Transient tachypnea of the newborn

The mechanisms of fetal lung liquid production and reabsorption involve active ion transport and hormonal regulation ( Fig. 51.1 ). Chloride ions enter the developing terminal air sac epithelium from the basolateral membrane via an Na/K/2Cl cotransporter (the transporter on which furosemide acts). Transepithelial (reabsorptive) movement of lung fluid at the time of birth involves passive movement of sodium through epithelial sodium channels (ENaC), which are inactive during fetal life and are activated during parturition by adrenergic stimulation. Although β-adrenergic agents such as terbutaline and epinephrine enhance Na ion trafficking and liquid reabsorption, in animal studies β-adrenergic blockade does not inhibit the reabsorption of lung liquid during spontaneous labor and delivery. Additional hormones of parturition, such as vasopressin and glucagon, may contribute to this process.

Mechanism of fetal and neonatal lung fluid transport. Cl, Chloride; ENaC, epithelial sodium channel; H ₂ O , water; K, potassium; Na, sodium.

(Data from Guglani L, Lakshminrusimha S, Ryan RM. Transient tachypnea of the newborn. Pediatr Rev . 2008;29:e59–65. Copyright Satyan Lakshminrusimha.)

The pulmonary circulation also plays a key role in fetal lung fluid clearance. Interstitial liquid drains directly into the circulation, and the dramatic increase in pulmonary blood flow occurring after birth enhances reabsorption of liquid from fetal airspaces. It is estimated that lung fluid approximates to 20 to 30 mL/kg near term. In the hours to days leading up to delivery, net lung fluid accumulation diminishes and, during labor, reabsorption predominates. As a result, extravascular lung liquid volume (i.e., liquid within the airspaces and interstitium) decreases. Any excess fluid remaining within the airspaces at the time of delivery is further resorbed as air entry into the lungs displaces liquid from the airways into the interstitium. Excessive residual extravascular liquid can impair gas exchange as interstitial liquid pressure compresses small airways, leading to atelectasis and gas trapping. Excess liquid remaining within airspaces will impair alveolar gas exchange.

The onset of breathing increases the surface area for liquid reabsorption and is associated with the opening of pores through which liquid can readily enter the interstitium. Drainage of interstitial liquid is generally complete by the end of initial neonatal transition (4–6 hours). Interstitial liquid appears to be directly absorbed into the microcirculation in a process governed by Starling forces; the contribution of lymphatic drainage appears to be negligible. Retention of liquid in airspaces and interstitium leads to impaired gas exchange and respiratory distress, with variable clinical presentations manifest by tachypnea and mild to moderate hypoxemia. The chest radiograph may show linear streaks of interstitial fluid radiating from the hilum on opaque areas similar in appearance to neonatal pneumonia or surfactant-deficient respiratory distress syndrome (RDS). The latter should resolve within approximately 24 hours if lung fluid is retained. This clinical picture is often termed retained fetal lung liquid or transient tachypnea of the newborn (TTN) .

Delayed fetal lung liquid clearance represents the most common type of respiratory disorder in the neonate. It occurs in an estimated 3.6 to 5.7 per 1000 term infants and in up to 10 per 1000 preterm infants. Infants who are born precipitously or by cesarean delivery, those who are male, and those born to mothers with diabetes are at highest risk for this disorder. The differential diagnosis includes neonatal pneumonia and meconium aspiration syndrome. Definitive diagnosis is often retrospective once the respiratory signs resolve, most often within 1 to 5 days, and requires minimal interventions.

Preterm infants who have a TTN-like presentation may be mistakenly assumed to have surfactant-deficient RDS. In both instances, supportive treatment is similar, although surfactant therapy is not indicated for infants with TTN. Lung ultrasound has been reported to be useful in making the distinction. Most infants can be treated with supplemental oxygen alone, administered via cannula or continuous positive airway pressure (CPAP). Supplemental oxygen is usually necessary for not more than 24 to 48 hours, but tachypnea may persist for several days. In addition, reactive airway disease is more likely to develop later in life in newborns who present with transient respiratory distress.

Surfactant-deficient respiratory distress syndrome

A seminal study by Avery and Mead in 1959 demonstrated that hyaline membrane disease, now termed respiratory distress syndrome (RDS) of the newborn is caused by a lack of pulmonary surfactant in preterm newborns. The phospholipids, proteins, genes, and cellular processes of surfactant biosynthesis and recycling were subsequently elucidated.

RDS is primarily a disease of prematurity. The incidence of RDS decreases with increasing gestational age, with occurrence in approximately 60% of babies born at less than 28 weeks of gestation, 30% born between 28 to 34 weeks, and 5% born after 34 weeks. Risk factors for RDS include prematurity, male sex, maternal gestational diabetes, perinatal asphyxia, and multiple gestations.

Surfactant-deficient alveoli are more prone to collapse, leading to diffuse atelectasis and the classic ground-glass appearance of chest radiographs. There is reduced compliance, atelectasis, and intrapulmonary shunting. Infants with surfactant deficiency have stiff, noncompliant lungs and require significant distending pressure for lung expansion and adequate ventilation. Affected neonates exhibit tachypnea, respiratory muscle (diaphragmatic, subcostal, and intercostal) retractions, and expiratory grunting. Complications include pulmonary air leak, pulmonary hemorrhage, intracranial hemorrhage, and chronic lung disease. Infants who require prolonged intubation and mechanical ventilation also are at risk for subglottic injury, including subglottic stenosis and tracheomalacia. Before the availability of exogenous surfactant therapy, the mortality rate from RDS exceeded 20%. Currently, infants treated in neonatal intensive care units (NICUs) rarely succumb to RDS unless they are extremely preterm or suffer severe complications.

Pulmonary surfactant disperses at the air-liquid interface of alveoli, reduces surface tension at this interface, and prevents alveolar collapse at end expiration. Pulmonary surfactant consists of 90% lipids and 10% proteins. Phospholipids (including phosphatidylcholine and phosphatidylglycerol) are enriched surfactants produced by alveolar type 2 pneumocytes. The lipids are synthesized in the endoplasmic reticulum and transferred into lamellar bodies (LBs) via an adenosine triphosphate–binding cassette transporter A3 (ABCA3) pathway. The hydrophobic surfactant apoproteins (SP-B and SP-C) are assembled into LBs and secreted into the alveolar space with lipids via G-protein coupled receptor (GPR 116) ^, at the epithelial surface. Under the influence of extracellular calcium ions, the LBs then unwind and interact with hydrophilic surfactant proteins (SP-D and SP-A) to form a tubular myelin mesh, which spreads into the surfactant film surface monolayer. Surfactant is also recycled and catabolized or reused. Maintenance of the surface film is a dynamic process. The unique surface tension–lowering property of surfactant is principally due to dipalmitoyl phosphatidylcholine, a disaturated phospholipid in which acyl groups are tightly interlaced as the film is compressed during exhalation.

