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Respiratory Distress Syndrome

Updated: Jan 16, 2015
Author: Arun K Pramanik, MD, MBBS; Chief Editor: Ted Rosenkrantz, MD
Overview
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
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.)
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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.
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.
Etiology
In premature infants, respiratory distress syndrome develops because of impaired surfactant synthesis and secretion leading to atelectasis, ventilation-perfusion (V/Q) inequality, and
hypoventilation with resultant hypoxemia and hypercarbia. Blood gases show respiratory and metabolic acidosis that cause pulmonary vasoconstriction, resulting in impaired
endothelial and epithelial integrity with leakage of proteinaceous exudate and formation of hyaline membranes (hence the name).
The relative deficiency of surfactant decreases lung compliance (see the image below) and functional residual capacity, with increased dead space. The resulting large V/Q mismatch
and right-to-left shunt may involve as much as 80% of the cardiac output.
Bottom curve reflects findings from lungs obtained at postmortem from an infant with hyaline membrane disease (HMD). 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. Arrows indicate inspiratory and expiratory limbs of the pressure-volume
curves. Note the decreased lung compliance and increased critical opening and closing pressures, respectively, in the premature infant with HMD.
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 bronchopulmonary dysplasia (BPD). Antioxidant deficiency and
free-radical injury worsen the injury.
Upon macroscopic evaluation, the lungs of affected newborns appear airless and ruddy (ie, liverlike). Therefore, the lungs require an increased critical opening pressure to inflate.
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 damage endothelial and epithelial cells lining these distal airways, resulting in exudation of fibrinous matrix derived from blood.
Hyaline membranes that line the alveoli (see the image below) may form within a half hour after birth. In larger premature infants, the epithelium begins to heal at 36-72 hours after
birth, and endogenous surfactant synthesis begins. The recovery phase is characterized by regeneration of alveolar cells, including type II cells, with a resultant increase in surfactant
activity. The healing process is complex.
Microscopic appearance of lungs of an infant with respiratory distress syndrome. Hematoxylin and eosin stain shows hyaline membranes (pink areas).
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. In extremely premature
infants, an arrest in lung development often occurs during the saccular stage, resulting in chronic lung disease termed "new" BPD.
Apoprotein deficiency
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.[1]
SP-B deficiency is an inherited deficiency caused by a pretranslational mechanism implied by the absence of messenger ribonucleic acid (mRNA). SP-B deficiency leads to death in
term or near-term neonates and clinically manifests as respiratory distress syndrome with pulmonary hypertension, or congenital alveolar proteinosis. 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, resulting in a complete absence of SP-B.
Approximately 15% of term infants who die of a syndrome similar to respiratory distress syndrome have SP-B deficiency. The lack of SP-B causes a lack of normal lamellar bodies in
type II cells, a lack of SP-C, and the appearance of incompletely processed SP-C in the airspaces. These pro SP-C forms are diagnostic of SP-B deficiency.
Analysis of lung tissue with immunologic and biologic methods reveals an absence of one of the surfactant specific proteins, SP-B, and its mRNA. In an 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 respiratory distress syndrome 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 familial and sporadic interstitial lung disease and emphysema as
patients age. Mutations in other genes that cause protein misfolding and misrouting may contribute to the pathogenesis of chronic interstitial lung disease.
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. 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 respiratory distress syndrome have SP-A and SP-D.
ABCA3 mutations
Mutations in the adenosine triphosphate (ATP)–binding casette gene (ABCA3) in newborns result in fatal surfactant deficiency. ABCA3 is critical for proper formation of lamellar bodies
and surfactant function and 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.[2]
The incidence of genetic abnormalities of pulmonary surfactant disorders is unknown. In a review of 300 term infants presenting as severe respiratory distress syndrome, 14% had
SP-B deficiency and 14% had a deficiency of ABCA3.
Risk factors
The greatest risk factor for respiratory distress syndrome is prematurity, although the syndrome does not occur in all premature newborns. Other risk factors include maternal
diabetes, cesarean delivery, and asphyxia.[3, 4]
Epidemiology
Occurrence in the United States
In the United States, respiratory distress syndrome has been estimated to occur in 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' gestation develop respiratory distress syndrome, whereas less than 30% of premature neonates born at 30-31 weeks'
gestation develop the condition.
In one report, the incidence rate of respiratory distress syndrome was 42% in infants weighing 501-1500g, with 71% reported in infants weighing 501-750g, 54% reported in infants
weighing 751-1000g, 36% reported in infants weighing 1001-1250g, and 22% reported in infants weighing 1251-1500g, 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, primarily because most premature infants who are small for their gestation are
stressed in utero because of malnutrition or pregnancy-induced hypertension. In addition, because most deliveries in developing countries occur at home, accurate records in these
regions are unavailable to determine the frequency of respiratory distress syndrome.
Race-related demographics
Respiratory distress syndrome has been reported in all races worldwide, occurring most often in white premature infants.
Prognosis
Acute complications of respiratory distress syndrome include the following[6] :
Alveolar rupture
Infection
Intracranial hemorrhage and periventricular leukomalacia
Patent ductus arteriosus (PDA) with increasing left-to-right shunt
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, pneumomediastinum, pneumopericardium, interstitial emphysema, pneumothorax) when an infant with respiratory distress syndrome suddenly deteriorates
with hypotension, apnea, or bradycardia or when metabolic acidosis is persistent.
Infection
Infections may complicate the management of respiratory distress syndrome and may manifest in various ways, including failure to improve, sudden deterioration, or a change in white
blood cell (WBC) count or thrombocytopenia. Also, invasive procedures (eg, venipuncture, catheter insertion, use of respiratory equipment) and use of postnatal steroids provide
access for organisms that may invade the immunologically compromised host.
With the advent of surfactant therapy, small and ill infants are surviving, with an increased incidence of septicemia occurring in them secondary to staphylococcal epidermidis and/or
candidal infection. When septicemia is suspected, obtain blood cultures from 2 sites and start appropriate antibiotics and/or antifungal therapy until culture results are obtained. Some
neonatal ICUs use prophylactic fluconazole in the extremely premature infants, achieving a decrease in the incidence of candidal septicemia.[7]
Intracranial hemorrhage and periventricular leukomalacia
Intraventricular hemorrhage is observed in 20-40% of premature infants, with greater frequency in infants with respiratory distress syndrome who require mechanical ventilation.
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, or as indicated (eg,
suspected seizures).
Use of antenatal steroids has decreased the frequency of intracranial hemorrhage in these patients with respiratory distress syndrome. Although a few studies have shown that
prophylactic indomethacin therapy may decrease intraventricular hemorrhage in premature infants, its routine use is discouraged because of the risk of intestinal perforation.
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, especially in infants weaned rapidly after surfactant therapy. Suspect patent ductus arteriosus (PDA) in any
infant who deteriorates after initial improvement or who has bloody tracheal secretions.
Although helpful in the diagnosis of PDA, cardiac murmur and wide pulse pressure are not always apparent in critically ill infants. An echocardiogram enables the clinician to confirm
the diagnosis. Infants requiring low fraction of inspired oxygen (FIO2) or who are clinically stable do not require treatment, as the PDA may close spontaneously. Ductal-dependant
