Respiratory distress syndrome, also known as hyaline membrane disease, occurs almost exclusively in premature infants.

The incidence and severity of respiratory distress syndrome are related inversely to the gestational age of the newborn infant. (See Etiology and Epidemiology.) Enormous strides have been made in understanding the pathophysiology and management of respiratory distress syndrome, leading to improvements in morbidity and mortality in infants with the condition. Advances include the following (see Treatment and Medication):
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The use of antenatal steroids to enhance pulmonary maturity Appropriate resuscitation facilitated by placental transfusion and immediate use of continuous positive airway pressure (CPAP) for alveolar recruitment Early administration of surfactant The use of gentler modes of ventilation, including early use of "bubble" nasal CPAP to minimize damage to the immature lungs Supportive therapies, such as the diagnosis and management of patent ductus arteriosus (PDA), fluid and electrolyte management, trophic feeding and nutrition, and the use of prophylactic fluconazole

These therapies have also resulted in the survival of extremely premature infants, some of who continue to be ill with complications of prematurity. (See the image below.)

Chest radiographs in a premature infant with respiratory distress syndrome before and after surfactant treatment. Left: Initial radiograph shows poor lung expansion, air bronchogram, and reticular granular appearance. Right: Repeat chest radiograph obtained when the neonate is aged 3 hours and after surfactant therapy demonstrates marked improvement.

Although reduced, the incidence and severity of complications of respiratory distress syndrome can result in clinically significant morbidities. Sequelae of respiratory distress syndrome include the following (see Prognosis, Clinical, and Workup):
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Septicemia Bronchopulmonary dysplasia (BPD) Patent ductus arteriosus (PDA) Pulmonary hemorrhage Apnea/bradycardia Necrotizing enterocolitis (NEC) Retinopathy of prematurity (ROP) Hypertension

or lecithin. 8-10% protein. Infants may recover completely or develop chronic lung damage. the remaining proteins are derived from alveolar exudate. primarily cholesterol. it is not necessary for normal lung function.) Schematic outlines the pathology of respiratory distress syndrome (RDS). and 10% neutral lipids. HMD = hyaline membrane disease. Phosphatidylglycerol makes up 4-15% of the phospholipids. . although it is a marker for lung maturity. V/Q = ventilation perfusion. FiO2 = fraction of inspired oxygen. is functionally the principle phospholipid. About 1% of the 10% protein component comprises surfactant apoproteins. Surfactant formation and physiology Surfactant is a complex lipoprotein (see the image below) composed of 6 phospholipids and 4 apoproteins.   Failure to thrive Intraventricular hemorrhage (IVH) Periventricular leukomalacia (PVL) . Bar chart demonstrates the composition of lung surfactant. Surfactant recovered by alveolar wash from most mammals contains 70-80% phospholipids.With associated neurodevelopmental and audiovisual handicaps Strategic goals include focusing direct attention on anticipating and minimizing these complications and preventing premature delivery whenever possible. resulting in bronchopulmonary dysplasia (BPD). (See the diagram below. Dipalmitoyl phosphatidylcholine (DPPC).