Maternal glucocorticoid therapy has reduced the incidence of RDS in preterm infants. Treatment with exogenous intratracheal surfactant has significantly reduced the clinical severity of RDS and improved survival. Over the last decade, standard practice comprises rapid initiation of CPAP and withholding intubation (and accompanying surfactant instillation) until a threshold of supplemental oxygen (e.g., 30%–40%) is reached. Use of an intratracheal catheter to administer surfactant shows promise as an alternative to endotracheal intubation.

Mutations in the genes encoding SP-B, SP-C, and ABCA3 can cause refractory respiratory failure and chronic interstitial lung disease in full-term infants despite mechanical ventilation and surfactant replacement. SP-B mutations (often autosomal recessive) can result in a complete loss of SP-B. Affected patients almost always present with respiratory failure in the neonatal period and usually die (without lung transplantation) in the first few months of life. SP-C mutations are inherited as an autosomal-dominant disorder, can present in infancy or later childhood, and are variable in severity. ABCA3 mutations are inherited as autosomal-recessive disorders and can present as a neonatal form or much later in life as chronic childhood interstitial lung disease. Molecular genetic diagnosis can identify affected infants and help predict fatal outcome.

Pulmonary air leak syndromes

Pulmonary air leak syndrome encompasses a spectrum of entities, including pneumothorax, pneumomediastinum, pneumopericardium, and pulmonary interstitial emphysema (PIE). Subcutaneous emphysema and pneumoperitoneum are rarer forms.

As a group, pulmonary air leaks are more common during the neonatal period than at any other time of life. The two most common types of air leak, pneumothorax and pneumomediastinum, occur spontaneously in 1% to 2% of term neonates and are apparently symptomatic only in an estimated 10% of these newborns. Preterm infants with surfactant-deficiency RDS historically had reported rates of air leaks in excess of 30%; these rates fell rapidly with the advent of surfactant therapy in the 1980s but still remain at about 5%. Infants who have meconium aspiration or hypoplastic lungs have much higher air leak rates.

Air leak initiates as rupture of an overdistended alveolus. Overdistention may be due to generalized air trapping or uneven distribution of air. After rupture of the alveolus or terminal airspace, air escapes into the lung interstitium and tracks along the perivascular connective tissue sheaths toward the hilum. If air leaks into the intrapleural space, pneumothorax results. If the leak is at the hilar pleural reflection, pneumomediastinum occurs; air leak at the pericardial reflection results in pneumopericardium. Rarely, air can dissect into the soft-tissue planes of the neck, causing subcutaneous emphysema, or across the diaphragmatic apertures and into the peritoneal abdominal space, leading to a pneumoperitoneum.

In the past, pulmonary air leaks most commonly occurred as a result of excessive ventilatory pressures due to either overly aggressive mechanical ventilation (barotrauma) or air trapping caused by partial airway obstruction by meconium or other debris (ball valving). More recently, air leaks are more commonly seen during the recovery phase of acute respiratory disease, when lung compliance dramatically improves and pressure-limited ventilation leads to excessive tidal volumes (volutrauma). This phenomenon explains the clinical observations that air leaks tend to occur during the recovery phase of RDS and why the incidence of air leaks actually increased during early trials of surfactant therapy. Both observations underscore the need to closely monitor ventilatory volumes and wean pressure aggressively as compliance improves. Moreover, evidence indicates that volume-limited ventilation may be a safer mode for neonatal mechanical ventilation even during the recovery phase of acute neonatal respiratory disease.

Pneumomediastinum is one of the most common air leaks and, considering the pathways by which air will track, is often the harbinger of further air leaks. Infants with isolated pneumomediastinum generally display few or no signs other than chest radiograph low-density widening of the mediastinum. On an anteroposterior view of the chest radiograph, air may form a lucency around the heart, whereas on a lateral view, air lifts the lobes of the thymus away from the cardiac silhouette (spinnaker sail sign).

Pneumothorax is a clinically common and more worrisome form of pulmonary air leak. The initial signs of pneumothorax result from lung compression and diminished lung compliance. If compromise is minimal, the infant will maintain minute ventilation simply by increasing ventilatory rate (tachypnea). An additional sign may be increased use of accessory muscles (retractions) in an effort to improve tidal volume. If positive pressure within the pleural space builds to the point of vascular compromise (i.e., tension pneumothorax), cardiac return will decrease and the heart rate will rise to compensate for diminished stroke volume. Eventually, blood pressure may fall; if oxygen delivery cannot be maintained, bradycardia and cardiopulmonary arrest may ensue.

Pneumopericardium is a rare but often life-threatening form of pulmonary air leak. The clinical signs closely resemble those of tension pneumothorax, with the addition that diminished heart sounds are invariably present. Mortality may be as high as 80%. Diagnosis is suspected if an infant experiences acute circulatory collapse; it is confirmed by lucency around the heart on the radiograph or by return of air on pericardiocentesis using an angiocatheter and syringe.

Pneumoperitoneum occurs when air dissects from the chest through a foramen of the diaphragm. This condition is generally benign and causes little clinical difficulty. It can, however, be confused with perforation of a viscus. Pneumoperitoneum is often distinguishable from bowel perforation by a clinical history of a prior pneumomediastinum or pneumothorax, especially when there is an absence of gastrointestinal (GI) signs. Pneumoperitoneum usually requires no treatment.

PIE is a more severe manifestation of the same pathophysiologic process that leads to other air leak syndromes. In this instance, air accumulates in the interstitial space rather than tracking toward the hilum. The chest radiograph may show a variable number of cystic or linear lucencies in the lung fields. ^, This air accumulation produces compression of the airways and vasculature, making ventilation more difficult.

There should be a high degree of suspicion for air leaks in a patient who has a sudden, unexpected cardiovascular deterioration. Transillumination of the relatively translucent neonatal chest wall using an intensely focused light source may be a quick and useful tool for diagnosing a large pneumothorax. Immediate aspiration of the air, preferentially with a large-bore angiocatheter, should be done even before radiographic confirmation if the infant is severely compromised. An unstable or recurrent pneumothorax may require a thoracotomy tube. Cardiac tamponade resulting from a pneumopericardium may be suggested by distant heart tones and hypotensive shock with a normal-appearing electrocardiogram tracing (electromechanical dissociation). Pneumomediastinum often is asymptomatic and rarely benefits from drainage, even in the presence of clinical signs. PIE occurs predominantly in preterm infants and often leads to a vicious cycle of increasing ventilator delivery pressures to open alveoli compressed by extrinsic air, which, in turn, leads to more extravasation of air and further collapse.

