Background

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):
 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


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.
Complications

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):
 Septicemia
 Bronchopulmonary dysplasia (BPD)
 Patent ductus arteriosus (PDA)
 Pulmonary hemorrhage
 Apnea/bradycardia
 Necrotizing enterocolitis (NEC)
 Retinopathy of prematurity (ROP)
 Hypertension
 Failure to thrive
 Intraventricular hemorrhage (IVH)
 Periventricular leukomalacia (PVL) - With associated neurodevelopmental and
audiovisual handicaps
Strategic goals include focusing direct attention on anticipating and minimizing these
complications and preventing premature delivery whenever possible. (See the diagram
below.)
 Schematic outlines the pathology of respiratory distress syndrome (RDS). Infants may
recover completely or develop chronic lung damage, resulting in bronchopulmonary
dysplasia (BPD). FiO2 = fraction of inspired oxygen; HMD = hyaline membrane disease;
V/Q = ventilation perfusion.

Surfactant formation and physiology

Surfactant is a complex lipoprotein (see the image below) composed of 6 phospholipids and 4
apoproteins. Surfactant recovered by alveolar wash from most mammals contains 70-80%
phospholipids, 8-10% protein, and 10% neutral lipids, primarily cholesterol. Dipalmitoyl
phosphatidylcholine (DPPC), or lecithin, is functionally the principle phospholipid.
Phosphatidylglycerol makes up 4-15% of the phospholipids; although it is a marker for lung
maturity, it is not necessary for normal lung function.

Bar chart demonstrates the composition of lung surfactant. About 1% of the 10% protein
component comprises surfactant apoproteins; the remaining proteins are derived from
alveolar exudate.

Among the 4 surfactant apoproteins identified, 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. 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, thus preventing atelectasis.
The SP-B gene is on human chromosome 2, and its primary translation product is 40 kd,
which is clipped to become an 8-kd protein in the type II cells before entering lamellar bodies
to be cosecreted with phospholipids. The SP-C gene is on chromosome 8; its primary
translation product, 22 kd, is processed to an extremely hydrophobic 4-kd protein that is
associated with lipids in lamellar bodies.
SP-A is an innate host defense, large molecular, hydrophilic (water soluble) lectin coded on
human chromosome 10 that regulates lung inflammation. SP-A contributes to the biophysical
properties of surfactant primarily by decreasing protein-mediated inhibition of surfactant
function. It binds to multiple organisms, such as group B streptococcus, Staphylococcus
aureus, influenza virus, adenovirus, herpes simplex type 1, and respiratory syncytial virus.
SP-A facilitates phagocytosis of pathogens by macrophages and their clearance from the
airways. Mice that lack SP-A have no tubular myelin and have normal lung function and
surfactant metabolism, indicating that SP-A is not a critical regulator of surfactant
metabolism. Patients with SP-A deficiency have not been described.
SP-D is also a hydrophilic protein of 43 kd that is a collectin with structural similarities to
SP-A. It has a collagenlike domain and a glycosylated region that gives it its lectinlike
functions. 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. It also binds pathogens and facilitates
their clearance. The absence of SP-D results in increased surfactant lipid pools in the
airspaces and emphysema in mice. No humans with SP-D deficiency have been described.
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.)
 Schematic show surfactant
metabolism, with a single alveolus is shown and the location and movement of surfactant
components. Surfactant components are synthesized from precursors in the endoplasmic
reticulum and transported through the Golgi apparatus by multivesicular bodies. Components
are ultimately packaged in lamellar bodies, which are intracellular storage granules for
surfactant before its secretion. After secretion (exocytosis) into the liquid lining of the
alveolus, surfactant phospholipids are organized into a complex lattice called tubular myelin.
Tubular myelin is believed to generate the phospholipid that provides material for a
monolayer at the air-liquid interface in the alveolus, which lowers surface tension. Surfactant
phospholipids and proteins are subsequently taken back into type II cells, in the form of small
vesicles, apparently by a specific pathway that involves endosomes, and then are transported
for storage into lamellar bodies for recycling. Alveolar macrophages also take up some
surfactant in the liquid layer. A single transit of the phospholipid components of surfactant
through the alveolar lumen normally requires a few hours. The phospholipid in the lumen is
taken back into type II cell and is reused 10 times before being degraded. Surfactant proteins
are synthesized in polyribosomes and extensively modified in the endoplasmic reticulum,
Golgi apparatus, and multivesicular bodies. Surfactant proteins are detected in lamellar
bodies or secretory vesicles closely associated with lamellar bodies before they are secreted
into the alveolus.

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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 depend on the apoproteins SP-B and SP-C to properly
configure 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. Surfactant proteins
are expressed in the fetal lung with increasing gestational age.

Patient education

Because the risk of prematurity and respiratory distress syndrome is increased for subsequent
pregnancies, counsel the parents.
Education and counseling of parents, caregivers, and families of premature infants must be
undertaken as part of discharge planning. These individuals should be advised of the potential
problems infants with respiratory distress syndrome may encounter during and after their
nursery stay. Audiovisual aids and handouts supplement such education.