Respiratory Distress Syndrome in the Neonate

Incidence

Respiratory distress syndrome is one of the most common causes of morbidity and mortality in preterm neonates, although lack of a precise definition among infants with very low birth weight necessitates cautious interpretation of statistics regarding incidence, mortality, and outcome. The diagnosis can be established pathologically or by biochemical documentation of surfactant deficiency; nonetheless, most series refer only to a combination of clinical and radiographic features. Without biochemical evidence of surfactant deficiency, it is difficult to clinically diagnose RDS in infants with extremely low birth weight. The term respiratory insufficiency of prematurity had been used in some centers for infants who require oxygen and ventilator support in the absence of typical radiographic evidence of RDS. More recently, the term respiratory instability of prematurity has been proposed to describe very low birth weight infants who require some respiratory support but may have additional contributing factors such as inconsistent central respiratory drive or poor inspiratory effort.

Respiratory distress syndrome occurs throughout the world and has a slight male predominance. The greatest risk factors appear to be young gestational age and low birth weight; however, European descent, late preterm delivery (35-36 weeks), or elective delivery in the absence of labor are also prominent risk factors. Given the associated adverse respiratory outcomes of late preterm and early term births, initiatives to delay elective deliveries until 39 weeks’ gestation have been successful in reducing pulmonary and nonpulmonary morbidity in these infants. Other risk factors include maternal diabetes and perinatal hypoxia-ischemia.

The incidence of RDS is inversely proportional to gestational age: nearly all infants born at 22-24 weeks’ gestation have RDS, decreasing to approximately 25% in infants with birth weights between 1251 and 1500 g. Even infants of 34 weeks’ gestation and greater, especially males of European descent, have a discernible risk of RDS that decreases from ~10% at 34 weeks to less than 1% at 37 weeks ( Fig. 64.1 ).

Pathophysiology

The lungs of infants who succumb from RDS have a characteristic uniformly ruddy and airless appearance, macroscopically resembling hepatic tissue. On microscopic examination, the striking feature is diffuse atelectasis such that only a few widely dilated alveoli are readily distinguishable ( Fig. 64.2 ). An eosinophilic membrane lines the visible airspaces that usually constitute terminal bronchioles and alveolar ducts. This characteristic membrane (from which the term hyaline membrane disease is derived) consists of a fibrinous matrix of materials derived from the blood and contains cellular debris derived from injured epithelium. The recovery phase is characterized by regeneration of alveolar cells, including the type II cells, with a resultant increase in surfactant activity. The development of RDS begins with impaired or delayed surfactant synthesis and secretion followed by a series of events that may progressively increase the severity of the disease for several days in the absence of exogenous surfactant replacement ( Fig. 64.3 ). Surfactant synthesis is a dynamic process that depends on factors such as pH, temperature, and perfusion and may be compromised by cold stress, hypovolemia, hypoxemia, and acidosis. Other unfavorable factors, such as exposure to high inspired oxygen concentration and the effects of barotrauma and volutrauma from assisted ventilation, can trigger the release of proinflammatory cytokines and chemokines and further damage the alveolar epithelial lining, resulting in reduced surfactant synthesis and function. The leakage of proteins such as fibrin in the intra-alveolar space further aggravates surfactant deficiency by promoting surfactant inactivation. Deficiency of surfactant and the accompanying decrease in lung compliance lead to alveolar hypoventilation and ventilation-perfusion (V/Q) imbalance.

Severe hypoxemia and systemic hypoperfusion result in decreased oxygen delivery with subsequent lactic acidosis secondary to anaerobic metabolism. Hypoxemia and acidosis also result in pulmonary hypoperfusion secondary to pulmonary vasoconstriction, and the result is a further aggravation of hypoxemia due to right-to-left shunting at the level of the ductus arteriosus, the foramen ovale, and within the lung itself.

The relative roles of surfactant deficiency and pulmonary hypoperfusion in the overall clinical picture of RDS vary somewhat with each patient. The natural history of RDS is now almost invariably altered by a combination of antenatal corticosteroid administration, exogenous surfactant therapy, assisted ventilation, and in some cases, intrauterine inflammation.

