I. INTRODUCTION. Respiratory distress syndrome (RDS), formerly known as hyaline membrane disease (HMD), describes a disease typical of preterm infants that is caused by insufficient pulmonary surfactant in alveoli. Pulmonary surfactant is a complex mixture of phospholipids, neutral lipids, and surfactant-specific proteins that is synthesized, packaged, and secreted from alveolar type II cells of the lung. In the alveolar spaces and small respiratory bronchioles that have poor structural support, surfactant sits at the air-liquid interface over the residual and protective liquid layer overlying the epithelium and disrupts the surface tension generated by the lung liquid. This surface tension is forceful enough to promote alveolar collapse at low lung volumes and to oppose reinflation of atelectatic airspaces. Absent or insufficient surfactant due to developmental immaturity of alveolar type II cells or spontaneous or inherited mutations of surfactant-related genes, or inactivation of surfactant due to inflammation, chemical modification, or lung injury, result in high surface tension and atelectasis. Preterm infants are particularly prone to RDS because alveolar type II cells do not develop until early in the third trimester, and their number and capacity to produce surfactant increase throughout the third trimester. Advances in preventive and rescue treatment strategies, including antenatal glucocorticoids, exogenous surfactant, and continuous positive airway pressure (CPAP), have greatly reduced the impact of RDS on neonatal morbidity and mortality, but RDS remains a particularly vexing problem for extremely low birth weight (ELBW) infants.

1. Lung maturity, which is distinct from structural lung development, is the most significant risk factor for RDS. By 24 weeks of gestation,
structural lung development has advanced sufficiently to provide gas exchange across lung epithelial and endothelial cells and provide a surface area sufficient to meet the oxygen consumption needs of the ELBW infant. However, the fetal lung at that gestation has insufficient numbers of alveolar type II cells to generate enough surfactant to avoid RDS. In contrast, the fetal lung at 36 weeks of gestation generally has sufficient surfactant stores and large numbers of alveolar type II cells to avoid RDS. In between, the preparedness for air breathing of the fetal lung depends on the extent of lung maturation, which is influenced by multiple genetic and environmental factors.

a. Fetal sex. Male infants are at higher risk for RDS due to the presence of circulating weak fetal androgens that inhibit the production of surfactant phospholipids.

b. Race. Infants of African ancestry are at lower risk for developing RDS, due in part to the increased presence of protective genetic polymorphisms.

c. Maternal diabetes. Poorly controlled maternal diabetes, in the absence of microvascular disease, is associated with RDS due to enhanced production of fetal insulin which inhibits the production of proteins important for surfactant function.

d. Mutations in surfactant-related proteins, specifically surfactant protein B and ABCA3, result in severe RDS typically in term infants from either dysfunctional surfactant or severely limited production, respectively. Infants with these mutations die without lung transplantation. Some mutations in ABCA3 and mutations of surfactant protein C are associated with progressive interstitial lung disease, often diagnosed beyond the neonatal period.

e. Labor, due to the production of endogenous maternal glucocorticoids, may enhance lung maturation, but inflammation often associated with preterm labor (w) can downregulate the production of many surfactant components.

1. Because gestational age is a strong predictor of RDS risk, invasive testing (amniocentesis) to confirm lung maturity in amniotic fluid samples is reserved for instances in which surfactant deficiency in addition to other fetal conditions would significantly impact morbidity and mortality. These conditions include fetal anomalies such as congenital diaphragmatic hernia and congenital heart disease where more precise timing of delivery of a near-term infant is desirable. Although the risk of adverse outcomes is low with amniocentesis in the third trimester, the widespread use of antenatal glucocorticoids has made the risk unnecessary for the majority of fetuses facing preterm delivery.

