniation of the abdominal contents into the chest of the developing fetus occurs if formation of the diaphragm is incomplete when the intestines return to the abdomen from the umbilical cord during the 10th week. Often, the stomach, spleen, and most of the intestines herniate into the thorax. In rare instances, the liver and kidneys may also be in the thoracic cavity. Herniation of the abdominal contents interferes with lung development and growth. Herniation of viscera in congenital diaphragmatic hernia usually occurs during the pseudoglandular stage of lung development. Lung compression results in pulmonary hypoplasia that is most severe on the ipsilateral side, although both lungs may be affected. There is a marked reduction in the number of bronchi and alveoli associated with a decrease in cross-sectional area of the pulmonary vasculature. In addition to parenchymal maldevelopment, the intra-acinar pulmonary arteries have increased muscularization. Pulmonary capillary blood flow is decreased because of the small cross-sectional area of the pulmonary vascular bed, and flow may be further decreased by abnormal pulmonary vasoconstriction. Surfactant production may also be affected by the pulmonary hypoplasia in infants with congenital diaphragmatic hernia.

Prenatal Diagnosis

Diaphragmatic hernia is often diagnosed by fetal ultrasound. The abdominal organs can be seen in the thorax, and fluid-filled bowel with peristalsis in the fetal thorax is diagnostic. Other associated findings may include a shift of the heart and mediastinum away from the side of the hernia. Polyhydramnios, pleural effusions, and ascites are also frequent in fetuses with congenital diaphragmatic hernia. The differential diagnoses of these sonographic findings include congenital cystic adenomatoid malformation, bronchogenic cysts, cystic teratoma, and neurogenic tumors. If CDH is suspected, fetal echocardiography and karyotype should be performed for potential prenatal diagnosis of common associated malformations. Referral to a tertiary treatment center for prenatal counseling and for delivery where effective treatment options are available is recommended. Fetal surgical procedures for CDH have been attempted for the past 2 decades but have failed to improve survival or decrease morbidity and are therefore not routinely recommended at present.

Clinical Features

Clinical presentation of congenital diaphragmatic hernia depends on the type and size of the hernia. The infant with a right-sided hernia may not have symptoms after birth, and the diagnosis may be incidental if not already made prenatally. With right-side hernias, the liver and some intestine may occupy the right hemithorax, but little or no displacement of the heart may occur (eFig. 50.5). These infants have a better prognosis because there will be less lung hypoplasia. When no prenatal diagnosis is available, the infant with a large left-sided hernia may present with a scaphoid abdomen and significant respiratory symptoms in the delivery room. On examination, breath sounds may not be heard on either side of the chest, and the heart sounds may be displaced to the right side. The infant’s respiratory status may worsen as air is swallowed and fills the bowel in the chest, further compressing the lungs. The diagnosis can be made with chest and abdominal radiographs, after an orogastric tube is placed into the stomach. These will reveal the abdominal organs and feeding tube in the thoracic cavity and displacement of the heart and mediastinum to the contralateral side (Fig. 50-5). Further evaluation of the infant with congenital diaphragmatic hernia should include heart echocardiography, chromosomal analysis, and renal ultrasonography secondary to the high incidence of associated malformations.

Approximately 40% of infants with congenital diaphragmatic hernia (CDH) have associated anomalies, most of which have minimal effect on survival, such as malrotation, Meckel diverticulum, undescended testes, unilateral kidney, and atrioseptal defects.54 The associated anomalies that will significantly affect survival include chromosomal and complex cardiac defects. Cardiac defects occur in 10% to 35% of patients with CDH. Isolated ventricular septal defects are the most common cardiac abnormality, occurring in 42% of the patients with CDH, but they have little effect on survival. The other more commonly seen defects are aortic arch obstruction (coarctation of the aorta) (15%) and univentricular anatomy (14%), and less than 5% of these patients survive. Other less common defects include tetralogy of Fallot (11%), total anomalous pulmonary venous return (4%), double outlet right ventricle (3%), transposition of the great arteries (35%), pulmonary stenosis (3%), and other complex defects (6%). During fetal life, the left ventricle is often small (probably as a result of increased intrathoracic pressure) and left ventricular output is reduced. Postnatally, the left ventricular size and output improve with correction of the hernia. Overall survival of patients with CDH and significant cardiac defects was lower than survival of those without heart abnormalities.54

Management

Fetal surgical procedures for congenital diaphragmatic hernia (CDH) have been attempted for the past 2 decades but have failed to improve survival or decrease morbidity and are therefore not routinely recommended at present. When CDH has been diagnosed prenatally, or as soon as the diagnosis is suspected, a double-lumen orogastric tube should be placed into the infant’s stomach in the delivery room to reduce air in the bowel and decrease compression of the lung. If assisted ventilation is required, it should be performed via an endotracheal tube, using the lowest peak pressure (⩽ 25 cm H2O) possible to prevent air leaks and lung injury and bag and mask ventilation for any sustained period should be avoided. Close monitoring of oxygenation and radiological evaluation should be promptly initiated with umbilical catheters placed for blood gas and blood pressure monitoring. Sedation may be needed with infants who resist ventilation to avoid the need for higher pressures and occurrence of pneumothorax. Immediate evaluation of associated anomalies is important and may influence the choice of treatment. In severe cases of lung hypoplasia or infants with CDH associated with severe cardiac or chromosomal defects, treatment may prolong a futile outcome.