Both high-frequency oscillatory ventilation (HFOV) and high-frequency jet ventilation (HFJV) can provide adequate gas exchange using extremely low tidal volumes and a supraphysiologic rate in neonates with acute pulmonary dysfunction, and they may reduce the potential risk of air leak syndrome in neonates. However, there is no conclusive evidence that HFOV or HFJV reduces the incidence of air leaks in neonates. ^,

Pulmonary hemorrhage

Pulmonary hemorrhage (PH) in the newborn is a life-threatening condition that has an incidence of 1 to 12 per 1000 live births and 50 per 1000 high-risk infants. Common risk factors for PH include prematurity, intrauterine growth restriction, and patent ductus arteriosus (PDA) with systemic steal and asphyxia. In most cases, what is called pulmonary hemorrhage is actually the most severe manifestation of pulmonary edema rather than anatomic vascular disruption. This conclusion is validated by determining measures of the hematocrit of hemorrhagic fluid suctioned from the airway. The hemorrhagic fluid hematocrit generally will be 15% to 20% lower than venous hematocrit in the same patient at the time. Finding whole blood in the airway is rare and usually results from trauma from mechanical injury. Most infants with PH will have more than one risk factor. In the neonate, the factors most commonly associated with hemorrhagic pulmonary edema are those that increase pulmonary blood flow, such as a left-to-right shunt through a PDA. Sudden improvement in lung compliance after surfactant therapy, with resultant decrease in pulmonary vascular resistance producing increased left-to-right shunting, may lead to PH.

The diagnosis is made when the appearance of bloody secretions within an endotracheal tube coincides with acute respiratory deterioration that requires increased oxygen and ventilator support. The chest radiograph is nonspecific and may show fluffy opacities, focal ground-glass opacities, or appear as a complete whiteout of the lung fields.

The goal of management is to stop hemorrhaging while maintaining adequate gas exchange. Increasing positive end-expiratory pressure (PEEP) reduces alveolar flooding and can improve oxygenation and left ventricular function. Although the airway must be kept clear, frequent suctioning not only may be traumatic but also can aggravate the condition by reducing PEEP. High mean airway pressures, which can be safely achieved with high-frequency ventilation (HFV), can be effective in massive pulmonary hemorrhage, yielding rapid improvement in oxygenation. Administration of endotracheal or nebulized epinephrine or iced saline solution via the endotracheal tube has been advocated in the past but has questionable efficacy, and epinephrine may worsen the condition by elevating pulmonary vascular pressure. Additional therapies that may be beneficial in specific instances include reversal of any coagulopathy or thrombocytopenia, and surfactant. The rationale for surfactant therapy is that red blood cell products—including hemoglobin, proteins, and lipids—can inactivate the infant’s pulmonary surfactant.

Even with aggressive management, mortality from hemorrhagic pulmonary edema may exceed 25%. The Trial of Indomethacin Prophylaxis in Preterm infants (TIPP) study (post-hoc analysis) showed that risks of death or survival with neurosensory impairment were doubled after serious PH. Approximately 60% of preterm infants who survive PH developed bronchopulmonary dysplasia. An increased incidence of cerebral palsy (odds ratio [OR], 2.86) and cognitive delay (OR, 2.4) has been reported. PH is also associated with an increased risk of seizures and periventricular leukomalacia in survivors at 18 months of age.

Pneumonia

Neonatal pneumonia is a common cause of significant morbidity and mortality. In developed countries, term infants have an incidence of less than 1%, whereas the incidence in preterm and sick infants may approach 10%. The World Health Organization (WHO) estimated that approximately 800,000 infants die annually from neonatal respiratory infections, most being pneumonia. Neonatal pneumonia can be congenital (acquired before labor and rupture of amniotic membrane via hematogenous or ascending infection or by aspiration), intrapartum (acquired during labor via ascending or hematogenous infection), or postnatal (acquired after birth).

The lungs represent the most commonly affected organ in neonates with sepsis. Bacterial or viral infection in the neonate may begin in utero by transplacental passage or, more commonly, by ascending infection from the maternal genital tract or by hematogenous spread. Prolonged rupture of membranes (>18 hours) increases the risk of an ascending infection, although some organisms may invade through intact membranes. Cervical bacterial colonization with group B streptococci (GBS) or primary herpes viral cervical infection during pregnancy increases the risk of transmitting those diseases. Cesarean delivery is not necessarily protective because fetuses may swallow contaminated amniotic fluid or aspirate organisms in utero. Infection occurring during the perinatal period may not present clinically for several days. Consequently, congenitally acquired infections may be indistinguishable from infections postnatally acquired (i.e., nosocomial). As a result, organisms that cause perinatal pneumonias are typically those found in the genital tract of the mother and include streptococci (groups A, B, and D), gram-negative rods (e.g., Escherichia coli and Klebsiella species), Listeria monocytogenes , ureaplasma, genital Haemophilus influenzae, and herpesvirus. Less commonly, maternal viral infections (e.g., adenovirus, enteroviruses, or varicella) can be vertically transmitted to the fetus. Although the incidence of GBS pneumonia has decreased dramatically due to maternal screening and intrapartum treatment, GBS remains a common bacterial cause of neonatal pneumonia. However, in very-low-birthweight preterm infants, E. coli now dominates.

Pneumonia may develop as a nosocomial infection in neonates, particularly in those who require mechanical ventilation for other critical illnesses. Although reported rates vary widely, in part because of the lack of a diagnostic standard in this population, some authors have suggested that the incidence of ventilator-associated pneumonia (VAP) may be as high as 30% in selected NICU populations. If a VAP is suspected, typical nosocomial pathogens such as Staphylococcus, Klebsiella, and Pseudomonas species, and the pathogens previously listed for congenital pneumonias should be considered as possible causes. Ureaplasma urealyticum and U. parvum have frequently been recovered from endotracheal aspirates shortly after birth in very-low-birthweight infants and have been associated with various adverse pulmonary outcomes, including bronchopulmonary dysplasia.

Diagnosis of congenital pneumonia may be challenging because clinical and radiographic signs may be nonspecific. Although congenital infections are generally introduced through the respiratory tract, signs are rarely limited to those of pneumonia; the neonate is particularly prone to rapid dissemination of either bacterial or viral infections and typically has signs of sepsis or meningitis in addition to respiratory distress. The chest radiograph initially may appear normal, except for slight streakiness or hyperinflation, or the lung fields may be sufficiently opaque to be confused with surfactant-deficient RDS. Meconium aspiration with resultant severe chemical pneumonitis may be indistinguishable radiographically from bacterial pneumonia. Heart failure or obstructed anomalous pulmonary venous drainage also can present with a clinical and radiographic picture similar to pneumonia/sepsis.

