AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Respiratory distress syndrome (RDS), also known as hyaline membrane disease (HMD), occurs almost exclusively in premature infants. The incidence and severity of RDS are related inversely to the gestational age of the newborn infant. Enormous strides have been made in our understanding of the pathophysiology and management of these infants, leading to improvements in morbidity and mortality. Advances include (1) the use of antenatal steroids to enhance pulmonary maturity, (2) appropriate resuscitation facilitated by placental transfusion and immediate use of continuous positive airway pressure (CPAP) (Neopuff infant resuscitator; Fisher & Paykel Healthcare, Auckland, New Zealand) for alveolar recruitment, (3) early administration of surfactant; and (4) using gentle modes of ventilation to minimize damage to the immature lungs. These therapies have also resulted in the survival of extremely premature infants who continue to be ill.

Although reduced, the incidence and severity of complications of RDS can result in clinically significant morbidities. Sequelae of RDS include septicemia, bronchopulmonary dysplasia (BPD), patent ductus arteriosus (PDA), pulmonary hemorrhage, apnea/bradycardia, Necritizing enterocolitis (NEC), Retinopathy of prematurity (ROP), hypertension, failure to thrive, intraventricular hemorrhage (IVH), and/or periventricular leukomalacia (PVL) with associated neurodevelopmental and audiovisual handicaps. Direct attention to anticipating and minimizing these complications and to preventing premature delivery whenever possible are strategic goals.

Pathophysiology

Considerable advances have been made in our understanding of the pathophysiology of RDS, lung development, ontogeny of surfactant proteins (SPs), protein leakage, and role of cytokines in lung damage. The cause of RDS is relative deficiency of surfactant, which decreases lung compliance (see Image 1) and functional residual capacity with increased dead space. The resulting large ventilation-perfusion (V/Q) mismatch and right-to-left shunt may involve as much as 80% of the cardiac output.

On macroscopic evaluation, the lungs appear airless and ruddy (ie, liverlike). Therefore, the lungs of affected newborn infants require an increased critical opening pressure to inflate (see Image 1). Diffuse atelectasis of distal airspaces along with distension of distal airways and perilymphatic areas are observed microscopically. Progressive atelectasis, barotrauma or volutrauma, and oxygen toxicity, damages endothelial and epithelial cells lining these distal airways, resulting in exudation of fibrinous matrix derived from blood.

Hyaline membranes that line the alveoli (see Image 2) are formed within a half hour after birth. At 36-72 hours after birth, the epithelium begins to heal, and surfactant synthesis begins. The healing process is complex (see Image 3). A chronic process often ensues in infants who are extremely immature and critically ill and in infants born to mothers with chorioamnionitis, resulting in BPD. The recovery phase is characterized by regeneration of alveolar cells, including type II cells, with a resultant increase in surfactant activity.

Surfactant is a complex lipoprotein (see Image 4) comprising six phospholipids and four apoproteins. Dipalmitoyl phosphatidylcholine (DPPC), or lecithin, is functionally the principle phospholipid. Apoproteins SP-B and SP-C and other substances (eg, nonionic detergent tyloxapol, C16:0 alcohol hexadecanol in Exosurf) facilitate adsorption and spreading of DPPC as a monolayer, which lowers the surface tension at the alveolar air-fluid interface in vivo.

The components of pulmonary surfactant are synthesized in the Golgi apparatus of the endoplasmic reticulum of the type II alveolar cell (see Image 5). The components are packaged in multilamellar vesicles in the cytoplasm of the type II alveolar cell. They are secreted by a process of exocytosis, the daily rate of which may exceed the weight of the cell. Once secreted, the vesicles unwind to form bipolar monolayers of phospholipid molecules that are dependent on the apoproteins SP-B and SP-C to configure properly in the alveolus. The lipid molecules are enriched in dipalmitoyl acyl groups attached to a glycerol backbone that pack tightly and generate low surface tension.