Postnatal Care

Postnatal care focuses on optimizing lung function and minimizing the pulmonary hypertension that invariably affects infants with significant congenital diaphragmatic hernia. In recent years, a new management strategy has led to improved outcomes for these infants.55-57 Surgical intervention is now delayed until the infant is hemodynamically stable and pulmonary hypertension is controlled.57,58 Mechanical ventilation is currently based on principles of “gentle ventilation.”55,59 These medical and surgical improvements have resulted in better outcomes at tertiary care institutions that can provide extracorporeal membrane oxygenation and the necessary surgery.55,56

Medical Interventions

Surfactant

There are no reported benefits of surfactant therapy with regard to survival, need for extracorporeal membrane oxygenation, or development of chronic lung disease in infants with isolated congenital diaphragmatic hernia (CDH). Studies57 have failed to show a primary surfactant deficiency in patients with CDH compared to age-matched control infants. Surfactant therapy for term infants with CDH associated with lung hypoplasia and pulmonary hypertension may cause clinical deterioration and is associated with increased risk of mortality.60

Ventilation Strategy

Pulmonary hypoplasia and pulmonary hypertension are significant factors contributing to mortality in infants with CDH. Pulmonary hypertension in CDH has both reactive and fixed components. The reactive component is secondary to the changing resistance of the pulmonary arterioles, and the fixed component is the diminished cross-sectional area of the pulmonary vascular bed. Mechanical ventilation should be geared toward maintaining appropriate lung volumes and adequate oxygenation while minimizing barotrauma and further lung injury. The use of hyperventilation and alkalosis in CDH has been replaced by a gentler ventilation strategy that allows for higher PaCO2 and lower preductal SaO2 as long as blood pressure and tissue perfusion are maintained.55,57,59 The use of high-frequency ventilation, especially high-frequency oscillatory ventilation, has become the respiratory support of choice both before and after surgery.58 A significant decrease in pneumothorax occurrence has coincided with these changes in approach to mechanical ventilation, and survival of infants with CDH has increased.56,57

Nitric Oxide

The use of inhaled nitric oxide (iNO) in infants with pulmonary hypertension in general has led to a decreased need for extracorporeal membrane oxygenation. This potent pulmonary vasodilator has improved the outcome for infants with respiratory failure associated with pulmonary hypertension but, unfortunately, has not had the same results for infants with congenital diaphragmatic hernia.55 The early use of nitric oxide in combination with high-frequency oscillatory ventilation may be associated with a positive response in the management of pulmonary hypertension associated with CDH, but no well-designed trials demonstrate the benefit of iNO for these infants.56,57 The use of inhaled nitric oxide after surgical repair of the diaphragmatic hernia is widely accepted, but outcome data are not available. (See Chapter 61 for further information.)

Extracorporeal Membrane Oxygenation

The use of extracorporeal membrane oxygenation (ECMO) was developed as the rescue therapy for pulmonary hypertension in infants with meconium aspiration syndrome and other lung injuries, but its efficacy in treating patients with congenital diaphragmatic hernia (CDH) remains controversial. The criteria for ECMO use varies widely from among centers, including the use of the oxygenation index, measured alveolar-arterial oxygen difference, or some combination of an oxygenation index and a prespecified level of respiratory support. Other centers base their decision for ECMO on evidence of poor systemic perfusion, nonreassuring blood gases, rising lactate levels, or dangerously high ventilator pressures.61 Finally, some centers only consider ECMO for infants who meet well-defined criteria and have evidence of adequate lung parenchyma for postnatal survival.56,61 The use of ECMO in CDH postoperatively has declined in the past few years.56,57 With the onset of delayed surgical repair, ECMO is now used more frequently during the stabilization period preoperatively. Overall, ECMO use in CDH has declined, possibly secondary to the changes in ventilation strategy and timing of surgical closure, which have improved outcomes.

Surgical Repair

Surgical repair of the diaphragmatic defect is ultimately required. In the past, surgical intervention was considered emergent, and as a consequence, postoperative management was plagued with severe pulmonary hypertension, tension pneumothoraces, and poor outcomes. Medical stabilization with high-frequency oscillatory ventilation, inhaled nitric oxide, or ECMO for several days to allow for physiologic stabilization and improvement in pulmonary hypertension is the preferred management strategy prior to surgery for congenital diaphragmatic hernia at the present time.55-57,59,62The surgical approach is through a subcostal opening with primary repair if enough diaphragm tissue is available. For those with a more significant defect, closure with a patch may be required. The use of chest drains or tubes postoperatively has also decreased in the past few years, but a consensus on their use has not been reached.

Outcomes

The overall survival rate is 60% to 85% for infants with gestational age older than 34 weeks, with no associated chromosomal or severe cardiac defects, and with delivery at a tertiary center with adequate experience in medical and surgical management of congenital diaphragmatic hernia.55-57,59 Survivors are at risk for chronic lung disease, feeding difficulties, gastroesophageal reflux, scoliosis, pectus excavatum, hearing loss, neurodevelopmental delay, brain injury, and recurrence of the diaphragmatic hernia.55,63

This chapter was prepared with grateful acknowledgment to our radiologist, Uygar Teomete, MD, Assistant Professor of Radiology, Miller School of Medicine, University of Miami, Miami, Florida.