Heritability of Respiratory Distress Syndrome

A genetic contribution to the risk of RDS has been suggested in twin studies where the concordance of RDS in monozygotic twins is greater than that in dizygotic twins and with isolated reports of recurrence in families. With the application of molecular techniques, the contribution of genetic variations to the pathogenesis of respiratory disorders in newborns is rapidly emerging.

Pathogenic mutations in genes encoding surfactant protein-B (SP-B, SFTPB ), surfactant protein-C (SP-C, SFTPC ), the ATP binding cassette subfamily A, member 3 (ABCA3, ABCA3 ), and the thyroid transcription factor (TTF-1, NKX2-1 ) represent rare monogenic causes of RDS. Inherited SP-B deficiency is a recessive disorder that presents as severe respiratory failure in the immediate newborn period and is unresponsive to standard neonatal intensive care interventions. With a disease frequency of approximately 1 per million live births, the absence of SP-B, the presence of an incompletely processed proSP-C, and a generalized disruption of surfactant metabolism cause surfactant dysfunction and the clinical syndrome. Dominant mutations in SFTPC are present in significantly less than 0.1% of the population and typically result in interstitial lung disease in infants older than 1 month of age, although an “RDS-like” presentation has been described. The accumulation of misfolded proSP-C within cellular secretory pathways results in activation of cell stress responses and apoptosis and impaired surfactant function. Monoallelic, predicted deleterious variants in ABCA3 are present in approximately 2%-4% of the population and biallelic (recessive) mutations have been identified in association with progressive respiratory failure in newborns and with chronic respiratory insufficiency and interstitial lung disease in children. Accumulating experience suggests that ABCA3 deficiency may be the most common of these disorders of surfactant homeostasis. Data from humans and mice suggest that ABCA3 mediates surfactant phospholipid transport (primarily phosphatidylcholine and phosphatidylglycerol) into lamellar bodies, and thus dysfunction of phospholipid transport into the lamellar body leads to reduced surfactant function. Dominant mutations in NKX2-1 were first identified in the context of benign hereditary chorea but since then have also been recognized in lethal and nonlethal neonatal RDS as well as interstitial lung disease in older children. A triad of neurologic disease, characterized by hypotonia, developmental delay and movement disorders, congenital hypothyroidism, and RDS has been termed the brain-thyroid-lung syndrome , but any single organ presentation or combination thereof may be the initial and only manifestation of the syndrome. Mutations in NKX2-1 are rare, but the frequency of disease is unknown. Disruption in structural lung development and/or decreased expression of surfactant-associated genes are the postulated mechanisms of disease.

Large-scale cohort-based resequencing efforts have demonstrated an over-representation of monoallelic, predicted deleterious variants in ABCA3 in newborns 34 weeks and greater with RDS, suggesting that these mutations are modifiers for the risk or severity of respiratory disease in developmentally susceptible newborns. These efforts have failed to identify an unequivocal contribution of rare or common variants in the surfactant protein-B or -C genes to RDS in newborns, suggesting that if these genes play a role in RDS, it is likely to be through interactions with variants in other lung-associated genes. Exome and genome sequencing are becoming more accessible and will yield additional insights into candidate genes that account for the heritability of RDS.

Prevention: Pharmacologic Acceleration of Pulmonary Maturation

In the early 1970s, Liggins, while studying the effects of steroids on premature labor in lambs, noticed the lack of RDS and increased survival in preterm animals prenatally exposed to steroids. The effects of various catecholamines as well as aminophylline and thyroid hormone have been studied; however, the most successful method to induce fetal lung maturation is prenatal corticosteroid administration (see Chapter 62 ).