cardiac anomalies should be excluded prior to initiating therapy. Treat PDA with ibuprofen or indomethacin, which can be repeated during the first 2 weeks if the PDA reopens.[8] In
refractory incidents of respiratory distress syndrome or in infants in whom medical therapy is contraindicated, surgically close the PDA.
The occurrence of pulmonary hemorrhage increases in tiny premature infants, especially after surfactant therapy. Increase positive end-expiratory pressure (PEEP) on the ventilator
and administer intratracheal epinephrine to manage pulmonary hemorrhage. In some patients, pulmonary hemorrhage may be associated with PDA; promptly treat pulmonary
hemorrhage in such individuals.
In a retrospective study, intratracheal surfactant therapy was used successfully, with the rationale that blood inhibits pulmonary surfactant.
Necrotizing enterocolitis and/or GI perforation
Suspect NEC and/or GI perforation in any infant with abnormal abdominal findings on physical examination. Radiography of the abdomen assists in confirming their presence.
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.
Apnea of prematurity
Apnea of prematurity is common in immature infants, and its incidence has increased with surfactant therapy, possibly because of early extubation. Manage apnea of prematurity with
methylxanthines (caffeine) and/or bubble or continuous flow nasal continuous positive airway pressure (CPAP), nasal intermittent ventilation, or with assisted ventilation in refractory
incidents. Exclude septicemia, seizures, gastroesophageal reflux, and metabolic and other causes in infants with apnea of prematurity.
Bronchopulmonary dysplasia
BPD is a chronic lung disease defined as a requirement for oxygen at a corrected gestational age of 36 weeks. BPD is related directly to the high volume and/or pressures used for
mechanical ventilation or to manage infections, inflammation, and vitamin A deficiency. BPD increases with decreasing gestational age.
Postnatal use of surfactant therapy, gentler ventilation, vitamin A, low-dose steroids, and inhaled nitric oxide may reduce the severity of BPD.[9]
Clinical studies have demonstrated various incidences of BPD, which has been attributed to increased survival of small and ill infants with respiratory distress syndrome. BPD may
also be associated with gastroesophageal reflux or sudden infant death syndrome. Hence, consider these entities in infants with unexplained apnea before discharging them from the
hospital.
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. Hence, closely monitor PaO2 and
maintain it at 50-70mm Hg. 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.
An ophthalmologist examines the eyes of all premature infants at 34 weeks' gestation and thereafter as indicated. If ROP progresses, laser therapy or cryotherapy is used to prevent
retinal detachment and blindness. Closely monitor infants with ROP for refractive errors.
Intraocular bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor, has been used successfully to treat ROP. Although it is a promising therapy for ROP,
further studies are needed before it can be recommended for routine use.[10]
Neurologic impairment
Neurologic impairment occurs in approximately 10-70% of infants and is related to the infant's gestational age, the extent and type of intracranial pathology, and the presence of
hypoxia and infections. Hearing and visual handicaps may further compromise development in affected infants. Patients may develop a specific learning disability and aberrant
behavior. Therefore, periodically follow up on these infants to detect those with neurologic impairment, and undertake appropriate interventions.
In a study that assessed the outcomes of 288 very preterm Chinese infants with severe respiratory distress syndrome on mechanical ventilation through 18 months of corrected age,
the incidence of cerebral palsy and mental developmental index (MDI) less than 70 were highest among infants born at younger than 28 weeks' gestation compared to those born at
28-30 and 30-32 weeks' gestation.[11] Factors associated with cerebral palsy and an MDI below 70 were the administration of antenatal corticosteroids, decreased weight gain, and
the presence of preeclampsia, fetal distress, and early/late bacteremia; factors that increased the risk of cerebral palsy and an MDI below 70 were increased length of mechanical
ventilator support and blood transfusions.[11]
Presentation
History
Respiratory distress syndrome frequently occurs in the following individuals:
White male infants
Infants born to mothers with diabetes
Infants born by means of cesarean delivery
Second-born twins
Infants with a family history of respiratory distress syndrome
In contrast, the incidence of respiratory distress syndrome 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)
Meconium aspiration pneumonia
Oxygen toxicity along with barotrauma or volutrauma to the lungs
Congenital diaphragmatic hernia and pulmonary hypoplasia
Physical Examination
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 in neonates may develop apnea and/or hypothermia.
DDx
Diagnostic Considerations
Conditions to consider in the differential diagnosis of respiratory distress syndrome include the following:
Metabolic problems
Hematologic problems
Pulmonary air leaks
Congenital anomalies of the lungs
Differential Diagnoses
Acute Anemia
Aspiration Syndromes
Pediatric Gastroesophageal Reflux
Pediatric Hypoglycemia
Pediatric Pneumonia
Pediatric Polycythemia
Pneumomediastinum
Pneumothorax Imaging
Sudden Infant Death Syndrome
Transient Tachypnea of the Newborn
Workup
Workup
Approach Considerations
Several diagnoses may coexist with and complicate the course of respiratory distress syndrome, including the following:
Pneumonia - Usually secondary to group B beta-hemolytic streptococci and often coexists with respiratory distress syndrome
Metabolic problems - Eg, hypothermia, hypoglycemia
Hematologic problems - Eg, anemia, polycythemia, jaundice
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 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; 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
Congenital anomalies of the heart
Congenital anomalies of the lungs and heart are uncommon in premature infants; these entities can be diagnosed on the basis of chest radiographic or echocardiographic findings.
They coexist only rarely with respiratory distress syndrome.
Fetal lung maturity tests
Prediction of fetal lung maturity is derived by estimating the lecithin-to-sphingomyelin ratio and/or by testing for the presence of phosphatidylglycerol in the amniotic fluid obtained with
amniocentesis.
Antenatal diagnosis of SP-B deficiency, a rare genetic disease, can also be antenatally diagnosed by analyzing the amniotic fluid; this diagnostic testing should be undertaken in
previously affected siblings.
Procedures
Vascular access procedures
Vascular access procedures used in infants with respiratory distress syndrome include:
Intravenous (IV) line placement
Umbilical arterial catheterization
Umbilical artery cut down
Peripheral artery cannulation
Umbilical venous catheterization
Other procedures
The following procedures may also be employed in infants with respiratory distress syndrome:
Sedation, analgesia, or anesthesia whenever feasible
Arterial puncture, venous puncture, and capillary blood sampling
Tracheal intubation or tracheostomy
Bronchoscopy
Placement of thoracotomy tubes
Placement of pericardial tubes
Placement of gastric tubes
Transfusion of blood, blood products, and exchange transfusion
Lumbar puncture
Suprapubic bladder aspiration and bladder catheterization
Blood Gases
Blood gases are usually obtained in respiratory distress syndrome, as clinically indicated, from an indwelling peripheral or central (umbilical) arterial catheter or by means of arterial
puncture. In a multicenter study by Billman and colleagues, an in-line, ex-vivo, point-of-care monitor was shown to be reliable in critically ill neonates and infants.[12] It can be reliably
used without adverse consequences associated with serial phlebotomy.
Blood gases show respiratory and metabolic acidosis along with hypoxia. Respiratory acidosis occurs because of alveolar atelectasis and/or overdistension of terminal airways.
Metabolic acidosis is primarily lactic acidosis, which results from poor tissue perfusion and anaerobic metabolism.
Hypoxia occurs from right-to-left shunting of blood through the pulmonary vessels, patent ductus arteriosus (PDA), and/or patent foramen ovale.
Pulse Oximetry
Pulse oximetry is used as a noninvasive tool to monitor oxygen saturation, which should be maintained at 90-95%. However, it is unreliable for determining hyperoxia because of the
flat-top portion of the S -shaped oxygen-hemoglobin dissociation curve. In the past, continuous, in-line arterial PaO2 monitoring and transcutaneous monitoring were used.
Transcutaneous CO2 monitors should be used in infants with ongoing respiratory distress to monitor ventilation if it correlates with PaCO2.
Chest Radiography and Echocardiography