Congenitally acquired pneumonia/sepsis can be a rapidly fatal disease, especially in the case of GBS or herpetic viral infections, for which mortality rates as high as 50% have been reported. Therefore, a high degree of suspicion is warranted. Antibiotics are routinely used in neonates with suspected pneumonia or sepsis. Antiviral therapy should be considered if the infant has systemic signs such as shock or disseminated intravascular coagulation or is not responding to initial therapy.

Meconium aspiration syndrome

Passage of meconium in utero is a sign of fetal distress (acute or chronic) and occurs because of relaxation of the fetal anal sphincter. Moderate distress occurring during labor results in passage of meconium in the final stages of delivery (terminal meconium), whereas more severe or chronic distress results in earlier passage, with resultant staining of the amniotic fluid and fetus. Meconium staining is a significant marker of fetal distress and occurs in 10% to 20% of all deliveries, but meconium aspiration syndrome (MAS) occurs in only 4% to 5% of these; MAS is most common in postmature infants. Intrauterine meconium passage is a maturational phenomenon and is rarely observed in fetuses younger than 34 weeks’ gestation.

Meconium is a lipid- and protein-rich substance containing desquamated cells from the gastrointestinal (GI) tract, skin, lanugo hair, bile salts, pancreatic enzymes, and mucopolysaccharides and is highly irritating to mucous membranes of the distal airways, resulting in a chemical pneumonitis. Dissolved meconium may travel down the respiratory tree and inactivate pulmonary surfactant. Meconium induces a potent inflammatory response, and MAS is associated with alterations in the pulmonary vasculature, including remodeling and thickening of the vessel muscle walls. This process results in pulmonary vascular hyperreactivity, vasoconstriction, and high resistance and pressure. Activation of the complement cascade leads to inflammation and constriction of pulmonary veins. As the proinflammatory cytokine profile improves, so does pulmonary function. More particulate meconium will remain trapped in small airways, which can lead to a ball-valve type of gas trapping. In most cases, the meconium is gradually removed from the respiratory tract through phagocytosis, and normal pulmonary function returns in 5 to 7 days. In more severe cases, MAS may lead to respiratory failure, and even death, despite aggressive intervention.

Infants with meconium aspiration are typically postmature and exhibit elongated nails; peeling skin; and staining of the umbilical cord, skin, and nails. Respiratory distress develops shortly after birth. The infant’s respirations initially may be depressed if meconium passage occurred in response to a recent intrauterine asphyxia episode. Gas trapping may lead to a barrel-shaped appearance of the chest, and respiratory distress may be severe. Chest radiographs often show characteristic patchy densities, hyperinflation, and areas of collapse. Air leaks are especially common.

Routine airway suctioning on the perineum or routine endotracheal suctioning for all meconium-stained newborns is no longer recommended. The American Academy of Pediatrics (AAP) and American Heart Association Neonatal Resuscitation Program currently recommends gentle clearing of the mouth and nose if necessary and initiation of positive pressure ventilation within the first minute of life in nonbreathing or ineffectively breathing newborns, although this may require further clarification.

Supplemental oxygen to maintain arterial oxygen saturation, endotracheal suctioning to clear remaining meconium, and ventilatory strategies aimed to minimize gas trapping have been mainstays of management. HFV may help to prevent the development of air leaks. Antibiotics are commonly used because distinguishing the clinical and radiographic picture from sepsis is difficult and because damage to the airways may predispose to subsequent bacterial infection. A systematic review of four clinical trials in term and near-term infants concluded that surfactant administration significantly reduced the need for extracorporeal membrane oxygenation (ECMO), although overall mortality was not affected. ^, Nevertheless, surfactant replacement therapy is sometimes combined with other therapies, including HFV and inhaled nitric oxide. The latter has become a mainstay of therapy for hypoxic respiratory failure, especially when pulmonary hypertension is a feature of MAS or other pneumonias.

Because intrauterine meconium passage and MAS are frequently associated with a hypoxic event, long-term neurologic outcome remains guarded. A cycle of hypoxia, meconium aspiration, and pulmonary hypertension may be established in utero. Mortality in the depressed newborn with MAS is as high as 7%, with an incidence of hypoxic-ischemic encephalopathy of 20% and occurrence of air leak syndromes in 11% of affected infants. Meconium aspiration during the perinatal period may be associated with an increased risk of reactive airway disease in early childhood.

Biological maturational considerations

The neural circuitry that generates respiratory rhythm and governs inspiratory and expiratory motor patterns is distributed throughout the pons and medulla. The medulla contains a specialized region known as the pre-Bötzinger complex, which contains neurons that exhibit intrinsic pacemaker activity capable of producing rhythmic respiratory motor output without sensory feedback. Although a fundamental feature of this network is that it enables breathing to occur automatically, this systematic central rhythmicity may fail in preterm infants. Meanwhile, central and peripheral sensory inputs from multiple sources allow adjustments to the patterns of inspiratory and expiratory activity in response to changing metabolic conditions. For example, inhibitory sensory inputs from the upper airway may be particularly prominent in early postnatal life to serve a protective function, although this may trigger potentially clinically significant apnea. Excitatory and inhibitory neurotransmitters and neuromodulators mediate the rhythmogenic synaptic communications between neurons of the medulla. Glutamate is the major neurotransmitter mediating excitatory synaptic input to brainstem respiratory neurons. γ-Aminobutyric acid and glycine are the two primary inhibitory neurotransmitters in the network.

Responsiveness to carbon dioxide (CO ₂ ) is the major chemical driver of respiratory neural output. This is apparent in fetal life, where breathing movements increase under hypercapnic conditions in animal models. As in later life, CO ₂ /hydrogen ion (H ⁺ ) responsiveness is predominantly based in the brainstem, although peripheral chemoreceptors contribute to the ventilatory response and respond more rapidly. The reduced ventilatory response to CO ₂ in small preterm infants, especially those with apnea, is primarily the result of decreased central chemosensitivity. However, mechanical factors—such as poor respiratory function and an unstable, compliant chest wall—may contribute. It is difficult to distinguish the neural from mechanical factors that contribute to respiratory failure in this population.

Preterm infants respond to a fall in inspired oxygen concentration with a transient increase in ventilation over approximately 1 minute followed by a return to baseline or even depression of ventilation. The characteristic response to low oxygen in infants appears to result from initial peripheral chemoreceptor stimulation followed by overriding depression of the respiratory center as a result of hypoxemia. Such hypoxic respiratory depression may be useful in the hypoxic intrauterine environment, where respiratory activity is intermittent and not contributing to gas exchange. The nonsustained response to low inspired oxygen concentration may, however, be a disadvantage postnatally. It may play an important role in the origin of neonatal apnea and offers a physiologic rationale for the decrease in incidence of apnea observed when a slightly increased concentration of inspired oxygen is administered to apneic infants who have a low baseline oxygen saturation.