If premature delivery of any infant appears probable or necessary, lung maturity can be hastened pharmacologically. Accelerated lung maturation occurs with physiologic stress levels of corticosteroids via receptor-mediated induction of specific developmentally regulated proteins, including those associated with surfactant synthesis. Steroids, when administered to the mother at least 24-48 hours before delivery, decrease the incidence and severity of RDS. Corticosteroids appear to be most effective before 34 weeks of gestation and when administered at least 24 hours and no longer than 7 days before delivery. Because corticosteroid therapy for less than 24 hours is still associated with significant reductions in neonatal mortality, RDS, and intraventricular hemorrhage (IVH), antenatal steroids should always be considered unless immediate delivery is anticipated. While antenatal corticosteroids have routinely been administered to women at risk for preterm delivery before 34 weeks’ gestation since the 1990s, recent data suggest that late preterm infants born at 34-36 weeks’ gestation may also benefit. Late preterm infants exposed to antenatal betamethasone are less likely to require respiratory support after birth; however, they require close monitoring for hypoglycemia. While preterm infants as early as 23 weeks’ gestation may benefit from antenatal corticosteroid exposure, their use before 23 weeks’ gestation remains controversial.

Less clear are the effects of repeated courses of antenatal corticosteroids on the short- and long-term outcomes of preterm infants. Decreased fetal growth and poorer neurodevelopmental outcomes have been reported with exposure to multiple courses of antenatal corticosteroids in retrospective clinical studies. Prospective data suggest benefit for a single rescue course for women less than 34 weeks’ gestation who are at risk for preterm delivery within 7 days and whose prior steroid course was greater than 14 days.

Concern about the possibility of increased infection in mother or infant appears to be unfounded. Indeed, even when corticosteroids are administered to women with prolonged rupture of membranes, there is no evidence of increased risk of infection, and the neuroprotective effects of corticosteroids are still evident. However, the use of a rescue course of corticosteroids in the setting of premature rupture of membranes remains controversial. Maternal steroids may induce an increase in total leukocyte and immature neutrophil counts in the infant, which should be considered if neonatal sepsis is suspected.

There is proven benefit from the combined use of prenatal corticosteroids and postnatal surfactant therapy in preterm infants (see Surfactant Therapy ). Their effects appear to be additive in improving lung function. Antenatal steroids induce structural maturation of the lung, as evidenced by physiologic and morphometric techniques, that is not secondary to increases in alveolar surfactant pool sizes. These structural changes translate into improved physiologic properties of the lung, such as increased lung volume, increased lung compliance, and increased response to exogenous surfactant treatment.

Antenatal corticosteroids appear to reduce the incidence of other co-morbidities associated with prematurity, including intracranial hemorrhage, periventricular leukomalacia, and necrotizing enterocolitis. The beneficial effect on intracranial hemorrhage does not correlate directly with improved pulmonary morbidity and may be secondary to stabilization of cerebral blood flow or a steroid-induced maturation of vascular integrity in the germinal matrix, or both.

In the 1990s, the observation that thyroid hormone could augment lung development and surfactant production in vitro prompted trials of antenatally administered thyrotropin releasing hormone (TRH). However, these trials failed to demonstrate a benefit and also raised concerns for adverse consequences on neurodevelopment, thereby significantly dampening enthusiasm for this therapy.

Clinical Features

The classic clinical presentation of RDS includes grunting respirations, retractions, nasal flaring, cyanosis, and increased oxygen requirement, together with diagnostic radiographic findings and onset of symptoms shortly after birth. The respiratory rate is usually regular and increased well above the normal range of 30-60 breaths per minute. These infants usually show progression of respiratory symptoms and require supplemental oxygen. The presence of apneic episodes at this early stage is an ominous sign that could reflect thermal instability or sepsis but more often is a sign of hypoxemia and respiratory failure. This characteristic picture is modified in many infants with low birth weight as a result of the early administration of exogenous surfactant and immediate noninvasive or invasive assisted ventilation.

Retractions are prominent and are the result of the compliant rib cage collapsing on inspiration as the infant generates high negative intrathoracic pressures to expand the poorly compliant lungs. The typical expiratory grunt is an early feature and may subsequently disappear. Grunting results from partial closure of the glottis during expiration and in this way acts to trap alveolar air and maintain functional residual capacity (FRC). Although these signs are characteristic for neonatal RDS, they can result from a wide variety of nonpulmonary causes, such as hypothermia, hypoglycemia, anemia, polycythemia, or sepsis; furthermore, such nonpulmonary conditions can complicate the clinical course of RDS.