Chest radiography
Chest radiographs of a newborn infant with respiratory distress syndrome reveal bilateral, diffuse, reticular granular or ground-glass appearances; air bronchograms; and poor lung
expansion. The prominent air bronchograms represent aerated bronchioles superimposed on a background of collapsed alveoli.
The cardiac silhouette may be normal or enlarged. Cardiomegaly may be the result of prenatal asphyxia, maternal diabetes, patent ductus arteriosus (PDA), an associated congenital
heart anomaly, or simply poor lung expansion. These findings may be altered with early surfactant therapy and adequate mechanical ventilation. (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.
The radiologic findings of respiratory distress syndrome cannot be reliably differentiated from those of pneumonia, which is most commonly caused by group B beta-hemolytic
streptococci. If the radiograph shows streaky opacities, the diagnosis of Ureaplasma or Mycoplasma pneumonia should be considered and confirmed by means of tracheal aspirate
cultures grown in the appropriate medium.
Echocardiography
Echocardiographic evaluation is performed in selected infants to assist in diagnosing PDA and in determining the direction and degree of shunting on Doppler study. It is also useful in
diagnosing pulmonary hypertension, assessing cardiac function, and excluding structural heart disease.
Pulmonary Mechanics Testing

Although pulmonary mechanics testing (PMT) has primarily been used as a research tool in the past, newer ventilators are equipped with PMT capabilities to assist the neonatologist
in adequately managing the changing pulmonary course of premature newborn infants with respiratory distress syndrome.
Constant PMT may be helpful in preventing volutrauma due to alveolar and airway overdistension. Monitoring may also facilitate weaning the infant from the ventilator after surfactant
therapy or in determining if the infant can be extubated. However, clinical studies of PMT to date have not proven its long-term outcome benefits in neonates with respiratory distress
syndrome.
Infants with respiratory distress syndrome have substantially decreased lung compliance, with a range of 0.0005-0.0001 L/cm water. Therefore, for the same pressure gradient, the
delivered tidal volume is reduced in premature infants with respiratory distress syndrome compared with healthy newborn infants.
Pulmonary compliance may considerably improve after surfactant administration. Hence, the patient's lung compliance and end-expiratory tidal volume should be monitored closely
after surfactant therapy, and the peak inspiratory pressure should be adjusted accordingly.
The resistance (airway and tissues) may be normal or increased. The time constant and the corresponding pressure and volume equilibration are shortened. The anatomic dead
space and the functional residual capacity are increased.
Treatment
Approach Considerations
Promptly manage high-risk factors, such as diabetes, hypertension, incompetent cervix, and chorioamnionitis.
Delivery and resuscitation
A neonatologist experienced in the resuscitation and care of premature infants should attend the deliveries of fetuses born at less than 28 weeks' gestation. These neonates are at a
high risk for maladaptation, which further inhibits surfactant production.
In the delivery room, nasal continuous positive airway pressure (CPAP) is often used in spontaneously breathing premature infants immediately after birth as a potential alternative to
immediate intubation and surfactant replacement to minimize the severity of bronchopulmonary dysplasia (BPD). Several centers have reported success with the use of nasal bubble
CPAP to decrease the complications associated with intubation and mechanical ventilation.[13, 14] By avoiding intubation, lung injury may be diminished. (See Table 1, below.)
Table 1. Meta-Analysis of Early Versus Delayed Surfactant Treatment of RDS (Open Table in a new window)
Number of Relative Risk Relative Difference

Outcome
Trials (95% CI) (95% CI)
Pneumothorax 3 0.70 (0.59, 0.82) -5.2% (-7.5%, -2.9%)
Bronchopulmonary dysplasia (BPD) 3 0.97 (0.88, 1.06) -1.2% (-4.6%, 2.2%)
Mortality 4 0.87 (0.77, 0.99) -2.8% (-5.5%, 0.0%)
BPD or death 3 0.94 (0.88, 1.00) -3.7% (-7.2%, 0.0%)
In a study that evaluated the use and effectiveness of adjunctive therapies (surfactant administration, inhalation of nitric oxide [iNO], high-frequency oscillatory ventilation [HFOV], and
extracorporeal membrane oxygenation [ECMO]) and newborn mortality from severe respiratory failure (respiratory distress syndrome, pneumonia sepsis, meconium aspiration
syndrome, congenital diaphragmatic hernia) among 397 German infants, German investigators reported the following results[15] :
Surfactant: Administered to 77% of all newborns, with 71.6% efficacy
iNO: Administered to more than 40% of all infants, with improvement in every second case
HFOV: Used in every third newborn, 60% efficacy
ECMO: Used in 1 in 7 infants, with 80% survival rate
Overall mortality was 10.3%, with 29 infants who died without ECMO support (potentially contraindicated in 10; not transferred for ECMO in 19)
Transfer
Transfer the following patients to a tertiary care center:
Mothers with high-risk pregnancy
Mothers in premature labor
Newborn infants with respiratory failure
Corticosteroids
Obstetricians with experience in fetal medicine should care for mothers whose infants are at an increased risk for respiratory distress syndrome, preferably at a tertiary perinatal
center. Strategies to prevent premature birth include bed rest, tocolytics, antibiotics, and antenatal steroids.[16, 17, 18, 19, 20, 21, 22, 23]
One course of antenatal corticosteroids reduces the risk of respiratory distress syndrome and neonatal death. However, in a Canadian study of 1858 women at 25-32 weeks' gestation
who remained undelivered after a single course of antenatal corticosteroids, multiple courses did not improve outcomes and were associated with decrease in weight, length, and
head circumference at birth.[24]
In another trial, in which a single repeat dose of prenatal betamethasone treatment was given in women with imminent preterm birth before 34 weeks' gestation, the requirement for
surfactant therapy was increased.
In contrast, however, several large clinical trials in which much higher fetal corticosteroid exposure occurred showed benefit, with less severe lung disease and no increased risks.
Another randomized, triple-blind clinical trial investigated the effectiveness of corticosteroids in reducing respiratory disorders in infants born at 34-36 weeks' gestation. The results
found that while antenatal treatment with corticosteroids reduced the need for phototherapy for jaundice, it did not reduce the risk of respiratory disorders in newborn infants.[25]
The increased incidence of cerebral palsy found in a study by Wapner et al could be avoided by limiting retreatment to less than 4 weekly treatments.[26] Results from studies by
Crowther and colleagues and Wapner and associates of multiple treatments with antenatal corticosteroids are not consistent with results from the alternative strategy (ie, a single
treatment when delivery is imminent).[27] Nevertheless, these weekly retreatment trials demonstrated considerable safety for retreatment.
Corticosteroid treatment at recognition of a risk of preterm delivery is indicated. If the mother does not deliver within 1 week, retreatment may be considered; most perinatologists
administer a single, 12-mg dose of betamethasone, rather than 2 doses.
Clinical judgment should be used about the risk for preterm delivery before any repeat dose is administered. If cervical dilation or signs of labor persist, a repeat dose may help. If the
pregnancy appears to be at lower risk, retreatment may be deferred. Multiple retreatment (>4 times) may increase risk; however, the effect of corticosteroid retreatment for the risk of
preterm delivery remains unclear.
In a recent study, among infants born at 23-25 weeks’ gestation, antenatal exposure to corticosteroids compared with nonexposure was associated with a low rate of death or
neurodevelopmental impairment at 18-22 months.[28]
Surfactant Replacement Therapy