Apnea of prematurity

During early postnatal life apneic events are ubiquitous; they can vary widely in duration and are often accompanied by bradycardia and/or intermittent hypoxemia. Accordingly, AAP guidelines have historically defined clinical apnea of prematurity as a respiratory pause of 20 seconds or shorter if accompanied by hypoxemia (<80%) and/or bradycardia (<80 beats/min). It should be noted that even short respiratory pauses, approximating 10 seconds or less, may be associated with desaturation and/or bradycardia. Apnea is categorized as (1) central, with loss of central respiratory drive, resulting in complete cessation of flow and absence of respiratory effort; (2) obstructive, with absence of flow in the presence of respiratory efforts; and (3) mixed, with both central and obstructive components. Unfortunately, standard impedance monitoring, which reflects chest wall motion, may fail to differentiate obstructed versus unobstructed inspiratory efforts. Simultaneous monitoring of heart rate and oxygen saturation ensures that such events are not missed.

There is increasing interest in the potential role of apnea with accompanying intermittent hypoxia (and reoxygenation) or later morbidities, both respiratory and neurodevelopmental. Intermittent hypoxia (IH) is almost always preceded by a respiratory pause, and often occurs rapidly (∼10 s) after cessation of airflow. Factors that can influence the initiation, duration, and severity of IH include baseline oxygen saturation, oxygen uptake from the alveoli, pulmonary oxygen stores, total blood oxygen-carrying capacity, the slope of the hemoglobin oxygen dissociation curve, and metabolic oxygen consumption. In extremely preterm infants, IH events are pervasive and transient during early postnatal life, with a relatively low incidence during the first week of life, followed by a rapid increase during the second and third weeks and a plateau or decrease thereafter. A secondary analysis of infants enrolled in the Canadian Oxygen Trial has shown an association between increased time spent less than 80% during IH events and a greater probability of death or disability, cognitive or language delay, severe retinopathy of prematurity, and motor impairment at 18 months of age that was limited to IH events of 1 minute or longer in duration.

Therapeutic options

Caffeine and CPAP are the mainstay of therapy used to treat apnea and IH. Caffeine and other methylxanthines have been prescribed in preterm infants for over 40 years ^, and have been shown to reduce apnea and the need for ventilation.

The largest trial of caffeine (Caffeine for Apnea of Prematurity Trial) randomly assigned 2006 infants with birthweights between 500 and 1250 g to caffeine or placebo in the first 10 days of life. Although apnea of prematurity was not measured in this clinical trial, caffeine administration was associated with a reduction in duration of positive-pressure support, oxygen supplementation, and the incidence of bronchopulmonary dysplasia. Caffeine significantly improved survival without neurodevelopmental disability at 18 to 21 months; it also improved developmental coordination disorders and motor deficits at school age.

There are various pharmacologic effects of caffeine in apnea of prematurity. Most important, it stimulates the respiratory center in the brainstem and increases sensitivity to CO ₂ . Mechanisms of action include blockade of adenosine A ₁ and A _2A receptor subtypes, resulting in excitation of respiration neural output. ^, Caffeine has also been shown to enhance peripheral chemoreceptor activation. A loading dose of caffeine showed a rapid (within 5 minutes) and a prolonged (2 hours) increase in diaphragmatic activity that was associated with an increase in tidal volume. Last, exposed prenatally to lipopolysaccharide endotoxin, neonatal rodents had improved lung resistance and cytokine profiles after caffeine treatment. Optimal strategies of caffeine therapy have yet to be determined, although common practice entails a caffeine citrate loading dose of 20 mg/kg followed by 5 to 10 mg/kg per day. ^,

Nasal CPAP is safe and effective and has a prominent role in treatment for apnea of prematurity. CPAP is a noninvasive form of applying a constant distending pressure level during inhalation and exhalation. It supports infants who are spontaneously breathing but who have airway instability, pulmonary edema, and atelectasis. CPAP enhances functional residual capacity, reduces work of breathing, and decreases mixed and obstructive apnea.

There is considerable controversy regarding the best mode of CPAP delivery. This is further complicated by the various low- and high-flow cannulae that are widely used for CPAP delivery despite limited comparative studies. Refinement of techniques to both delivery of CPAP and effective synchronized noninvasive ventilation may be the answer.

Pulmonary hypoplasia

Both static and dynamic expansions of the fetal lung are important determinants of normal fetal lung development. Static lung expansion occurs as a result of fetal lung liquid production. Epithelial cells within the lung actively secrete fluid into the lung lumen, distending the future airspaces. Inadequate production or excessive drainage of fetal lung liquid leads to pulmonary hypoplasia. Dynamic lung expansion occurs during fetal breathing movements, which are rhythmic and occur with increasing frequency during the latter part of gestation. Absent or abnormal fetal breathing also results in pulmonary hypoplasia.

Hypoplastic lungs are small in volume and deoxyribonucleic acid content relative to body size. They have reduced numbers of alveoli (mean alveolar count [MAC]), bronchioles, and arterioles per unit mass. Although its pathophysiologic origins are not well understood, pulmonary hypoplasia can result from impairment of normal fetal lung expansion. It generally occurs in conjunction with one of the following conditions: (1) a space-occupying lesion within a hemithorax, such as a diaphragmatic hernia; (2) an inadequate thoracic cage, as occurs in some types of osteochondrogenesis-like asphyxiating thoracic dystrophy or achondrogenesis; (3) a deficiency of amniotic fluid (oligohydramnios) due to leakage (preterm rupture of fetal membranes) or underproduction (renal dysplasia); (4) inadequate vascular supply to the developing lung; (5) an absence of fetal breathing movements; or (6) chromosomal anomalies, such as trisomy 13 or 18. If the insult occurs before the pseudoglandular stage of lung development (7–17 weeks), the degree of hypoplasia is severe. Pulmonary hypoplasia may occur in the absence of any of these conditions, but such cases of primary isolated pulmonary hypoplasia are rare.

Infants with pulmonary hypoplasia generally show signs of respiratory failure in the immediate newborn period. Reduced lung volume impairs ventilation and leads to hypercarbia. Decreased surface area for gas exchange (due to a reduced number of alveoli) leads to hypoxemia. A decreased cross-sectional area of the vasculature makes these infants particularly susceptible to pulmonary hypertension, which further exacerbates the hypoxemia. The chest radiograph in infants with pulmonary hypoplasia shows low lung volumes but may be otherwise unremarkable. The severity of respiratory distress depends on the degree of hypoplasia and presence of associated conditions, such as fetal hydrops or cyanotic heart disease. The most common association is renal dysplasia or agenesis. In these cases, infants have a history of moderate to severe oligohydramnios and have severe respiratory distress and compression deformities of the face and extremities (Potter sequence). An antenatal sonographic assessment of lung-to-head ratio can be a useful predictor of pulmonary hypoplasia.

