Respiratory Distress Syndrome 

Updated: Jan 06, 2020
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.)

Chest radiographs in a premature infant with respi 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, Presentation, 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 di 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 six phospholipids and four 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 sur 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 four surfactant apoproteins identified, surfactant protein B (SP-B) and SP-C are two 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 singl 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 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 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 cassette 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

United States data

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 data

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

  • 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, 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 two 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-dependent 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.

Pulmonary hemorrhage

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)

  • Pulmonary hemorrhage

  • 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

 

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 respi 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, 15] 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)

Outcome

Number of

Trials

Relative Risk

(95% CI)

Relative Difference

(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[16] :

  • 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.[17, 18, 19, 20, 21, 22, 23, 24]

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.[25]

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.[26]

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.[27] 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).[28] 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.[29]

Surfactant Replacement Therapy

The advent of surfactant therapy has reduced the mortality rate from respiratory distress syndrome by approximately 50%.[30, 31, 32, 33, 34]

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 six 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).[35, 36] 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 a multicenter, randomized controlled trial, Olivier et al evaluated the efficacy of minimally invasive surfactant therapy (MIST) in moderate and late preterm neonates who required CPAP in the first 24 hours of life. The study included 45 patients; 24 were assigned to the MIST group and 21 received standard management. Of the infants in the MIST group, 8 required mechanical ventilation and 1 developed a pneumothorax, compared with 19 patients in the control group who required mechanical ventilation and 1 who developed a pneumothorax. The investigators concluded that MIST therapy significantly reduces the need for mechanical ventilation in moderate and late preterm infants with respiratory distress syndrome.[37]

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.[38]

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.[39, 40, 41, 42, 43, 44, 45, 46]

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)[47] and STAR (SURFAXIN Therapy Against RDS)[46] 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[47] :

  • 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[46] :

  • 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[48, 47] 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 lung mince

Dipalmitoyl phosphatidylcholine (DPPC), tripalmitin, SP-B < 0.5%, SP-C 99% of TP wt/wt

4mL/kg (100mg/kg), 1-4 doses every 6h

Refrigerate

Surfactant-TA (Surfacten)

Bovactant (Alveofact)

Bovine lung lavage

99% PL, 1% SP-B and SP-C

45mg/mL

From the Federal Republic of Germany

Bovine lipid extract surfactant (bLES)

Bovine lung lavage

75% phosphatidylcholine (PC) and 1% SP-B and SP-C

135mg/kg/dose (5mL/kg), 1-4 doses every 12h

Canadian

Infasurf

Calf lung lavage

DPPC, tripalmitin, SP-B 290g/mL, SP-C 360g/mL

3mL/kg (105mg/kg), 1-4 doses every 6-12h

6mL vials, refrigerate

Calf lung surfactant extract (CLSE)

Similar to Infasurf

Poractant alpha (Curosurf)

Minced pig lung

Phospholipids (DPPC, phosphatidylglycerol [PG]), neutral lipids, fatty acids; SP-B and SP-C; 80mg/mL of PL/mL [54mg PC (30.5mg DPPC and 1mg protein includes 0.3mg of SP-B)]

Initially 2.5mL/kg (200mg/kg), followed by 1.25mL (100mg)/kg

1.5 and 3mL

Colfosceril palmitate (Exosurf)

Synthetic

85% DPPC, 9% hexadecanol, 6% tyloxapol

5mL/kg (67.5mg/kg),

1-4 doses every 12h

No longer available; lyophilized, dissolve in 8mL

Lucinactant (Surfaxin)

Synthetic

Protein: KL4 (sinapultide) resembles SP-B; Phospholipids: DPPC, palmitoyloleoyl phosphatidylcholine (POPG)

175 mg/kg/dose phospholipid

FDA-approved March 2012; warmed for 15min at 44°C on a heating block, followed by vigorous shaking until a uniform, free-flowing suspension forms

Artificial lung expanding compound (ALEC)

Synthetic

70% DPPC, 30% unsaturated phosphatidylglycerol

No data

Discontinued

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

Outcome

Number of Trials

Relative Risk (95% Confidence Interval [CI])

Relative Difference (95% CI)

Number of Trials

Relative Risk (95% CI)

Relative Difference (95% CI)

Pneumothorax

12

0.43 (0.35, 0.52)

-17% (-21%, -13%)

5

0.64 (0.55, 0.76)

-9% (-12%, -6%)

Bronchopulmonary dysplasia (BPD)

9

0.94 (0.72, 1.22)

-2% (-9%, 4%)

5

0.75 (0.61, 0.92)

-4% (-6%, -1%)

Mortality

12

0.68 (0.57, 0.80)

-9% (-13%, -5%)

6

0.73 (0.61, 0.88)

-5% (-7%, -2%)

BPD or death

10

0.76 (0.65, 0.90)

-14% (-21%, -7%)

4

0.73 (0.65, 0.83)

-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)

Relative Difference (95% CI)

Number of Trials

Relative Risk (95% CI)

Relative Difference (95% CI)

Pneumothorax

8

0.35 (0.26, 0.49)

-13% (-20%, -11%)

6

0.67 (0.50, 0.90)

-5% (-9%, -2%)

BPD

7

0.93 (0.80, 1.07)

-4% (-9%, -3%)

4

1.06 (0.83, 1.36)

1% (-4%, 6%)

Mortality

7

0.60 (0.44, 0.83)

-7% (-12%, -3%)