2. If lung maturity testing is indicated, the most readily available tests assess the lecithin (disaturated phosphatidylcholine) component of surfactant. Lecithin is the most abundant surfactant phospholipid, and its production is developmentally regulated. However, it is also present
in cell membranes, necessitating correction for the presence of contaminants like blood.

a. The lecithin/sphingomyelin (L/S) ratio corrects for the presence of a neutral lipid in low abundance in surfactant, whereas the TDx-FLM II corrects for the presence of albumin in the amniotic fluid sample. In both cases, samples contaminated significantly by blood or meconium can be difficult to interpret. RDS risk is low when the L/S ratio is >2, but notable exceptions to this include maternal diabetes, erythroblastosis fetalis, and intrapartum asphyxia. The TDx-FLM II has established gestational age-specific cutoffs but in general is predictive of low RDS risk at >55 mg lecithin per gram albumin.

b. The presence of lamellar bodies in amniotic fluid samples is a rapid and inexpensive test that may be useful in resource-poor settings. Lamellar bodies are the organelles in alveolar type II cells that receive, concentrate, and store surfactant constituents for regulated secretion. Upon exocytosis at the plasma membrane, surfactant is extruded into the alveolar space and the constituents must unravel and disperse to form a monolayer at the air-liquid interface. Unwound phospholipid can be discriminated by light microscopy or fluorescence-activated cell sorting (FACS), and >50,000 lamellar bodies per microliter of amniotic fluid has been correlated with lung maturity. Alternatively, the optical density of the amniotic fluid sample can be used as a proxy for the presence of lamellar bodies in amniotic fluid.

C. Diagnosis. RDS should be suspected in a preterm infant, typically <34 weeks’ gestation, with signs of respiratory distress that develop soon after birth. These include tachypnea, retractions, flaring of the nasal alae, grunting, and cyanosis. Blood gas measurement will demonstrate hypoxemia and hypercarbia.

1. Infants with RDS who are spontaneously breathing may overcome surfactant deficiency by using a set of physiologic maneuvers to establish functional residual capacity (FRC) and optimize gas exchange. These result in characteristic signs/symptoms of RDS (see section II.C).

a. Tachypnea. Inadequate FRC leads to inadequate tidal volumes. To maintain minute ventilation (the product of tidal volume × respiratory rate), infants with RDS increase respiratory rate.

b. Retractions. To maximize negative inspiratory pressure and thus lung inflation, affected infants use accessory muscles of breathing to supplement diaphragmatic contractions. The high negative inspiratory pressure draws in the highly compliant chest wall resulting in suprasternal, intercostal, and subcostal retractions.

c. Flaring of the alae nasi. To maximize air entry into the lungs in babies who are obligate nose breathers, flaring of the alae nasi reduces the resistance to air flow through the upper airways.

d. Grunting. Grunting is active exhalation against a partially closed glottis and results in a pressure gradient at the level of the vocal cords that provides expiratory distending pressure to stabilize patent but surfactant-poor alveoli.

D. Radiographic evidence. RDS is a homogeneous lung disease due to the developmental deficiency of surfactant throughout the lung parenchyma.
Typical radiographic findings include low lung volumes, homogeneous microatelectasis that has the appearance of ground glass, and air bronchograms highlighted by the surrounding microatelectasis.

a. Transient tachypnea of the newborn (see Chapter 32). Excess fetal lung fluid can mimic RDS and can complicate RDS. Signs are indistinguishable from RDS, but TTN often resolves rapidly over the first several hours after birth. Radiographic findings are consistent with retained fetal lung fluid, with characteristic prominent perihilar streaking (sunburst pattern) due to engorgement of periarterial lymphatics that participate in the clearance of alveolar fluid and often fluid retained in the lateral fissure of the right lung.

b. Pneumonia, especially due to group B Streptococcus. Proinflammatory cytokines elaborated in the course of an infection can inactivate surfactant constituents and downregulate surfactant production. Signs and radiographic findings of group B Streptococcus (GBS) sepsis/pneumonia are indistinguishable from RDS; therefore, obtaining blood cultures and initiating antibiotics should be considered.

c. Genetic disorders of the surfactant system. Although more common in term and near-term infants, the presentation and radiographic findings are identical to RDS. Respiratory signs may be evident at birth or may develop over hours in a vigorous term infant able to initially spontaneously recruit FRC. However, the infant shows little to no response to the administration of artificial surfactant. Genetic mutations in surfactant protein B and ABCA3 can result in an RDS picture in the immediate newborn period.