Treatment of infants with pulmonary hypoplasia is supportive. Outcome depends on the severity of the hypoplasia and presence of associated lethal anomalies, such as renal agenesis or achondrogenesis. The lungs of infants with severe pulmonary hypoplasia may be extremely difficult to ventilate, and pneumothoraces are common because of the need for high distending pressures. HFV may be an effective means of ventilating these infants’ lungs, using a combination of high ventilatory rates with extremely low tidal volumes. Survival depends on etiology or associated conditions.

Congenital diaphragmatic hernia

Congenital diaphragmatic hernia (CDH) occurs in approximately 1 in 2500 to 3000 live births and is the most common cause of pulmonary hypoplasia in the neonate. ^, At least 750 babies die of CDH in the United States annually, excluding a 15% prenatal termination rate. CDH can be associated with other anomalies as part of chromosomal defects, single-gene defects (Denys-Drash syndrome, spondylocostal dysostosis, or neonatal Marfan syndrome), or multiple gene disorders. Most cases of CDH are nonsyndromic.

Failure of the pleuroperitoneal canal to close at 6 to 8 weeks’ gestation results in a diaphragmatic defect that allows GI structures to enter the thoracic cavity as the intestines return from outside the fetus into the abdominal cavity. The resulting mass effect in the chest impairs ipsilateral lung growth, characterized by a quantitative reduction in airways and their associated preacinar arteries. The defect occurs on the left side in 80% to 85% of cases, because closure of the right pleuroperitoneal membrane normally precedes the left during development. Because herniation often occurs before the tenth week of gestation when normal gut rotation occurs, malrotation is common. Nongastrointestinal anomalies are found in approximately 25% of cases; the most common involve the cardiovascular system.

The clinical presentation of CDH depends on the degree of pulmonary hypoplasia present. In addition, the abdomen is often scaphoid because of a paucity of abdominal contents. As the infant cries and swallows air, the degree of lung compression may worsen, and an infant who appears healthy at delivery may undergo respiratory decompensation within minutes. The chest radiograph will show a cystic lesion in the lower lung field, often extending upward along the lateral chest wall. Initially, when the intestines remain fluid filled, the radiograph may be similar to that seen with pulmonary sequestrations or fluid-filled cysts. As the infant swallows more air, the radiographic findings may be confused with congenital emphysema or even pneumothorax. Small or right-sided defects may not present for weeks or even months. Indeed, cases have occasionally been incidentally diagnosed during childhood when chest radiographs are obtained for other reasons. With the widespread use of antenatal sonography, most cases of CDH are diagnosed before birth, facilitating planned neonatal stabilization. In cases in which sonographic findings are equivocal, prenatal magnetic resonance imaging may be particularly useful.

Initial management focuses on stabilization, including immediate endotracheal intubation and GI decompression. Ventilation by bag and mask is avoided to prevent introducing more gas into the GI tract. As with pulmonary hypoplasia, the clinical course may be complicated. Persistent pulmonary hypertension accompanying CDH may require nitric oxide inhalation therapy or ECMO. ^, The contralateral nonhypoplastic lung in experimental CDH is functionally immature, implying potential benefit for surfactant therapy. However, this maneuver has not been effective in a review of a large national CDH registry.

Attempts at intrauterine intervention, either to close the defect or to encourage lung growth through temporary obstruction of fetal lung liquid egress at the trachea, have been disappointing. Fetal surgery for CDH has been associated with an unacceptably high incidence of complications, including recurrence of the defect, preterm delivery, and miscarriage. Fetoscopic tracheal occlusion by clips or removable balloons has also been attempted.

Although early postnatal corrective surgery was advocated in the past, there has been a more recent shift toward delayed repair, in large measure because respiratory function often worsened in the immediate postoperative period. Consequently, early aggressive cardiorespiratory stabilization followed by delayed surgical plication is the recommended approach and is associated with improved outcome.

Surviving children with CDH may have neurodevelopmental disability, hearing loss, feeding difficulties, gastroesophageal reflux, lung disease, scoliosis, and recurrence after repair. In patients who required ECMO, 35% had brain abnormalities assessed by computed tomography (CT), and 35% to 45% needed a hearing aid. Perhaps the most successful advance since the 1990s has been improvement in postnatal treatment to preserve and protect lung parenchyma using gentler ventilatory strategies.

Congenital pulmonary airway malformation

Congenital pulmonary airway malformation (CPAM), previously known as congenital cystic adenomatoid malformation (CCAM), is a relatively infrequent lesion, estimated to occur in 1 in 10,000 pregnancies. ^, CPAM is a discrete nonfunctioning, intrapulmonary mass characterized by overgrowth of terminal respiratory bronchioles that form cysts ranging from less than 1 mm to more than 10 cm. These cysts suppress alveolar growth and can communicate with the tracheobronchial tree, evidenced by air trapping seen after postnatal resuscitation. Cysts may also communicate with each other. Histologically, the lesions are notable for a preponderance of elastic tissue and for an absence of cartilage. The cysts are usually multiple and, in more than 95% of cases, the cystic malformations lie within a single lobe. No single lobar predilection exists. A contributory gene influencing CPAM development is HOXB5 ; its expression is maintained at a level typical of early lung development. Other growth and maturational factors—including FGF7, KGF, and FGF10—have been implicated.

CPAMs are often divided into three types, which vary in anatomic and clinical characteristics according to the Stocker classification scheme. A revised classification has added two new types, type 0 and type 4. Type 0 is bronchial dysplasia; type 4 is the peripheral form of CPAM. ^, Type 1 CPAM, which accounts for about half of cases, occurs as a few large (>2 cm) cysts, usually one to four in number, or as a single large cyst surrounded by much smaller satellite cysts. Type 2 CPAM, which accounts for about 40% to 45% of cases, consists of multiple small (<2 cm), evenly spaced cysts scattered throughout the affected area. Compared with type 1 CPAM, type 2 cysts are associated with a much higher incidence (about 25%) of anomalies in other organs, particularly in the genitourinary tract (e.g., renal dysgenesis). Type 3 CPAM, which accounts for fewer than 10% of cases, occurs as large collections of tiny cysts. The affected area can be large, and this type often leads to early cardiovascular compromise, resulting in fetal hydrops or immediate postnatal complications. In the alveolo-acinar type of CPAM, small cysts are formed later in development. In the bronchial epithelial type, larger cysts are formed early in the pseudoglandular phase of development.

