eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Neonatology
Respiratory Distress Syndrome
Updated: Oct 20, 2006
Introduction
Background
Respiratory distress syndrome (RDS), also known as hyaline membrane disease (HMD), occurs almost exclusively in premature infants. The incidence and severity of RDS are related inversely to the gestational age of the newborn infant. Enormous strides have been made in our understanding of the pathophysiology and management of these infants, leading to improvements in morbidity and mortality. Advances include (1) the use of antenatal steroids to enhance pulmonary maturity, (2) appropriate resuscitation facilitated by placental transfusion and immediate use of continuous positive airway pressure (CPAP) (Neopuff infant resuscitator; Fisher & Paykel Healthcare, Auckland, New Zealand) for alveolar recruitment, (3) early administration of surfactant; and (4) using gentle modes of ventilation to minimize damage to the immature lungs. These therapies have also resulted in the survival of extremely premature infants who continue to be ill.
Although reduced, the incidence and severity of complications of RDS can result in clinically significant morbidities. Sequelae of RDS include septicemia, bronchopulmonary dysplasia (BPD), patent ductus arteriosus (PDA), pulmonary hemorrhage, apnea/bradycardia, Necritizing enterocolitis (NEC), Retinopathy of prematurity (ROP), hypertension, failure to thrive, intraventricular hemorrhage (IVH), and/or periventricular leukomalacia (PVL) with associated neurodevelopmental and audiovisual handicaps. Direct attention to anticipating and minimizing these complications and to preventing premature delivery whenever possible are strategic goals.
Pathophysiology
Considerable advances have been made in our understanding of the pathophysiology of RDS, lung development, ontogeny of surfactant proteins (SPs), protein leakage, and role of cytokines in lung damage. The cause of RDS is relative deficiency of surfactant, which decreases lung compliance (see Image 1) and functional residual capacity with increased dead space. The resulting large ventilation-perfusion (V/Q) mismatch and right-to-left shunt may involve as much as 80% of the cardiac output.
On macroscopic evaluation, the lungs appear airless and ruddy (ie, liverlike). Therefore, the lungs of affected newborn infants require an increased critical opening pressure to inflate (see Image 1). Diffuse atelectasis of distal airspaces along with distension of distal airways and perilymphatic areas are observed microscopically. Progressive atelectasis, barotrauma or volutrauma, and oxygen toxicity, damages endothelial and epithelial cells lining these distal airways, resulting in exudation of fibrinous matrix derived from blood.
Hyaline membranes that line the alveoli (see Image 2) are formed within a half hour after birth. At 36-72 hours after birth, the epithelium begins to heal, and surfactant synthesis begins. The healing process is complex (see Image 3). A chronic process often ensues in infants who are extremely immature and critically ill and in infants born to mothers with chorioamnionitis, resulting in BPD. The recovery phase is characterized by regeneration of alveolar cells, including type II cells, with a resultant increase in surfactant activity.
Surfactant is a complex lipoprotein (see Image 4) comprising six phospholipids and four apoproteins. Dipalmitoyl phosphatidylcholine (DPPC), or lecithin, is functionally the principle phospholipid. Apoproteins SP-B and SP-C and other substances (eg, nonionic detergent tyloxapol, C16:0 alcohol hexadecanol in Exosurf) facilitate adsorption and spreading of DPPC as a monolayer, which lowers the surface tension at the alveolar air-fluid interface in vivo.
The components of pulmonary surfactant are synthesized in the Golgi apparatus of the endoplasmic reticulum of the type II alveolar cell (see Image 5). The components are packaged in multilamellar vesicles in the cytoplasm of the type II alveolar cell. They are secreted by a process of exocytosis, the daily rate of which may exceed the weight of the cell. Once secreted, the vesicles unwind to form bipolar monolayers of phospholipid molecules that are dependent on the apoproteins SP-B and SP-C to configure properly in the alveolus. The lipid molecules are enriched in dipalmitoyl acyl groups attached to a glycerol backbone that pack tightly and generate low surface tension.
Tubular myelin stores surfactant and depends on SP-B. Corners of the myelin lattice appear to be glued together with the large apoprotein SP-A, which may also have an important role in phagocytosis. RDS develops because of impaired surfactant synthesis and secretion leading to atelectasis, V/Q inequality, and hypoventilation with resultant hypoxemia and hypercarbia. Blood gases show respiratory and metabolic acidosis that causes pulmonary vasoconstriction resulting in impaired endothelial and epithelial integrity with leakage of proteinaceous exudate and formation of hyaline membranes (hence the name). Hypoxia, acidosis, hypothermia, and hypotension may impair surfactant production and/or secretion. In many neonates, oxygen toxicity with barotrauma and volutrauma in their structurally immature lungs causes an influx of inflammatory cell, which exacerbates the vascular injury, leading to BPD. Antioxidant deficiency and free-radical injury worsens the injury.
The hydrophobic SP-B and SP-C are essential for lung function and pulmonary homeostasis after birth. These proteins enhance the spreading, adsorption, and stability of surfactant lipids required to reduce surface tension in the alveolus. SP-B and SP-C participate in regulating intracellular and extracellular processes critical for maintaining respiratory structure and function. SP-B deficiency is an inherited deficiency caused by a pretranslational mechanism implied by the absence of messenger RNA (mRNA).