Tubular myelin stores surfactant and depends on SP-B. Corners of the myelin lattice appear to be glued together with the large apoprotein SP-A, which may also have an important role in phagocytosis. RDS develops because of impaired surfactant synthesis and secretion leading to atelectasis, V/Q inequality, and hypoventilation with resultant hypoxemia and hypercarbia. Blood gases show respiratory and metabolic acidosis that causes pulmonary vasoconstriction resulting in impaired endothelial and epithelial integrity with leakage of proteinaceous exudate and formation of hyaline membranes (hence the name). Hypoxia, acidosis, hypothermia, and hypotension may impair surfactant production and/or secretion. In many neonates, oxygen toxicity with barotrauma and volutrauma in their structurally immature lungs causes an influx of inflammatory cell, which exacerbates the vascular injury, leading to BPD. Antioxidant deficiency and free-radical injury worsens the injury.

The hydrophobic SP-B and SP-C are essential for lung function and pulmonary homeostasis after birth. These proteins enhance the spreading, adsorption, and stability of surfactant lipids required to reduce surface tension in the alveolus. SP-B and SP-C participate in regulating intracellular and extracellular processes critical for maintaining respiratory structure and function. SP-B deficiency is an inherited deficiency caused by a pretranslational mechanism implied by the absence of messenger RNA (mRNA).

SP-B deficiency clinically manifests in term or near-term neonates with respiratory distress, pulmonary hypertension, or congenital alveolar proteinosis. Analysis of lung tissue with immunologic and biologic methods reveals an absence of 1 of the surfactant specific proteins, SP-B, and its mRNA. In a recent in vitro study, critical structure and function in the N-terminal region of pulmonary SP-B was noted. W9 is critical to optimal surface activity, whereas prolines may promote a conformation that facilitates rapid insertion of the peptide into phospholipid monolayers compressed to the highest pressures during compression-expansion cycling.

Mutations of SP-B and SP-C cause acute RDS and chronic lung disease that may be related to the intracellular accumulation of injurious proteins, extracellular deficiency of bioactive surfactant peptides, or both. Mutations in the gene for SP-C are a cause of both familial and sporadic interstitial lung disease. Mutations in other genes that cause protein misfolding and misrouting may contribute to the pathogenesis of chronic interstitial lung disease.

ABCA3 genetic mutations in newborns result in fatal surfactant deficiency. ABCA3 is critical for proper formation of lamellar bodies and surfactant function, and it may also be important for lung function in other pulmonary diseases. Because it is closely related to the ABCA1 and ABCA4-encoded proteins that transport phospholipids in macrophages and photoreceptor cells, it may have a role in surfactant phospholipid metabolism.

Hydrophilic SP-A and SP-D are lectins. In vivo and in vitro studies provide compelling support for SP-A and SP-D as mediators of various immune-cell functions. Recent studies have shown novel roles for these proteins in the clearance of apoptotic cells, direct killing of microorganisms, and initiation of parturition. None of the currently available surfactant preparations to treat RDS have SP-A and SP-D.

Frequency

United States

In the United States, RDS occurs in approximately 20,000-30,000 newborn infants each year and is a complication in about 1% pregnancies. Approximately 50% of the neonates born at 26-28 weeks of gestation develop RDS, whereas <30% of premature neonates born at 30 to 30-31 weeks develop RDS.

Fanaroff et al reported results of the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network study. Rates of RDS were 42% in infants weighing 501-1500 g, with 71% in those 501-750 g, 54% in those 751-1000 g, 36% in those 1001-1250 g, and 22% in those 1251-1500 g.

International

RDS has been reported in all races worldwide, occurring most often in premature infants of Caucasian ancestry. RDS is encountered less frequently in the developing countries than elsewhere, primarily because most premature infants who small for their gestation are stressed in utero because of malnutrition or pregnancy-induced hypertension. Because most deliveries occur at home, accurate records are unavailable to determine the frequency of RDS in developing countries.

Race

Infants of Caucasian origin are at increased risk for RDS.