The advent of surfactant therapy has reduced the mortality rate from respiratory distress syndrome by approximately 50%.[29, 30, 31, 32, 33]
Meta-analysis of clinical trials comparing early natural and synthetic surfactant therapy versus controls showed a decrease in air leaks. Meta-analysis of comparisons of early versus
delayed selective treatment for neonatal respiratory distress syndrome suggested a decrease in pulmonary air leaks and chronic lung disease.
Early surfactant therapy in tiny neonates followed by rapid extubation to nasal continuous positive airway pressure (CPAP) decreased the need for and duration of mechanical
ventilation and decreased the rate of pulmonary air leakage and 28-day mortality compared with selective surfactant therapy in respiratory distress syndrome followed by ventilation.
Rates of pulmonary hemorrhage, necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), and
bronchopulmonary dysplasia (BPD) did not differ between the groups.
Neonates with respiratory distress syndrome who require assisted ventilation with a fraction of inspiratory oxygen (FIO2) of more than 0.40 should receive intratracheal surfactant as
soon as possible, preferably within 2 hours after birth.
Stevens et al, in a meta-analysis of 6 studies, concluded that administration of surfactant via transient intubation using a low treatment threshold (FIO2< 0.45) is preferable to
employing later, selective surfactant therapy using transient intubation and a higher threshold for study entry (FIO2 >0.45).[34, 35] Extremely premature neonates administered
surfactant in the delivery room may have improvement in short-term outcomes and milder BPD.
Because surfactant protects the immature lungs, several investigators have recommended its prophylactic use after resuscitation in extremely premature neonates (< 27 weeks'
gestation). In addition, pulmonary inflammation leads to leakage of proteins, inactivating the surfactant, damaging the surfactant phospholipids and fatty acids, affecting hydrolytic
activity on surfactant proteins by proteolytic enzymes, and decreasing the synthesis of surfactant by type II cells after oxidant injury.
In developing countries, surfactant is not only expensive but is also unnecessary in most instances because more than 60% of premature infants do not have surfactant deficiency; the
infants are intubated, with the resulting inherent risks. As an alternative, nasal bubble CPAP has been widely used in recent years to manage respiratory distress syndrome and apnea
of prematurity.[36]
Dosage
Premature neonates with surfactant deficiency and respiratory distress syndrome have an alveolar pool of about 5mg/kg. Full-term animal models have pools of 50-100mg/kg.
Recommended dosages of clinically available surfactant preparations are 50-200mg/kg, approximately the surfactant pool of term newborn lungs. Rapid bolus administration of
surfactant after adequate lung recruitment with 3-4cm of positive end-expiratory pressure (PEEP) and adequate positive pressure may improve its homogeneous distribution.
Most neonates require 2 doses; however, as many as 4 doses, given at 6-hour to 12-hour intervals, were used in several clinical trials. If the patient rapidly improves after 1 dose,
respiratory distress syndrome is unlikely. Conversely, in infants who have a poor or no response, patent ductus arteriosus (PDA), pneumonia, and complications of ventilation (air leak)
should be excluded, especially before subsequent surfactant doses are given.
Surfactant comparisons
The ideal surfactant preparation to treat premature infants with respiratory distress syndrome and its sequelae has not been identified.[37, 38, 39, 40, 41, 42, 43, 44]
Lucinactant (Surfaxin), a KL4 polypeptide exogenous surfactant, was approved by the US Food and Drug Administration (FDA) in March 2012. Approval was based on the SELECT
(Safety and Effectiveness of Lucinactant vs. Exosurf in a Clinical Trial)[45] and STAR (SURFAXIN Therapy Against RDS)[44] studies.
SELECT enrolled 1294 patients in a multinational, multicenter, randomized trial to demonstrate the safety and efficacy of lucinactant compared with colfosceril palmitate (Exosurf),
which is no longer on the US market. Beractant (Survanta), an animal-derived surfactant that is a US market leader served as a reference arm. Key results from the SELECT trial can
be summarized as follows[45] :
Lucinactant demonstrated a significant improvement in RDS related mortality profile through 14 days of life compared with beractant (P ≤.001) and colfosceril palmitate (P ≤.01)
No significant difference in improvement in RDS at 24 hours of life was observed compared with beractant
Lucinactant significantly (P ≤.05) improved survival without BPD and overall incidence of BPD compared with colfosceril palmitate
Lucinactant treated infants required significantly fewer (P ≤.05) reintubations compared with beractant
A pharmacoeconomic assessment of lucinactant demonstrated a reduction in total NICU days and patient days on ventilator compared with beractant
The STAR trial was a supportive, multinational, multicenter Phase 3 clinical trial enrolling 252 patients and was designed as a noninferiority trial comparing lucinactant with poractant
alfa (Curosurf), a porcine (pig) derived surfactant and the leading surfactant used in Europe. Key results from the STAR trial can be summarized as follows[44] :
Lucinactant was noninferior to poractant alfa in survival without BPD
Survival profile through one year of life (corrected age) was significantly improved in lucinactant treated infants (P ≤.05) compared with poractant alfa
Lucinactant treated infants required significantly fewer (P ≤.05) reintubations compared with poractant alfa
However, these studies[46, 45] had several limitations. They were designed as "equivalent to the approved surfactant products" studies, presumably to satisfy product licensing
requirements rather than to evaluate the role of various surfactant components. In one study, lucinactant was compared with colfosceril palmitate, which has been discontinued. The
second study was halted halfway and was thus underpowered to establish equivalency of KL4 with poractant.
Most patients were enrolled in centers outside the United States experienced in conducting research. Data regarding the participation rate at each center and concerning the outcome
range varied among the 55 and 22 centers in the 2 respective studies.
The dose of phospholipid ranged from 67.5-76 mg/kg, and the volume varied from 2.2-5.5 mL among the participating centers. This was apparently done for obtaining licensing
requirements to compare with existing surfactant products. Furthermore, KL4 polypeptide does not lipid-associate as readily as SP-B and SP-C. Lucinactant forms a gel in its storage
form and must be heated to 44ºC and shaken before administration and placed on a special heating block prior to administration. The metabolism reuptake of KL4 polypeptide by type
II pneumocyte and its interaction with natural surfactant in these infants is unclear. Table 2 shows the source, composition, and dosages of several surfactant preparations.
Table 2. Surfactant Preparations: Type, Source, Composition, Dosages, and Other Information (Open Table in a new window)
Type Source Composition Dosing Comments
Beractant
(Survanta)
Bovine
Dipalmitoyl phosphatidylcholine (DPPC), tripalmitin, SP-B < 4mL/kg (100mg/kg),
lung Refrigerate
0.5%, SP-C 99% of TP wt/wt 1-4 doses every 6h
mince
Surfactant-TA
(Surfacten)
Bovine
Bovactant
lung 99% PL, 1% SP-B and SP-C 45mg/mL From the Federal Republic of Germany
(Alveofact)
lavage
Bovine lipid
Bovine 135mg/kg/dose
extract
lung 75% phosphatidylcholine (PC) and 1% SP-B and SP-C (5mL/kg), 1-4 doses Canadian
surfactant
lavage every 12h
(bLES)
Infasurf Calf lung DPPC, tripalmitin, SP-B 290g/mL, SP-C 360g/mL 3mL/kg (105mg/kg), 6mL vials, refrigerate
lavage 1-4 doses every 6-
12h
Calf lung
surfactant
Similar to Infasurf
extract
(CLSE)
Initially 2.5mL/kg
Poractant Phospholipids (DPPC, phosphatidylglycerol [PG]), neutral lipids,
Minced (200mg/kg),
alpha fatty acids; SP-B and SP-C; 80mg/mL of PL/mL [54mg PC 1.5 and 3mL
pig lung followed by 1.25mL
(Curosurf) (30.5mg DPPC and 1mg protein includes 0.3mg of SP-B)]
(100mg)/kg
5mL/kg
Colfosceril (67.5mg/kg),
palmitate Synthetic 85% DPPC, 9% hexadecanol, 6% tyloxapol No longer available; lyophilized, dissolve in 8mL
(Exosurf) 1-4 doses every
12h
FDA-approved March 2012; warmed for 15min at