Depending on the type, CPAM presents during the neonatal period in 50% to 85% of infants, but presentation may be delayed for up to several years. Cases are occasionally discovered incidentally. Lesions may be detected prenatally during routine sonography. The most common presentation of CPAM is respiratory distress that results from obstruction, although infection of the cyst leading to recurrent lobar pneumonias can also occur. The elastic walls of the cyst allow easy expansion on inspiration, but the lack of cartilaginous support results in premature closure during exhalation and a ball-valve type of respiratory compromise.

Chest radiograph findings are variable and depend on the type of CPAM. In the neonate, a solid space-occupying mass will appear, becoming air filled over the next several hours or days. In types 1 and 2, multiple air-filled cysts may become evident. This appearance may be confused with diaphragmatic hernia. Placement of a nasogastric tube to determine the location of the stomach and intestines as well as the absence of a scaphoid abdomen helps distinguish between the two entities. The multiple small cysts of type 3 CPAM cannot be delineated on a chest radiograph. In this case, a CT scan of the chest can be helpful.

Treatment of symptomatic infants may require noninvasive or positive pressure ventilation. Definitive treatment is surgical removal of the affected lobe, which can often be performed thoracoscopically. Even if an infant is asymptomatic, surgical resection is recommended by 3 to 6 months of age because of the high risk of expansion or infection if the cysts are left untreated.

Prognosis depends on the type and extent of the CPAM. The large type 3 lesions are more likely to cause immediate respiratory distress and have higher mortality, especially if associated with pulmonary hypoplasia or fetal hydrops. The prognosis in type 2 CPAM depends on the presence and nature of associated anomalies. ^, In addition, malignant transformation of CPAM (mucinous adenocarcinoma) has been reported. ^, Most cases of CPAM, however, have a good prognosis.

A CPAM volume ratio may be measured prenatally by sonography. An index of length × width × height × 0.52 that exceeds 1.6 at initial diagnosis predicts an increased risk for fetal hydrops. Maternal prenatal glucocorticoid treatment increases survival rates and favors the resolution of hydrops in some cases.

Bronchogenic cysts

Bronchogenic cysts are rare and occur as a result of anomalous budding of the ventral or tracheal diverticulum of the foregut during the sixth week of gestation, with subsequent separation from the normally developing bronchi by the sixteenth week of gestation. If separation occurs early (<12 weeks), the bronchogenic cyst tends to be located in the mediastinum (the most common type). If separation occurs later, it is more likely to be located in the peripheral pulmonary parenchyma. The cyst walls are cartilaginous and receive either systemic or pulmonary blood supply, depending on location. Bronchogenic cysts are more common in male infants, usually singular, more commonly right sided, and generally smaller than 10 cm in diameter. These lesions generally do not communicate with the airway and remain fluid filled, which differentiates them from pulmonary parenchymal cysts.

Bronchogenic cysts generally do not present in the neonatal period unless they are large, expand rapidly, or are located near major airways. In these instances, infants may show moderate to severe respiratory distress. More commonly, the young child will have recurring episodes of wheezing or infection. Treatment may require ventilatory support for infants with respiratory distress. In all cases, surgical resection is indicated. The prognosis for infants who have a bronchogenic cyst, whether mediastinal or pulmonary, is good.

Pulmonary parenchymal cysts

Pulmonary parenchymal cysts may represent a disorder of bronchial growth, although they may alternatively be acquired. Like adenomatoid malformations and bronchogenic cysts, congenital cysts arise early in fetal life. Pulmonary parenchymal cysts are thought to develop when completion of the terminal bronchioles and development of the alveoli occur. Pulmonary cysts are typically thin walled, singular, multilocular, and located in the periphery. Unlike bronchogenic cysts, some communication usually exists between the pulmonary cyst and the tracheobronchial tree; thus approximately 75% fill with air.

Like adenomatoid malformations, pulmonary cysts contain mostly elastic tissue and little or no cartilage. Although pulmonary cysts are generally small (1–2 cm in diameter), they can expand dramatically and are much more likely to cause respiratory insufficiency than are bronchogenic cysts. As in adenomatoid malformations, an absence of cartilaginous support leads to trapping of air. However, unlike adenomatoid malformations, pulmonary cysts are rarely associated with other anomalies. Rupture of a peripheral cyst can result in a pneumothorax. Rarely, multiple cysts occur, which may extensively involve both lungs. These cases are generally fatal within the perinatal period.

Chest radiographs typically reveal thin-walled, round cysts with an air density. Often, faint strands of lung tissue can be seen within the cysts. A large pulmonary cyst may be confused with congenital lobar emphysema. In this circumstance, a CT scan can easily distinguish the cystic nature of the former condition. Cysts are identified prenatally in 70% of cases using high-resolution ultrasonography. Reports of spontaneous resolution of pulmonary cysts have been infrequent. As with other cystic lesions of the lung, surgical resection of the affected lobe is usually indicated.

Pulmonary sequestrations

Like bronchogenic cysts, pulmonary sequestrations result from an abnormal budding of the foregut, which retains its embryonic systemic arterial connections. Thus a sequestration is a mass of nonfunctioning, ectopic pulmonary tissue that has its own (systemic) blood supply. Sequestrations do not communicate with the trachea-bronchial tree.

There are two types of pulmonary sequestrations, which are histologically similar. Extralobar sequestrations are surrounded by a separate pleura, whereas intralobar sequestrations are surrounded by lung tissue and have no separate pleural covering. Extralobar sequestrations account for about 25% of cases, are more common (90%) on the left side, more common in males (80%), and usually located in a subpulmonic location. Extralobar sequestrations are commonly associated (50%–60%) with other anomalies, including direct esophageal communication, bronchial atresia, colonic duplication, CPAM, pulmonary hypoplasia, and diaphragmatic hernia. Most cases of extralobar sequestration become apparent during infancy. Presentations range from fetal hydrops with massive pleural effusions or pulmonary hypoplasia to recurrent lower respiratory infections (particularly if a GI communication is present). Intralobar sequestrations are the more common type (75%). They are usually left sided (65%–70%) and typically occur in the lower lobes. Unlike extralobar sequestrations, they are rarely associated with other anomalies. Most cases are asymptomatic and are discovered on chest radiographs obtained for other reasons. Symptomatic cases typically present in late childhood with recurrent infections. Distinguishing between extralobar and intralobar sequestrations on chest radiographs may be difficult. Both lesions can appear as either solid or cystic structures, although extralobar lesions are more often solid and intralobar lesions are more often cystic. Delineation of the vascular supply to the sequestration is important to differentiate extralobar sequestrations from CPAMs and to guide surgical management. Magnetic resonance imaging has replaced arteriography for obtaining this information. Some authors recommend a study of the GI tract, particularly if communication with the sequestration is suspected. As with other cystic lesions of the lung, surgical removal is indicated and may be done thoracoscopically. Whereas extralobar sequestrations can be removed en bloc because of their separate pleural covering, intralobar sequestrations require lobectomy. Partial success with a nonsurgical approach using transumbilical artery embolization during the newborn period has been reported.