SP-B deficiency clinically manifests in term or near-term neonates with respiratory distress, pulmonary hypertension, or congenital alveolar proteinosis. Analysis of lung tissue with immunologic and biologic methods reveals an absence of 1 of the surfactant specific proteins, SP-B, and its mRNA. In a recent in vitro study, critical structure and function in the N-terminal region of pulmonary SP-B was noted. W9 is critical to optimal surface activity, whereas prolines may promote a conformation that facilitates rapid insertion of the peptide into phospholipid monolayers compressed to the highest pressures during compression-expansion cycling.
Mutations of SP-B and SP-C cause acute RDS and chronic lung disease that may be related to the intracellular accumulation of injurious proteins, extracellular deficiency of bioactive surfactant peptides, or both. Mutations in the gene for SP-C are a cause of both familial and sporadic interstitial lung disease. Mutations in other genes that cause protein misfolding and misrouting may contribute to the pathogenesis of chronic interstitial lung disease.
ABCA3 genetic mutations in newborns result in fatal surfactant deficiency. ABCA3 is critical for proper formation of lamellar bodies and surfactant function, and it may also be important for lung function in other pulmonary diseases. Because it is closely related to the ABCA1 and ABCA4 -encoded proteins that transport phospholipids in macrophages and photoreceptor cells, it may have a role in surfactant phospholipid metabolism.
Hydrophilic SP-A and SP-D are lectins. In vivo and in vitro studies provide compelling support for SP-A and SP-D as mediators of various immune-cell functions. Recent studies have shown novel roles for these proteins in the clearance of apoptotic cells, direct killing of microorganisms, and initiation of parturition. None of the currently available surfactant preparations to treat RDS have SP-A and SP-D.
Frequency
United States
In the United States, RDS occurs in approximately 20,000-30,000 newborn infants each year and is a complication in about 1% pregnancies. Approximately 50% of the neonates born at 26-28 weeks of gestation develop RDS, whereas <30% of premature neonates born at 30 to 30-31 weeks develop RDS.
Fanaroff et al reported results of the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network study. Rates of RDS were 42% in infants weighing 501-1500 g, with 71% in those 501-750 g, 54% in those 751-1000 g, 36% in those 1001-1250 g, and 22% in those 1251-1500 g.
International
RDS has been reported in all races worldwide, occurring most often in premature infants of Caucasian ancestry. RDS is encountered less frequently in the developing countries than elsewhere, primarily because most premature infants who small for their gestation are stressed in utero because of malnutrition or pregnancy-induced hypertension. Because most deliveries occur at home, accurate records are unavailable to determine the frequency of RDS in developing countries.
Race
Infants of Caucasian origin are at increased risk for RDS.
Clinical
History
- RDS frequently occurs in the following individuals:
- Caucasian male infants
- Infants born to mothers with diabetes
- Infants born by means of cesarean delivery
- Second-born twins
- Infants with a family history of RDS
- In contrast, the incidence of RDS decreases with the following:
- Use of antenatal steroids
- Pregnancy-induced or chronic maternal hypertension
- Prolonged rupture of membranes
- Maternal narcotic addiction
- Secondary surfactant deficiency may occur in infants with the following:
- Intrapartum asphyxia
- Pulmonary infections (eg, group B beta-hemolytic streptococcal pneumonia)
- Pulmonary hemorrhage
- Meconium aspiration pneumonia
- Oxygen toxicity along with barotrauma or volutrauma to the lungs
- Congenital diaphragmatic hernia and pulmonary hypoplasia
Physical
- Physical findings are consistent with the infant's maturity assessed by using the Dubowitz examination or its modification by Ballard.
- Progressive signs of respiratory distress are noted soon after birth and include the following:
- Tachypnea
- Expiratory grunting (from partial closure of glottis)
- Subcostal and intercostal retractions
- Cyanosis
- Nasal flaring
- Extremely immature ineonates may develop apnea and/or hypothermia.
- Several diagnoses may coexist and complicate the course of RDS, including the following:
- Pneumonia is often secondary to group B beta-hemolytic streptococci and often coexists with RDS.
- Metabolic problems (eg, hypothermia, hypoglycemia) may occur.
- Hematologic problems (eg, anemia, polycythemia) may occur.
- Transient tachypnea of the newborn usually occurs in term or near-term neonates, often after cesarean delivery. The chest radiograph of an infant with transient tachypnea shows good lung expansion and, often, fluid in the horizontal fissure.
- Aspiration syndromes may result from aspiration of amniotic fluid, blood, or meconium. Aspiration syndrome is also observed in more mature infants and is differentiated by obtaining a history and by viewing the chest radiographs.
- Pulmonary air leaks (eg, pneumothorax, interstitial emphysema, pneumomediastinum, pneumopericardium) may occur. In premature infants, these complications may be due to excessive positive-pressure ventilation. In rare cases, spontaneous pneumothorax may occur in large infants.
- Congenital anomalies of the lungs (eg, diaphragmatic hernia, chylothorax, congenital cystic adenomatoid malformation of the lung, lobar emphysema, bronchogenic cyst, pulmonary sequestration) and heart (eg, cardiac anomalies) are rare in premature infants. These entities can be diagnosed on the basis of chest radiographic or echocardiographic findings. On rare occasions, they coexist with RDS.
Causes
The greatest risk factor for RDS is prematurity. Other risk factors are maternal diabetes, cesarean delivery, and asphyxia. Not all prematurely born newborn infants develop RDS. Surfactant deficiency and risk factors are outlined in History.
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Further Reading
Keywords
respiratory distress syndrome, RDS, HMD, hyaline membrane disease, premature infant, surfactant therapy, mechanical ventilation, continuous positive airway pressure, CPAP, inhaled nitric oxide