Lucinactant Protein: KL4 (sinapultide) resembles SP-B; Phospholipids: 175 mg/kg/dose 44°C on a heating block, followed by vigorous
Synthetic
(Surfaxin) DPPC, palmitoyloleoyl phosphatidylcholine (POPG) phospholipid shaking until a uniform, free-flowing suspension
forms
Artificial lung
expanding
Synthetic 70% DPPC, 30% unsaturated phosphatidylglycerol No data Discontinued
compound
(ALEC)
Clinical outcomes
Tables 3-7 summarize some complication assessments derived from a meta-analysis of several clinical trials of surfactants conducted worldwide. In the trials, fewer complications and
more rapid improvement in infants’ respiratory status occurred with protein-containing natural surfactant than with synthetic surfactant. Currently marketed natural surfactants have
various amounts of phospholipids (mostly desaturated phosphatidylcholine) and apoprotein B and C, but not apoprotein A and D. Apoprotein A and D may be important for host
defense.
Table 3. Results of a Meta-Analysis of Separate Clinical Trials of the Treatment of Respiratory Distress Syndrome With Natural or Synthetic Surfactant Preparations (Open Table in a
new window)
Natural Surfactant Treatment Synthetic Surfactant Treatment
Relative Risk (95% Confidence Interval [CI]) Relative Risk (95% CI)
Outcome Number of Trials Number of Trials
Relative Difference (95% CI) Relative Difference (95% CI)
0.43 (0.35, 0.52) 0.64 (0.55, 0.76)

Pneumothorax 12 5
-17% (-21%, -13%) -9% (-12%, -6%)
0.94 (0.72, 1.22) 0.75 (0.61, 0.92)

Bronchopulmonary dysplasia (BPD) 9 5
-2% (-9%, 4%) -4% (-6%, -1%)
0.68 (0.57, 0.80) 0.73 (0.61, 0.88)

Mortality 12 6
-9% (-13%, -5%) -5% (-7%, -2%)
0.76 (0.65, 0.90) 0.73 (0.65, 0.83)

BPD or death 10 4
-14% (-21%, -7%) -8% (-11%, -5%)
Table 4. Results of a Meta-Analysis of Separate Clinical Trials of the Prophylactic Use of Natural or Synthetic Surfactant Preparations (Open Table in a new window)
Natural Prophylaxis Synthetic Prophylaxis
Outcome Number of Trials Relative Risk (95% CI) Number of Trials Relative Risk (95% CI)
Relative Difference (95% CI) Relative Difference (95% CI)
0.35 (0.26, 0.49) 0.67 (0.50, 0.90)

Pneumothorax 8 6
-13% (-20%, -11%) -5% (-9%, -2%)
0.93 (0.80, 1.07) 1.06 (0.83, 1.36)

BPD 7 4
-4% (-9%, -3%) 1% (-4%, 6%)
0.60 (0.44, 0.83) 0.70 (0.58, 0.85)

Mortality 7 7
-7% (-12%, -3%) -7% (-11%, -3%)
0.84 (0.75, 0.93) 0.80 (0.77, 1.03)

BPD or death 7 4
-10% (-16%, -4%) -4% (-10%, 1%)
Table 5. Results of a Meta-Analysis of Head-to-Head Trials With Natural Versus Synthetic Surfactants (Open Table in a new window)

Outcome
Pneumothorax 5 0.68 (0.56, 0.83) -4.1% (-6.3%, -2.0%)
BPD 4 0.97 (0.88, 1.07) -1.2% (-5.4%, -2.9%)
Mortality 7 0.88 (0.76, 1.02) -2.2% (-4.7%, 0.4%)
BPD or death 2 0.94 (0.87, 1.01) -3.6% (-8.0%, 0.8%)
Table 6. Meta-Analysis of Clinical Trials Comparing Prophylactic Use of Surfactant Versus Rescue Treatment of Infants With Respiratory Distress Syndrome (Open Table in a new
window)

Outcome
Pneumothorax 6 0.62 (0.42, 0.89) -2.1% (-3.7%, -0.55)
BPD 7 0.95 (0.81, 1.11) -0.9% (-3.5%, 1.7%)
Mortality 6 0.59 (0.46, 0.76) -4.6% (-6.8%, -2.5%)
BPD or death 7 0.85 (0.76, 0.95) -4.5% (-7.4%, -1.5%)
Infants < 30 wk of gestation
Mortality 6 0.60 (0.47, 0.77) -6.5% (-9.6%, -3.4%)
BPD or death 7 0.86 (0.77, 0.96) -5.5% (-9.6%, -1.5%)

Table 7. Results of a Meta-Analysis of Clinical Trials to Compare Multiple Doses With a Single Dose of Surfactant (Open Table in a new window)

Outcome
Pneumothorax 2 0.51 (0.30, 0.88) -8.7% (-15.4%, -2.0%)
BPD 1 1.10 (0.63, 1.93) 1.2% (-5.8%, 8.3%)
Mortality 2 0.63 (0.57, 1.11) -7.0% (-14%, 0%)
BPD or death 1 0.80 (0.57, 1.11) -6.6%, (-16.2%. 3%)
Oxygenation and CPAP