7

0.70 (0.58, 0.85)

-7% (-11%, -3%)

BPD or death

7

0.84 (0.75, 0.93)

-10% (-16%, -4%)

4

0.80 (0.77, 1.03)

-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

Number of

Trials

Relative Risk

(95% CI)

Relative Difference

(95% CI)

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

Number of

Trials

Relative Risk

(95% CI)

Relative Difference

(95% CI)

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

Number of

Trials

Relative Risk

(95% CI)

Relative Difference

(95% CI)

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.[49, 50, 51]

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.[52]

CPAP keeps the alveoli open at the end of expiration, decreasing the right-to-left pulmonary shunt. CPAP is often administered using nasal prongs.[53] 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.[54]

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.[55]

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.[34]

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.[56] 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.[57]

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.[58]

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.[59] 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.[60]

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.[61] 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.[62] 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.[63]

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, 64]

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 Enrolled

Mean

Gestational Age (wk)

Mean

Birth Weight (g)

Mean

Oxygen Index

Placebo

Death Rate

Therapy

Duration (d)

Maximum

Dose

% Change in Death/BPD

Kinsella et al[65]

80

27

1000

30

53%

7

5 ppm

-15%

Schreiber et al[66]

201

27.2

970

10

22.5%

7

10 ppm

-15%

Van Meurs et al[67]

420

26

839

22

44%

3

10 ppm

-2%

Ballard et al[68]

587

26

760

7

6%

24

20 ppm

-11%

Kinsella et al[69]

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 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 wit 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 n 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.

 

Guidelines

Respiratory Distress Syndrome Clinical Practice Guidelines (2019)

In 2019, an update to the European Consensus Guidelines on the Management of Respiratory Distress Syndrome, as developed by an expert panel backed by the European Society of Paediatric Research, was released.[70] These guidelines are summarized below.

Prenatal Care

For women at risk of preterm delivery, a single course of prenatal corticosteroids should be offered from the time the pregnancy is considered potentially viable up to 34 weeks' gestation (ideally, at least 24 hours prior to birth).

Prior to 32 weeks' gestation, in cases of threatened preterm birth, women may undergo a single repeat course of steroids, provided that administration of the first course occurred at least 1-2 weeks earlier.

In cases of imminent labor prior to 32 weeks' gestation, women should receive magnesium sulfate (MgSO4).

In very preterm pregnancies, short-term use of tocolytic agents should be considered to permit completion of a corticosteroid course and/or safe in utero transfer to a perinatal center.

Stabilization in the Delivery Room

Umbilical cord clamping should be delayed for at least 1 minute to promote placento-fetal transfusion.

Using a mask or nasal prongs, continuous positive airway pressure (CPAP) of at least 6 cm H2O should be used to stabilize spontaneously breathing babies. Because it provides no long-term benefit, sustained inflation should not be used. Infants who are persistently apneic or bradycardic should be treated with gentle positive-pressure lung inflations with 20-25 cm H2O peak inspiratory pressure.

Only infants who do not respond to positive-pressure ventilation delivered through a face mask or nasal prongs should undergo intubation. Surfactant should be administered to babies in whom stabilization must be achieved through intubation.

During stabilization in the delivery suite, hypothermia risk in babies delivered at less than 28 weeks' gestation should be reduced via the use of plastic bags or occlusive wrapping, under radiant warmers.

Surfactant Therapy

An animal-derived surfactant preparation should be administered to infants with respiratory distress syndrome (RDS).

The use of early rescue surfactant should be standard policy, but occasions exist, including when intubation is required for stabilization, in which surfactant should be administered in the delivery suite.

In rescue therapy, an initial 200 mg/kg dose of poractant alfa is preferable to a 100 mg/kg dose of the drug or a 100 mg/kg dose of beractant.

When ongoing evidence of RDS, such as persistent high oxygen requirement, exists (with other problems having been excluded), a second and, occasionally, third dose of surfactant should be administered.

Noninvasive Respiratory Support

In all infants at risk of RDS, such as those born at less than 30 weeks' gestation, who do not need to be stabilized via intubation, CPAP treatment should begin at birth.

Although it is of little importance which CPAP administration system is used, the interface should consist of short binasal prongs or a mask with a starting pressure of approximately 6-8 cm H2O.

Optimally, infants with RDS should be treated with CPAP with early rescue surfactant.

Mechanical Ventilation

After stabilization, infants in whom other respiratory support methods have failed should undergo mechanical ventilation (MV).

It is up to the clinical team to decide on the primary ventilation mode, but conventional MV, if employed, should involve the use of targeted tidal volume ventilation.

In infants who, after 1-2 weeks, are still on MV, consider facilitating extubation through a short tapering course of low- or very low–dose dexamethasone.

For infants in whom the risk of bronchopulmonary dysplasia is very high, inhaled budesonide can be considered.

It is not recommended that morphine or midazolam infusions routinely be used in ventilated preterm infants.

Persistent Ductus Arteriosus

Indomethacin, ibuprofen, or paracetamol can be employed in light of a decision to attempt therapeutic closure of a persistent ductus arteriosus.

Resources

For the complete guidelines, please go to The European Consensus Guidelines on the Management of Respiratory Distress Syndrome – 2019 Update.

For more information, please go to Respiratory Distress Syndrome and Respiratory Distress Syndrome Imaging.

For more Clinical Practice Guidelines, please go to Guidelines.

 

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.[39, 40]

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.