Cyanosis is a consequence of right-to-left shunting in RDS and is typically relieved by administering a higher concentration of oxygen and ventilatory support. Impaired cardiac output resulting from respiratory effort that is asynchronous with the ventilator may further impede oxygen delivery and lead to poor peripheral perfusion or cyanosis. The consistency of the arterial waveform with invasive blood pressure monitoring or the pulse signal with oxygen saturation monitoring can provide information about the effectiveness of cardiac output. Acrocyanosis of the hands and feet is a common finding in healthy infants and should not be confused with central cyanosis, which always must be investigated. Peripheral edema, often present in RDS, is of no particular prognostic significance unless it is associated with hydrops fetalis.

During auscultation of the chest, breath sounds are widely transmitted and cannot be relied upon to reflect pathologic conditions. Nonhomogeneous aeration plus elevated endogenously or exogenously generated intrathoracic pressures can cause pulmonary air leaks. Thus, unilaterally decreased breath sounds (with mediastinal shift to the opposite side) or bilaterally decreased air entry could indicate pneumothorax and immediate transillumination should be performed. Chest radiography is also needed to confirm endotracheal tube placement if air entry sounds are asymmetric. The murmur of a PDA is most often audible during the recovery phase of RDS, when pulmonary vascular resistance has fallen below systemic levels and there is left-to-right shunting. Distant, muffled heart sounds should alert one to the possibility of pneumopericardium. Percussion of the chest is of no diagnostic value in preterm infants.

A constant feature of RDS is the early onset of clinical signs of the disease. Most infants present with signs and symptoms either in the delivery room or within the first 6 hours after birth. Inadequate observation can lead to the impression of a symptom-free period of several hours. The uncomplicated clinical course is characterized by a progressive worsening of symptoms, with a peak severity by days 2-3 and onset of recovery by 72 hours. Surfactant therapy often shortens this course as it reconstitutes the surfactant pool and prevents atelectasis until endogenous surfactant production is sufficient. When the disease process is severe enough to require assisted ventilation or is complicated by the development of air leak, significant shunting through a PDA, concomitant infection, or early signs of BPD, recovery can be delayed for days, weeks, or months (see Fig. 64.3 ). In the most affected patients, the transition from the recovery phase of RDS to BPD is clinically imperceptible.

Radiographic Findings

The diagnosis of RDS is based on a combination of the previously described clinical features, evidence of prematurity, exclusion of other causes of respiratory distress, and characteristic radiographic appearance (see Chapter 38 ). The typical radiographic features consist of a diffuse reticulogranular pattern, giving the classic ground-glass appearance in both lung fields with superimposed air bronchograms ( Fig. 64.4 ). Although the radiologic appearance of RDS is typically symmetric and homogeneous, asymmetry has also been described, especially if surfactant therapy has been administered preferentially to one side.

The reticulogranular pattern is primarily caused by alveolar atelectasis, although there may be some component of pulmonary edema. The prominent air bronchograms represent aerated bronchioles superimposed on a background of nonaerated alveoli. An area of localized air bronchograms may be normal in the left lower lobe overlying the cardiac silhouette, but in RDS they are widely distributed, particularly in the upper lobes. In the most severe cases, a complete opacification of the lungs can be observed, with total loss of the cardiac borders. Heart size is typically normal or slightly increased. Cardiomegaly may herald the development of congestive cardiac failure from a PDA. After the administration of exogenous surfactant therapy, the chest radiograph usually shows improved aeration of the lungs bilaterally; however, asymmetric clearing of the lungs may occur.

The radiographic appearance of RDS, typical or atypical, cannot be reliably differentiated from that of neonatal pneumonia, which is most commonly caused by group B streptococcal or Gram-negative (e.g., E. coli ) infection. This problem has been the major reason for the widespread use of empiric antibiotics in the initial management of infants with RDS. Infants with RDS reportedly have a larger thymic silhouette than infants of comparable size without RDS. This supports the theory that patients with RDS have had reduced exposure to endogenous corticosteroids during fetal life.

Echocardiographic evaluation of selected infants with RDS may be of value in the diagnosis of a PDA to quantitate elevations in pulmonary artery pressure, to assess cardiac function, and to exclude congenital heart disease (e.g., obstructed total anomalous pulmonary venous return) (see Chapter 75 ).