Continuous positive airway pressure (CPAP) was introduced as the primary therapeutic modality when Gregory et al demonstrated a marked reduction in respiratory distress
syndrome mortality.[47, 48, 49]
Oxygen was the primary therapeutic mode before the introduction of CPAP. Oxygen is administered via a hood or nasal canula or in the isolette to treat infants with mild respiratory
distress syndrome or after discontinuation of CPAP or assisted ventilation.[50]
CPAP keeps the alveoli open at the end of expiration, decreasing the right-to-left pulmonary shunt. CPAP is often administered using nasal prongs.[51] In a Cochrane database review
in which devices and pressure sources for administration of nasal CPAP were assessed, short, binasal prong devices were found to be more effective than single prongs and also
reduced the rate of reintubation.[14]
A meta-analysis of studies on prophylactic use of nasal CPAP for preventing morbidity and mortality in very preterm infants concluded that intermittent positive pressure ventilation
(IPPV) was not beneficial.[52]
In a retrospective, observational study of nasal CPAP in infants born at less than 27 weeks' gestation, the probability of an individual baby remaining on nasal CPAP was 66% on day
1 and 80% on day 2.[53]
A retrospective analysis of the first 48 hours in 225 infants of 23-28 weeks’ gestational age found that medical history and initial blood gas values could not adequately be used to
predict the failure of nasal CPAP.[33]
In another trial, investigators found no reduction in death or bronchopulmonary dysplasia (BPD) with early nasal CPAP. In the study, 610 infants born at 25-28 weeks' gestation were
randomly assigned to CPAP or intubation 5 minutes after birth, and their outcomes were assessed at age 28 days, at age 36 weeks, and before discharge.[54] The CPAP group had
an increase in the incidence of pneumothorax (9% vs 3%) but also fewer days on ventilator, and fewer infants in the group received oxygen at age 28 days.
CPAP is an adjunct therapy given after surfactant if prolonged assisted ventilation is not required. Use of nasal CPAP after initial surfactant therapy has been successful in some
infants. In a retrospective study, bubble nasal CPAP was successful in 76% of infants who weighed less than 1250 g and in 50% of infants who weighed less than 750 g.[55]
CPAP may be used after extubation in individuals with respiratory distress syndrome to prevent atelectasis and to prevent apnea in premature infants. A randomized, controlled trial
compared postextubation bubble CPAP with infant flow driver CPAP in preterm infants with respiratory distress syndrome[13] ; although both were equally effective, bubble CPAP was
associated with a significantly higher rate of successful extubation and reduced duration of CPAP in infants younger than age 14 days.
The goal of therapy for patients with respiratory distress syndrome is to maintain a pH of 7.25-7.4, a partial pressure of oxygen (PaO2) of 50-70mm Hg, and a carbon dioxide pressure
(PCO2) of 40-65 mm Hg, depending on the infant's clinical status.
In a nonblinded, randomized, observational 4-period cross-over level 3 NICU study that compared bi-level nasal CPAP (bi-PAP) with conventional nasal CPAP in 20 newborns with
persistent oxygen needs following recovery from respiratory distress syndrome, Lampland et al found that at similar mean airway pressures, bi-PAP did not improve CO 2 removal or
oxygenation but did improve mean blood pressure, albeit without clinical significance.[56]
Vapotherm
Vapotherm with heated and humidified, high-flow nasal canula (>2 L/min) has been used for respiratory support of neonates and to facilitate early extubation.[57] Neonatal units in the
United States and the United Kingdom use Vapotherm as a means of providing respiratory support. This device allows the delivery of high flows of gas at body temperature with close
to 100% relative humidity.[58]
Evidence suggests that Vapotherm may be an effective and well-tolerated method of providing babies with respiratory support. It has numerous advantages over therapies such as
nasal continuous positive airway pressure (CPAP), including a reduction in the number of ventilator days and reduced nasal trauma. It may be better tolerated than other forms of
noninvasive respiratory therapy.
Some evidence suggests that weight gain is improved using Vapotherm and that oral feeding can be introduced earlier. Further research is required, especially into the methods of
weaning Vapotherm and, as with all neonatal treatments, the long-term effects.
Assisted Ventilation
Kirby and deLemos introduced assisted ventilation several decades ago.[59] Assisted ventilation further decreased respiratory distress syndrome–related morbidity and mortality;
however, early ventilators were associated with complications, such as air leaks, bronchopulmonary dysplasia (BPD; secondary to barotrauma or volutrauma), airway damage, and
intraventricular hemorrhage.
See the video of assisted ventilation of the newborn, below.
Assisted ventilation newborn –Intubation and meconium aspiration. Video courtesy of Therese Canares, MD, and Jonathan Valente, MD, Rhode Island Hospital, Brown University.
Advances in microprocessor-based technology, transducers, and real-time monitoring have enabled patient-driven ventilator control and synchronization of mechanical ventilation with
patient effort. The novelty of the newer ventilation techniques has generated controversies that remain to be resolved. Among these are signal detection and transduction, optimal
volume delivery (ventilation modes), and weaning from mechanical ventilation.
Consider ventilation as a necessary physiologic support while the infant recovers from respiratory distress syndrome. Several investigators have suggested that permissive
hypercapnia with arterial partial pressure of carbon dioxide (PaCO2) of 45-55mm Hg (with adequate lung volume) may facilitate weaning during recovery from respiratory distress
syndrome. To minimize the complications of conventional intermittent mandatory ventilation, new ventilation techniques have been introduced, as described below.
Synchronous intermittent mandatory ventilation
Synchronous intermittent mandatory ventilation is a technique in which some of the patient's respirations are synchronized with breaths the ventilator delivers.[60] In a randomized,
controlled trial, the incidence of BPD (defined as oxygen requirement at a corrected gestational age of 36 wk) was significantly reduced with this therapy compared with standard
intermittent mandatory ventilation (47% vs 72%, respectively).
In another study, the duration of intubation was shortened and the need for oxygen was decreased with this strategy compared with conventional ventilation. The study involved
neonates born at 28-34 weeks’ gestational age with respiratory distress syndrome who required surfactant, with early extubation to synchronous, intermittent positive-pressure
ventilation
Assist-control ventilation and pressure-support ventilation
Assist-control ventilation has been suggested to improve outcomes. In a comparison of pressure-regulated volume control and the assist-control mode of ventilation from birth, the
time to extubation was not altered in infants with respiratory distress syndrome.
Some physicians use pressure-support ventilation to wean infants who develop chronic lung changes. Further studies are required to evaluate its long-term benefits.
High-Frequency Ventilation
With high-frequency ventilation (HFV), small tidal volumes (less than anatomic dead space) are usually delivered at rapid frequencies, thus eliminating the wide pressure swings seen
with conventional ventilators. Conventional ventilators may deliver high or low tidal volumes (barotrauma or volutrauma), cause wide pressure swings, or cause cardiovascular
compromise.
HFV was originally designed to treat patients with air leak. Many studies in animal models of respiratory distress syndrome demonstrated that HFV promoted uniform lung inflation,
improved lung mechanics and gas exchange, and reduced exudative alveolar edema, air leak, and lung inflammation.
Adequate clinical trials controlled for resuscitation techniques, time and type of surfactant therapy, and similar strategies with the same types of HFV versus synchronous intermittent
mandatory ventilation are awaited to evaluate short-term and long-term respiratory and neurologic outcomes.
HFV techniques involve a learning curve, and optimal ventilator strategies vary with the stage of respiratory distress syndrome.
High-frequency oscillatory ventilation
High-frequency oscillatory ventilation (HFOV) has a frequency range of 10-15Hz. Early in its use, high-HFOV was found to be clearly superior to conventional ventilation. In one
clinical trial, prophylactic HFOV reduced chronic lung disease.[61]
Because expiration actively occurs, monitor patients for hypocarbia to prevent periventricular leukomalacia (PVL).]
Controlled trials of HFOV to reduce bronchopulmonary dysplasia (BPD) in infants with respiratory distress syndrome have been controversial. This is because of the varied types of
ventilators used, varied learning curve by the users, time of lung recruitment, differences in surfactant treatment, and management of patent ductus arteriosus (PDA) and fluids.
The unfavorable outcome of HFOV in some studies has been attributed to (1) a low incidence of BPD with antenatal steroid use and, therefore, an inadequate sample size to detect a
difference; (2) use of a suboptimal lung volume strategy in patients treated with HFOV; (3) definition of and differences in chorioamnionitis; and (4) differences in resuscitation
techniques at birth.
High-frequency jet ventilation
The frequency range of this modality is 4-11Hz (usually 7Hz). High-frequency jet ventilation has to be used in tandem with conventional ventilation to provide positive end-expiratory
pressure (PEEP) and sigh breaths. It decreases air leaks. Because the solenoid valves open intermittently to provide jet breaths, some neonatologists prefer to use high-frequency jet
ventilation to treat infants with pulmonary air leaks.
High-frequency flow interrupter
The frequency range of this modality is 6-15Hz, with the advantages of a built-in conventional ventilator and an ability to provide sigh breaths. Its use is also associated with a
decreased incidence of air leaks in infants with respiratory distress syndrome.
Nitric Oxide
Although inhaled nitric oxide (iNO) is a safe and effective treatment for near-term and term newborn infants with pulmonary hypertension and hypoxic respiratory failure, its role in
premature infants with respiratory distress is ill defined.[9, 62]
Inhaled NO has selective pulmonary vasodilation and, in premature infants, it may have a role in decreasing inflammation, reducing oxidative stress, and enhancing alveolarization
and lung growth.
The effects of iNO in premature newborn infants with respiratory distress syndrome may be dependent on the timing, dose, and duration of iNO therapy and on the extent of the
infant's lung disease. The results of several clinical trials are summarized in Table 8, below.
Table 8. Inhaled Nitric Oxide Therapy in Preterm Infants and Outcome Measures (Open Table in a new window)
Study Number Mean Mean Mean Placebo Therapy Maximum % Change in