surfactant protein B (SP-B) and SP-C are 2 small hydrophobic proteins that make up 2-4% of the surfactant mass and are present in commercially available surfactant preparations. It binds to multiple organisms. surfactant phospholipids are organized into a . Staphylococcus aureus. and its primary translation product is 40 kd. The absence of SP-D results in increased surfactant lipid pools in the airspaces and emphysema in mice. The SP-B gene is on human chromosome 2. 22 kd. SP-A is an innate host defense. SP-D is also a hydrophilic protein of 43 kd that is a collectin with structural similarities to SP-A. SP-D is a large multimer that is synthesized by type II alveolar cells and Clara cells in addition to other epithelial cells in the body. SP-B and SP-C work in concert to facilitate rapid adsorption and spreading of DPPC as a monolayer to lower the surface tension at the alveolar air-fluid interface in vivo during expiration. which are intracellular storage granules for surfactant before its secretion. Surfactant components are synthesized from precursors in the endoplasmic reticulum and transported through the Golgi apparatus by multivesicular bodies. is processed to an extremely hydrophobic 4-kd protein that is associated with lipids in lamellar bodies. influenza virus.) Schematic show surfactant metabolism. indicating that SP-A is not a critical regulator of surfactant metabolism. herpes simplex type 1. hydrophilic (water soluble) lectin coded on human chromosome 10 that regulates lung inflammation.Among the 4 surfactant apoproteins identified. Patients with SP-A deficiency have not been described. No humans with SP-D deficiency have been described. The SP-C gene is on chromosome 8. After secretion (exocytosis) into the liquid lining of the alveolus. SP-A contributes to the biophysical properties of surfactant primarily by decreasing protein-mediated inhibition of surfactant function. which is clipped to become an 8-kd protein in the type II cells before entering lamellar bodies to be cosecreted with phospholipids. and respiratory syncytial virus. SP-A facilitates phagocytosis of pathogens by macrophages and their clearance from the airways. its primary translation product. The components of pulmonary surfactant are synthesized in the Golgi apparatus of the endoplasmic reticulum of the type II alveolar cell. (See the image below. with a single alveolus is shown and the location and movement of surfactant components. thus preventing atelectasis. Components are ultimately packaged in lamellar bodies. It also binds pathogens and facilitates their clearance. adenovirus. such as group B streptococcus. Mice that lack SP-A have no tubular myelin and have normal lung function and surfactant metabolism. It has a collagenlike domain and a glycosylated region that gives it its lectinlike functions. large molecular.

Education and counseling of parents. Corners of the myelin lattice appear to be glued together with the large apoprotein SP-A. Surfactant phospholipids and proteins are subsequently taken back into type II cells. Surfactant proteins are synthesized in polyribosomes and extensively modified in the endoplasmic reticulum. and multivesicular bodies. Surfactant proteins are expressed in the fetal lung with increasing gestational age. and families of premature infants must be undertaken as part of discharge planning. They are secreted by a process of exocytosis. the daily rate of which may exceed the weight of the cell. and hypoventilation with resultant hypoxemia and hypercarbia. The phospholipid in the lumen is taken back into type II cell and is reused 10 times before being degraded. Surfactant proteins are detected in lamellar bodies or secretory vesicles closely associated with lamellar bodies before they are secreted into the alveolus. Golgi apparatus. in the form of small vesicles. The components are packaged in multilamellar vesicles in the cytoplasm of the type II alveolar cell. Audiovisual aids and handouts supplement such education. The relative deficiency of surfactant decreases lung compliance (see the image below) and functional residual capacity. Tubular myelin is believed to generate the phospholipid that provides material for a monolayer at the air-liquid interface 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. with increased dead space. Alveolar macrophages also take up some surfactant in the liquid layer. Patient education Because the risk of prematurity and respiratory distress syndrome is increased for subsequent pregnancies. the vesicles unwind to form bipolar monolayers of phospholipid molecules that depend on the apoproteins SP-B and SP-C to properly configure in the alveolus. which lowers surface tension. The resulting large V/Q mismatch and right-to-left shunt may involve as much as 80% of the cardiac output.complex lattice called tubular myelin. which may also have an important role in phagocytosis. Etiology In premature infants. caregivers. Blood gases show respiratory and metabolic acidosis that cause pulmonary vasoconstriction. respiratory distress syndrome develops because of impaired surfactant synthesis and secretion leading to atelectasis. Once secreted. apparently by a specific pathway that involves endosomes. counsel the parents. ventilation-perfusion (V/Q) inequality. These individuals should be advised of the potential problems infants with respiratory distress syndrome may encounter during and after their nursery stay. . and then are transported for storage into lamellar bodies for recycling. resulting in impaired endothelial and epithelial integrity with leakage of proteinaceous exudate and formation of hyaline membranes (hence the name). A single transit of the phospholipid components of surfactant through the alveolar lumen normally requires a few hours. Tubular myelin stores surfactant and depends on SP-B.