Congenital lobar emphysema

Congenital lobar emphysema is an unusual disorder characterized by progressive lobar overdistention of the lung as a consequence of developmental disruptions. ^{, ,} In fewer than 25% of cases, clinical and radiographic findings are typical of a ball-valve type of obstruction. More commonly, the cause for air trapping remains uncertain. Intrinsic bronchial obstruction may result from a deficiency of cartilaginous support or an intraluminal mass, such as a mucous plug. Extrinsic bronchial obstruction usually results from an underlying cardiovascular abnormality, such as a vascular sling or, rarely, a PDA. An intrathoracic mass, such as an enlarged lymph node or a bronchogenic cyst, also can cause extrinsic obstruction.

Congenital lobar emphysema is more common in male infants and typically occurs in the upper lobes or the right middle lobe. Fewer than 1% of cases occur in the lower lobes. Up to 20% of cases show bilateral involvement. Associated cardiovascular anomalies are common. Rib cage anomalies and aplasia/dysplasia of the kidneys have been reported in a small percentage of cases. In most infants with congenital lobar emphysema, the condition presents within the first month of life, and about one-third of infants exhibit respiratory signs within hours of birth. Respiratory compromise is directly related to the degree of overinflation. Typically, infants have mild to moderate tachypnea, asymmetric inflation of the chest, and cyanosis. A chest radiograph reveals the overinflated lobe with ipsilateral atelectasis and flattening of the hemidiaphragm; mediastinal shift away from the affected side may be observed. A CT scan may help to identify the cause of obstruction, if one is present. Lobectomy is the definitive treatment and may be performed thoracoscopically. Surgery is limited to symptomatic cases. Favorable outcomes are reported in asymptomatic or minimally symptomatic cases in which surgery was not performed.

Pulmonary agenesis and aplasia

Pulmonary agenesis and aplasia are rare, highly lethal disorders with similar underlying causes that differ from causes of pulmonary hypoplasia. Pulmonary agenesis and aplasia result from an arrested development of the embryonic lung. The earlier in development arrest occurs, the more severe the defect. In pulmonary agenesis, the bronchial tree, pulmonary parenchyma, or pulmonary vasculature does not develop. In pulmonary aplasia, there is a rudimentary bronchial pouch. The resulting lesions may involve one lobe or the entire lung. Focal or bilateral defects are rare. Pulmonary agenesis or aplasia may be associated with other nonpulmonary anomalies, including microphthalmia/anophthalmia, cleft palate, cardiac defects, congenital diaphragmatic hernia/eventration, and limb abnormalities. Abnormal blood flow in the dorsal aortic arch during the 4th week of gestation has been hypothesized to cause pulmonary agenesis. The contralateral lung may develop as many as two-fold more alveoli in response to pulmonary aplasia/agenesis.

The clinical presentation is variable. If the defect is focal and isolated, the infant may have normal respirations, though mild respiratory distress may be present. A chest radiograph reveals unilateral lung or lobar collapse with a shift of mediastinal structures, which leads to a suspicion of bronchial or bronchiolar obstruction. Misdiagnosis may subject the infant to unnecessary risks of bronchoscopy despite CT being readily available for diagnosis. Associated anomalies of the cardiovascular, GI, genitourinary, central nervous, and musculoskeletal systems have all been described. If the defect is isolated to a single lobe, surgical resection will reduce respiratory signs and lower the risk for infection. If the defect is extensive but the fetus is potentially viable, an ex utero intrapartum procedure may be attempted.

Prognosis depends on the degree of pulmonary involvement, whether there have been recurrent pulmonary infections, and the presence of associated anomalies. Bilateral defects are invariably lethal. If the defect is focal, the remaining normal lung undergoes compensatory hypertrophy. Nevertheless, mortality exceeds 50%, generally because of the presence of associated malformations. Right-sided defects have a poorer prognosis than left-sided lesions, partly because of a higher association with other anomalies and partly because of an increased risk for disseminating infection. Right-sided lesions also may produce a more severe mediastinal shift, distorting the trachea and great vessels. Repeated lower respiratory infections can result in progressive pulmonary debilitation and increase the risk of death.

Congenital defects of the lymphatics

Congenital chylothorax is thought to result from a failure of peripheral and central lymphatic channels to fuse or, perhaps, from a rupture of inadequately fused channels at birth. The congenital condition has a different course and prognosis from postoperatively acquired chylothorax. Most affected infants show respiratory signs within hours from birth and may require mechanical ventilation. Congenital chylothorax may be associated with chromosomal abnormalities or other malformations. Familial cases are especially common in babies with associated congenital pulmonary lymphangiectasis with bilateral chylothoraces.

Progressive respiratory compromise develops as fluid accumulates in the hemithorax. Pleural drainage is both diagnostic and therapeutic. Initially, the lymphocyte-rich fluid is clear, but it becomes opaque when milk feedings are introduced. Nutritional support is critical because of a loss of protein in the chylous drainage. Most cases spontaneously resolve in 2 to 3 weeks. Occasionally, a several-day course of a somatostatin analog, which reduces chyle flow, or surgical closure of the thoracic duct is indicated. Whether congenital or postoperative, common chylothorax complications include nosocomial infection, hemodynamic disturbance, and protein loss.

In the congenital form, time to resolution is significantly affected by additional underlying problems. Pulmonary lymphangiectasia is a rare condition that can be a primary or due to secondary dilation of pulmonary lymphatics from obstructed pulmonary venous flow. Primary lymphangiectasia can be isolated, termed congenital pulmonary lymphangiectasia , or it can be part of a generalized condition that includes intestinal lymphangiectasia, in which pulmonary involvement is less severe. Congenital pulmonary lymphangiectasia may result from the failure of connective tissue elements to regress during fetal lung development. In some cases, a hereditary pattern has been suggested. Affected infants usually show respiratory signs soon after birth. However, some infants may remain symptom free for several weeks. Affected infants are usually born at term and may have a normal examination except for mild tachypnea. They may be more severely affected with cyanosis or frankly hydropic. Preterm infants may be mistaken as having surfactant-deficient RDS. Radiographs generally reveal streaky reticular densities as a result of engorged lymphatics and, occasionally, a finer, ground-glass appearance may be confused with surfactant deficiency.