Enrolled Death/BPD
Gestational Age Birth Weight Oxygen Death Duration Dose
(wk) (g) Index Rate (d)
Kinsella et al[63] 80 27 1000 30 53% 7 5 ppm -15%
Schreiber et al[64] 201 27.2 970 10 22.5% 7 10 ppm -15%
Van Meurs et
420 26 839 22 44% 3 10 ppm -2%
al[65]
Ballard et al[66] 587 26 760 7 6% 24 20 ppm -11%
Kinsella et al[67] 793 25 792 5 25% 14 5 ppm -4%
Some evidence suggests that low-dose iNO may be safe and effective for reducing the risk of death and bronchopulmonary dysplasia (BPD) for a subset of premature infants with a
birth weight of less than 1000g (although the data represented in the first graph below shows no benefit for BPD in infants < 1000g).
Effects of early treatment of preterm infants with low-dose inhaled nitric oxide (iNO) on bronchopulmonary dysplasia (BPD) incidence by birth weight strata. No difference in
reduction was reported in infants weighing less than 1000 g (n = 129). Control = □; iNO = ■.
Effects of inhaled nitric oxide (iNO) survival without bronchopulmonary dysplasia (BPD) for infants aged 7-21 days. iNO increased survival without BPD in infants who were treated
before age 14 days (n = 727).
In addition, a neuroprotective effect of iNO has been demonstrated in large, randomized, clinical trials, although its exact relationship and mechanism of action are unclear.
Hintz et al reported no improvement in the neurodevelopmental outcome at a mean corrected age of 20 months in premature infants with a birth weight of less than 1500 g and severe
respiratory failure enrolled in a randomized, controlled trial of iNO.[5] The investigators suggested that routine use of iNO in premature infants should be limited to research settings.
However, they lost more than 50% of their patients to follow-up; therefore, interpretation of these results is difficult. (Results summarized in the graph below show a beneficial effect for
iNO therapy on brain injury in infants < 1250g.)
Effects of early treatment with low-dose inhaled nitric oxide (iNO) on brain injury (ie, grade 3-4 intracranial hemorrhage [ICH], periventricular leukomalacia [PVL], ventriculomegaly)
in premature infants according to birth weight strata. iNO reduced ultrasonography findings of brain injury for the overall group (n = 793), with the largest effect in the 750-g to 999-
g group (n = 280). Control = □; iNO = ■.
In selected premature neonates born at less than 32 weeks' gestation with respiratory distress syndrome and hypoxic respiratory failure, low pulmonary blood flow, as determined with
Doppler echocardiography, may be helpful in determining which patients are likely to benefit from iNO therapy.
However, a NIH Consensus Development Conference on “Inhaled Nitric Oxide Therapy for Premature Infants” held October 27-29, 2010 concluded the following:
“(1) Taken as a whole, the evidence does not support use of inhaled nitric oxide in early routine, early rescue, or later rescue regimens in the care of premature infants < 34
weeks gestation who require respiratory support.”
“(2) There are rare clinical situations, including pulmonary hypertension or hypoplasia, that have been inadequately studied in which inhaled nitric oxide may have benefit in
infants < 34 weeks gestation. In such situations, clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining
uncertainties.”
“(3) Basic research and animal studies have contributed to important understandings of inhaled nitric oxide benefits on lung development and function in infants at high risk of
bronchopulmonary dysplasia. These promising results have only partially been realized in clinical trials. Future research should seek to understand this gap.”
“(4) Predefined subgroup and post hoc analysis of previous trials showing potential benefits of inhaled nitric oxide have generated hypothesis for future research for clinical
trials. Prior strategies shown to be ineffective are discouraged unless new evidence emerges. The positive results of one multicenter trial, which was characterized by later
timing, higher dose, and longer duration of treatment, require confirmation. Future trials should attempt to quantify the individual effects of each of these treatment-related
variables (timing, dose, and duration), ideally by randomizing them separately.”
Supportive Therapy
Temperature regulation
Hypothermia increases oxygen consumption, further compromising neonates with respiratory distress syndrome who are born prematurely. Therefore, prevent hypothermia in
neonates with respiratory distress syndrome during delivery, resuscitation, and transport. Care for these patients in a neutral thermal environment with the use of a double-walled
incubator or radiant warmer.
Fluid, metabolic, and nutritional support
In infants with respiratory distress syndrome, initially administer 5% or 10% dextrose intravenously at a rate of 60-80 mL/kg/d. Closely monitor blood glucose (with Dextrostix testing),
electrolytes, calcium, and phosphorous levels, as well as renal function and hydration (as determined by body weight and urine output), to prevent any imbalance.
Add calcium at birth to the initial IV fluid. IV sodium bicarbonate is often misused and is considered to be an unproven therapy. Electrolytes should be added as soon as the patient
voids and as indicated by estimated serum electrolyte levels.
Gradually increase fluid intake to 120-140 mL/kg/d. Extremely premature infants occasionally require fluid intake of 200-300mL/kg or more because of insensible water loss occurring
from their large body surfaces.
After the neonate is stable, IV nutrition with amino acids and lipid are commenced within 24-48 hours of birth. As soon as the patient can tolerate oral feedings, trophic feeding with
small volumes (preferably breast milk) is commenced by using the orogastric tube to stimulate gut development. Gastric feedings are increased as tolerated, and IV nutritional support
is decreased proportionately to maintain adequate fluid and calorie intake.
Data suggest that an adequate supply of macronutrients, micronutrients, vitamins, and antioxidants should be provided to maintain optimal lung, brain, eye, and somatic growth.
Circulation and anemia
Assess the baby's circulatory status by monitoring his or her heart rate, peripheral perfusion, and blood pressure. Administer blood or volume expanders, and use appropriate
vasopressors to support circulation. Closely monitor blood withdrawn for laboratory tests in tiny patients and replace the blood with packed-cell transfusion when it reaches 10% of the
patient's estimated blood volume or if the hematocrit level is less than 40-45%.
Anemia and blood loss can be minimized by using placental transfusion at delivery, by limiting blood loss with in vivo blood gas and electrolyte estimations, and by using erythropoietin
with iron in extremely premature neonates.
Antibiotic administration
Start antibiotics in all infants who present with respiratory distress at birth after blood cultures, a complete blood count (CBC) with differential, and C-reactive protein levels are
obtained. Discontinue antibiotics after 2-5 days if blood cultures are negative and if no maternal risk factors are found. Some neonatologists do not start antibiotics in infants whose
mothers have received adequate antenatal care and have a recent negative cervix culture for beta-streptococci.
Parent and Family Support