and endogenous surfactant synthesis begins. Diffuse atelectasis of distal airspaces along with distension of distal airways and perilymphatic areas are observed microscopically. Microscopic appearance of lungs of an infant with respiratory distress syndrome. . and hypotension may impair surfactant production and/or secretion. Progressive atelectasis. Hypoxia. In many neonates. and oxygen toxicity damage endothelial and epithelial cells lining these distal airways. liverlike). Lungs with HMD require far more pressure than to achieve a given volume of inflation than do lungs obtained from an infant dying of a nonrespiratory cause. which exacerbates the vascular injury. with a resultant increase in surfactant activity. hypothermia. Arrows indicate inspiratory and expiratory limbs of the pressure-volume curves. oxygen toxicity with barotrauma and volutrauma in their structurally immature lungs causes an influx of inflammatory cell. The healing process is complex. The recovery phase is characterized by regeneration of alveolar cells. the epithelium begins to heal at 36-72 hours after birth. Upon macroscopic evaluation. resulting in BPD. an arrest in lung development often occurs during the saccular stage.Bottom curve reflects findings from lungs obtained at postmortem from an infant with hyaline membrane disease (HMD). A chronic process often ensues in infants who are extremely immature and critically ill and in infants born to mothers with chorioamnionitis. acidosis. Antioxidant deficiency and freeradical injury worsen the injury. resulting in chronic lung disease termed "new" BPD. Therefore. Note the decreased lung compliance and increased critical opening and closing pressures. barotrauma or volutrauma. In larger premature infants. Hyaline membranes that line the alveoli (see the image below) may form within a half hour after birth. leading to bronchopulmonary dysplasia (BPD). the lungs require an increased critical opening pressure to inflate. the lungs of affected newborns appear airless and ruddy (ie. including type II cells. resulting in exudation of fibrinous matrix derived from blood. in the premature infant with HMD. In extremely premature infants. Hematoxylin and eosin stain shows hyaline membranes (pink areas). respectively.

and initiation of parturition. and the appearance of incompletely processed SP-C in the airspaces. Analysis of lung tissue with immunologic and biologic methods reveals an absence of one of the surfactant specific proteins. SP-B and SP-C participate in regulating intracellular and extracellular processes critical for maintaining respiratory structure and function. W9 is critical to optimal surface activity.and ABCA4 -encoded proteins that transport .[1] SP-B deficiency is an inherited deficiency caused by a pretranslational mechanism implied by the absence of messenger ribonucleic acid (mRNA). and its mRNA. critical structure and function in the N-terminal region of pulmonary SP-B was noted. Because it is closely related to the ABCA1 . resulting in a complete absence of SP-B. ABCA3 is critical for proper formation of lamellar bodies and surfactant function and may also be important for lung function in other pulmonary diseases. The genetic absence of SP-B is most often caused by a 2-base pair insertion (121 ins 2) that produces a frame shift and premature terminal signal. None of the currently available surfactant preparations to treat respiratory distress syndrome have SP-A and SP-D. In an in-vitro study. Studies have shown novel roles for these proteins in the clearance of apoptotic cells. a lack of SP-C. or both. direct killing of microorganisms. whereas prolines may promote a conformation that facilitates rapid insertion of the peptide into phospholipid monolayers compressed to the highest pressures during compressionexpansion cycling. or congenital alveolar proteinosis. adsorption. SP-B. extracellular deficiency of bioactive surfactant peptides.Apoprotein deficiency The hydrophobic SP-B and SP-C are essential for lung function and pulmonary homeostasis after birth. Mutations of SP-B and SP-C cause acute respiratory distress syndrome and chronic lung disease that may be related to the intracellular accumulation of injurious proteins. and stability of surfactant lipids required to reduce surface tension in the alveolus. ABCA3 mutations Mutations in the adenosine triphosphate (ATP)–binding casette gene (ABCA3) in newborns result in fatal surfactant deficiency. In vivo and in vitro studies provide compelling support for SP-A and SP-D as mediators of various immune-cell functions. These proteins enhance the spreading. Approximately 15% of term infants who die of a syndrome similar to respiratory distress syndrome have SP-B deficiency. SP-B deficiency leads to death in term or near-term neonates and clinically manifests as respiratory distress syndrome with pulmonary hypertension. Hydrophilic SP-A and SP-D are lectins. Mutations in other genes that cause protein misfolding and misrouting may contribute to the pathogenesis of chronic interstitial lung disease. These pro SP-C forms are diagnostic of SP-B deficiency. The lack of SP-B causes a lack of normal lamellar bodies in type II cells. Mutations in the gene for SP-C are a cause of familial and sporadic interstitial lung disease and emphysema as patients age.

Approximately 50% of the neonates born at 26-28 weeks' gestation develop respiratory distress syndrome. accurate records in these regions are unavailable to determine the frequency of respiratory distress syndrome. whereas less than 30% of premature neonates born at 30-31 weeks' gestation develop the condition. Other risk factors include maternal diabetes. In a review of 300 term infants presenting as severe respiratory distress syndrome. In one report. among the 12 university hospitals participating in the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network.[5] International occurrence Respiratory distress syndrome is encountered less frequently in developing countries than elsewhere. 14% had SP-B deficiency and 14% had a deficiency of ABCA3. the incidence rate of respiratory distress syndrome was 42% in infants weighing 501-1500g. Prognosis Acute complications of respiratory distress syndrome include the following[6] : . and asphyxia.000 newborn infants each year and is a complication in about 1% pregnancies. 4] Epidemiology Occurrence in the United States In the United States. Race-related demographics Respiratory distress syndrome has been reported in all races worldwide.[2] The incidence of genetic abnormalities of pulmonary surfactant disorders is unknown. although the syndrome does not occur in all premature newborns. it may have a role in surfactant phospholipid metabolism. occurring most often in white premature infants. 54% reported in infants weighing 751-1000g. cesarean delivery. respiratory distress syndrome has been estimated to occur in 20. with 71% reported in infants weighing 501-750g.phospholipids in macrophages and photoreceptor cells. Risk factors The greatest risk factor for respiratory distress syndrome is prematurity. primarily because most premature infants who are small for their gestation are stressed in utero because of malnutrition or pregnancy-induced hypertension. because most deliveries in developing countries occur at home. 36% reported in infants weighing 1001-1250g. In addition.[3.000-30. and 22% reported in infants weighing 1251-1500g.

When septicemia is suspected. use of respiratory equipment) and use of postnatal steroids provide access for organisms that may invade the immunologically compromised host. its routine . with an increased incidence of septicemia occurring in them secondary to staphylococcal epidermidis and/or candidal infection. Use of antenatal steroids has decreased the frequency of intracranial hemorrhage in these patients with respiratory distress syndrome. pneumopericardium. or as indicated (eg. or bradycardia or when metabolic acidosis is persistent. pneumomediastinum. Some neonatal ICUs use prophylactic fluconazole in the extremely premature infants. invasive procedures (eg. apnea. venipuncture. sudden deterioration. achieving a decrease in the incidence of candidal septicemia. With the advent of surfactant therapy. small and ill infants are surviving. Cranial ultrasonography is performed in the first week in premature neonates younger than 32 weeks' gestation and at 36 weeks or at the time of discharge. with greater frequency in infants with respiratory distress syndrome who require mechanical ventilation. including failure to improve. Although a few studies have shown that prophylactic indomethacin therapy may decrease intraventricular hemorrhage in premature infants. Infection Infections may complicate the management of respiratory distress syndrome and may manifest in various ways.[7] Intracranial hemorrhage and periventricular leukomalacia Intraventricular hemorrhage is observed in 20-40% of premature infants. or a change in white blood cell (WBC) count or thrombocytopenia. pneumothorax) when an infant with respiratory distress syndrome suddenly deteriorates with hypotension. obtain blood cultures from 2 sites and start appropriate antibiotics and/or antifungal therapy until culture results are obtained.       Alveolar rupture Infection Intracranial hemorrhage and periventricular leukomalacia Patent ductus arteriosus (PDA) with increasing left-to-right shunt Pulmonary hemorrhage Necrotizing enterocolitis (NEC) and/or gastrointestinal (GI) perforation Apnea of prematurity Chronic complications of respiratory distress syndrome include the following:    Bronchopulmonary dysplasia (BPD) Retinopathy of prematurity (ROP) Neurologic impairment Alveolar rupture Suspect an air leak (eg. catheter insertion. suspected seizures). interstitial emphysema. Also.