Parents often undergo much emotional and/or financial stress with the birth of a critically ill, premature baby with respiratory distress syndrome and its associated complications. The
parents may feel guilty, they may be unable to relate to the neonate in the intensive care setting, and they may be anxious about their child's prognosis. In addition, the baby may be
unable to provide adequate cues to arouse mothering. These factors interact to prevent maternal-infant bonding. Hence, adequate support must be provided to parents and other
family members to prevent or minimize these problems.
Staff members (preferably a physician and a nurse) should keep the patient’s parents well informed by frequently talking to them, especially during the acute stage of respiratory
distress syndrome. Encourage parents and assist them in frequently visiting their child. Explain the equipment and procedures to the parents, and encourage them to touch, feed, and
care for their baby as soon as possible. Before the patient is discharged from the hospital, he or she is immunized, and follow-up care is arranged with a multidisciplinary team and
coordinated by a pediatrician experienced in the care of problems of premature infants.
Familial psychopathology
Infants with respiratory distress syndrome are at increased risk for child abuse and failure to thrive; therefore, obtain home clearance in conjunction with a nurse and social worker
before discharging the patient from the hospital. Encourage and document parental visits and the parent's interaction with the infant.
Advise parents to spend time with their infant with respiratory distress syndrome in a separate room before discharge, especially if the parents of an extremely premature infant are at
high social risk (eg, teenagers).
Advise parents of infants who are discharged with oxygen and/or an apnea monitor, with a gastrostomy or a requirement for tube feeding, or with a tracheostomy or other special
needs to spend time with their infants with respiratory distress syndrome in a separate room before discharge.
Physicians who are skilled in recognizing the problems encountered in these infants should be involved with their ongoing care because of the high risk of morbidity and mortality in
infancy.
Medication
Medication Summary
As previously mentioned, the advent of surfactant therapy has reduced the mortality rate from respiratory distress syndrome by approximately 50%. However, the ideal surfactant
preparation to treat premature infants with respiratory distress syndrome and its sequelae has not been identified.[37, 38]
Because surfactant protects the immature lungs, several investigators have recommended its prophylactic use after resuscitation in extremely premature neonates (< 27 weeks'
gestation).
Lung Surfactants
Class Summary
Exogenous surfactant can be helpful in treating respiratory distress syndrome (RDS). It has also been used in treating newborn infants with meconium aspiration syndrome,
pneumonia, and pulmonary hemorrhage. In RDS, after intratracheal administration of surfactant, surface tension is reduced, alveoli are stabilized, work of breathing is decreased, and
lung compliance is increased.
A number of studies have demonstrated the critical function of SP-B or specific SP-B peptide sequences in pulmonary surfactant, particularly the highly conserved amino- and
carboxyl-terminal sequences consisting of a repeating arginine-lysine (R-L) motif (RL4).
The evolution of surfactants from modified animal surfactant has included use of selective peptide sequences of SP-B; synthetic peptide mimics, including RL4 and KL4; modification
of SP-C; and peptoids of SP-B and SP-C.
In head-to-head clinical trials to compare synthetic surfactant with animal-derived preparations, animal-derived surfactants were superior, with immediate benefits in pulmonary air
leaks, intraventricular hemorrhage, bronchopulmonary dysplasia (BPD), and mortality.
Beractant (Survanta)
Beractant is a natural/modified bovine lung extract that lowers surface tension on alveolar surfaces during respiration and stabilizes alveoli against collapse at resting transpulmonary
pressures. For endotracheal (ET) use only. Survanta contains 10% SP-B.
Poractant (Curosurf)
Poractant lowers surface tension on alveolar surfaces during respiration and stabilizes alveoli against collapse at resting transpulmonary pressures. It is indicated to treat respiratory
distress syndrome in premature infants. Poractant is for ET use only. Curosurf has an SP-B content of 30%.
Calfactant (Infasurf)
Calfactant is a natural calf lung extract containing phospholipids, fatty acids, and surfactant-associated proteins B (260mcg/mL) and C (390mcg/mL). It is for ET use only.
Lucinactant (Surfaxin)
Synthetic KL4 protein (sinapultide) similar to SP-B. Contains DPPC and palmitoyloleoyl phosphatidylcholine (POPG) phospholipids.
Contributor Information and Disclosures
Author
Arun K Pramanik, MD, MBBS Professor of Pediatrics, Louisiana State University Health Sciences Center
Arun K Pramanik, MD, MBBS is a member of the following medical societies: American Academy of Pediatrics, American Thoracic Society, National Perinatal Association, Southern
Society for Pediatric Research
Disclosure: Nothing to disclose.
Chief Editor
Ted Rosenkrantz, MD Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine
Ted Rosenkrantz, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, Eastern Society for Pediatric Research, American
Medical Association, Connecticut State Medical Society, Society for Pediatric Research
Acknowledgements
David A Clark, MD Chairman, Professor, Department of Pediatrics, Albany Medical College
David A Clark, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Pediatric Society, Christian Medical & Dental
Society, Medical Society of the State of New York, New York Academy of Sciences, and Society for Pediatric Research
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
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Respiratory Distress Syndrome

The use of antenatal steroids to enhance pulmonary maturity

Early administration of surfactant

Bronchopulmonary dysplasia (BPD)

Patent ductus arteriosus (PDA)

Necrotizing enterocolitis (NEC)

Retinopathy of prematurity (ROP)

Intraventricular hemorrhage (IVH)

Periventricular leukomalacia (PVL) - With associated neurodevelopmental and audiovisual handicaps

Surfactant formation and physiology

Intracranial hemorrhage and periventricular leukomalacia

Patent ductus arteriosus (PDA) with increasing left-to-right shunt

Necrotizing enterocolitis (NEC) and/or gastrointestinal (GI) perforation

Chronic complications of respiratory distress syndrome include the following:

Bronchopulmonary dysplasia (BPD)

Retinopathy of prematurity (ROP)

Intracranial hemorrhage and periventricular leukomalacia

Patent ductus arteriosus with increasing left-to-right shunt

Necrotizing enterocolitis and/or GI perforation

White male infants

Infants born to mothers with diabetes

Infants born by means of cesarean delivery

Infants with a family history of respiratory distress syndrome

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:

Pulmonary infections (eg, group B beta-hemolytic streptococcal pneumonia)

Meconium aspiration pneumonia

Oxygen toxicity along with barotrauma or volutrauma to the lungs

Congenital diaphragmatic hernia and pulmonary hypoplasia

Expiratory grunting (from partial closure of glottis)

Subcostal and intercostal retractions

Extremely immature in neonates may develop apnea and/or hypothermia.

Pulmonary air leaks

Congenital anomalies of the lungs

Pediatric Gastroesophageal Reflux

Sudden Infant Death Syndrome

Transient Tachypnea of the Newborn

Metabolic problems - Eg, hypothermia, hypoglycemia

Hematologic problems - Eg, anemia, polycythemia, jaundice

Congenital anomalies of the heart

Fetal lung maturity tests

Intravenous (IV) line placement

Umbilical arterial catheterization

Umbilical artery cut down

Peripheral artery cannulation

Umbilical venous catheterization

Sedation, analgesia, or anesthesia whenever feasible

Arterial puncture, venous puncture, and capillary blood sampling

Tracheal intubation or tracheostomy

Placement of thoracotomy tubes

Placement of pericardial tubes

Placement of gastric tubes

Transfusion of blood, blood products, and exchange transfusion

Suprapubic bladder aspiration and bladder catheterization

Chest Radiography and Echocardiography

Pulmonary Mechanics Testing

Delivery and resuscitation

Number of Relative Risk Relative Difference

Pneumothorax 3 0.70 (0.59, 0.82) -5.2% (-7.5%, -2.9%)

Bronchopulmonary dysplasia (BPD) 3 0.97 (0.88, 1.06) -1.2% (-4.6%, 2.2%)