promptly treat pulmonary hemorrhage in such individuals. and its incidence has increased with surfactant therapy. Ductal-dependant cardiac anomalies should be excluded prior to initiating therapy. In some patients. Apnea of prematurity Apnea of prematurity is common in immature infants. Pulmonary hemorrhage The occurrence of pulmonary hemorrhage increases in tiny premature infants. Although helpful in the diagnosis of PDA. as the PDA may close spontaneously. with the rationale that blood inhibits pulmonary surfactant. seizures. Hypocarbia and chorioamnionitis are associated with an increase in periventricular leukomalacia. Patent ductus arteriosus with increasing left-to-right shunt This shunt may complicate the course of respiratory distress syndrome. pulmonary hemorrhage may be associated with PDA. An echocardiogram enables the clinician to confirm the diagnosis. intratracheal surfactant therapy was used successfully.use is discouraged because of the risk of intestinal perforation. Exclude septicemia. possibly because of early extubation. surgically close the PDA. Suspect patent ductus arteriosus (PDA) in any infant who deteriorates after initial improvement or who has bloody tracheal secretions. Treat PDA with ibuprofen or indomethacin. Radiography of the abdomen assists in confirming their presence. cardiac murmur and wide pulse pressure are not always apparent in critically ill infants. or with assisted ventilation in refractory incidents. gastroesophageal reflux. Increase positive end-expiratory pressure (PEEP) on the ventilator and administer intratracheal epinephrine to manage pulmonary hemorrhage. Infants requiring low fraction of inspired oxygen (FIO2) or who are clinically stable do not require treatment. Spontaneous perforation (not necessarily as part of NEC) occasionally occurs in critically ill premature infants and has been associated with the use of steroids and/or indomethacin. Necrotizing enterocolitis and/or GI perforation Suspect NEC and/or GI perforation in any infant with abnormal abdominal findings on physical examination. Manage apnea of prematurity with methylxanthines (caffeine) and/or bubble or continuous flow nasal continuous positive airway pressure (CPAP). Bronchopulmonary dysplasia . and metabolic and other causes in infants with apnea of prematurity. especially after surfactant therapy. nasal intermittent ventilation. which can be repeated during the first 2 weeks if the PDA reopens. especially in infants weaned rapidly after surfactant therapy. In a retrospective study.[8] In refractory incidents of respiratory distress syndrome or in infants in whom medical therapy is contraindicated.

the extent and type of intracranial pathology. and vitamin A deficiency. vitamin A. Retinopathy of prematurity Infants with respiratory distress syndrome who have a partial pressure of oxygen (PaO2) value of over 100mm Hg are at increased risk for ROP. has been used successfully to treat ROP. and inhaled nitric oxide may reduce the severity of BPD. a monoclonal antibody targeting the vascular endothelial growth factor. and the presence of hypoxia and infections. Intraocular bevacizumab. BPD may also be associated with gastroesophageal reflux or sudden infant death syndrome. Hearing and visual handicaps may further compromise development in affected infants. If ROP progresses. closely monitor PaO2 and maintain it at 50-70mm Hg. Patients may develop a specific learning disability and aberrant behavior. which has been attributed to increased survival of small and ill infants with respiratory distress syndrome.BPD is a chronic lung disease defined as a requirement for oxygen at a corrected gestational age of 36 weeks. periodically follow up on these infants to detect those with neurologic impairment. Therefore. . Closely monitor infants with ROP for refractive errors. inflammation. gentler ventilation. BPD increases with decreasing gestational age. Although it is a promising therapy for ROP. laser therapy or cryotherapy is used to prevent retinal detachment and blindness.[10] Neurologic impairment Neurologic impairment occurs in approximately 10-70% of infants and is related to the infant's gestational age. Postnatal use of surfactant therapy. An ophthalmologist examines the eyes of all premature infants at 34 weeks' gestation and thereafter as indicated. consider these entities in infants with unexplained apnea before discharging them from the hospital. Hence. BPD is related directly to the high volume and/or pressures used for mechanical ventilation or to manage infections. Although pulse oximetry is used in all premature infants. it is not helpful in preventing ROP in tiny infants because of the flat portion of the oxygen-hemoglobin dissociation curve. and undertake appropriate interventions. low-dose steroids. Hence.[9] Clinical studies have demonstrated various incidences of BPD. further studies are needed before it can be recommended for routine use.

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