CLINICAL

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History

• RDS frequently occurs in the following individuals:
• • Caucasian male infants
  • Infants born to mothers with diabetes
  • Infants born by means of cesarean delivery
  • Second-born twins
  • Infants with a family history of RDS
• In contrast, the incidence of RDS decreases with the following:
• • Use of antenatal steroids
  • Pregnancy-induced or chronic maternal hypertension
  • Prolonged rupture of membranes
  • Maternal narcotic addiction
• Secondary surfactant deficiency may occur in infants with the following:
• • Intrapartum asphyxia
  • Pulmonary infections (eg, group B beta-hemolytic streptococcal pneumonia)
  • Pulmonary hemorrhage
  • Meconium aspiration pneumonia
  • Oxygen toxicity along with barotrauma or volutrauma to the lungs
  • Congenital diaphragmatic hernia and pulmonary hypoplasia

Physical

• Physical findings are consistent with the infant's maturity assessed by using the Dubowitz examination or its modification by Ballard.
• Progressive signs of respiratory distress are noted soon after birth and include the following:
• • Tachypnea
  • Expiratory grunting (from partial closure of glottis)
  • Subcostal and intercostal retractions
  • Cyanosis
  • Nasal flaring
• Extremely immature ineonates may develop apnea and/or hypothermia.
• Several diagnoses may coexist and complicate the course of RDS, including the following:
• • Pneumonia is often secondary to group B beta-hemolytic streptococci and often coexists with RDS.
  • Metabolic problems (eg, hypothermia, hypoglycemia) may occur.
  • Hematologic problems (eg, anemia, polycythemia) may occur.
  • Transient tachypnea of the newborn usually occurs in term or near-term neonates, often after cesarean delivery. The chest radiograph of an infant with transient tachypnea shows good lung expansion and, often, fluid in the horizontal fissure.
  • Aspiration syndromes may result from aspiration of amniotic fluid, blood, or meconium. Aspiration syndrome is also observed in more mature infants and is differentiated by obtaining a history and by viewing the chest radiographs.
  • Pulmonary air leaks (eg, pneumothorax, interstitial emphysema, pneumomediastinum, pneumopericardium) may occur. In premature infants, these complications may be due to excessive positive-pressure ventilation. In rare cases, spontaneous pneumothorax may occur in large infants.
  • Congenital anomalies of the lungs (eg, diaphragmatic hernia, chylothorax, congenital cystic adenomatoid malformation of the lung, lobar emphysema, bronchogenic cyst, pulmonary sequestration) and heart (eg, cardiac anomalies) are rare in premature infants. These entities can be diagnosed on the basis of chest radiographic or echocardiographic findings. On rare occasions, they coexist with RDS.

Causes

The greatest risk factor for RDS is prematurity. Other risk factors are maternal diabetes, cesarean delivery, and asphyxia. Not all prematurely born newborn infants develop RDS. Surfactant deficiency and risk factors are outlined in History.

DIFFERENTIALS

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Other Problems to be Considered

Pneumonia
Metabolic problems
Hematologic problems
Transient tachypnea
Aspiration syndromes
Pulmonary air leaks
Congenital anomalies of the lungs

WORKUP

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Lab Studies

• Blood gases are usually obtained, as clinically indicated, from an indwelling peripheral or central (umbilical) arterial catheter or by means of arterial puncture. Recent studies have shown that in-line ex vivo monitoring can be used reliably 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, PDA, and/or foramen ovale.
• 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 partial pressure of oxygen (PaO₂) monitoring and transcutaneous monitoring was used.

Imaging Studies

• Chest radiographs of a newborn infant with RDS show bilateral, diffuse reticular granular or ground-glass appearances, air bronchograms, and poor lung expansion (see Image 6).
• • 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, PDA, an associated congenital heart anomaly, or simply poor lung expansion.
  • These findings may be altered with either early surfactant therapy (see Image 6) or a PDA or with mechanical ventilation.
  • The radiologic findings of RDS cannot be differentiated reliably 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.
• 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.

Other Tests

• Although pulmonary mechanics testing (PMT) has been used primarily 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 prematurely born newborn infants with RDS.
• Constant PMT monitoring 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 RDS.
• Infants with RDS have substantially decreased lung compliance with a range of 0.0005-0.0001 L/cm H₂O. Therefore, for the same pressure gradient, the delivered tidal volume is reduced in premaature nfants with RDS 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.

Procedures

• Sedation, analgesia, or anesthesia whenever feasible
• Arterial puncture, venous puncture, and capillary blood sampling
• Vascular access
• • Intravenous line placement
  • Umbilical arterial catheterization
  • Umbilical artery cut down
  • Peripheral artery cannulation
  • Umbilical venous catheterization
• 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

Histologic Findings

See Pathophysiology and Image 2.

TREATMENT

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Medical Care

• Prenatal prevention and prediction of RDS
• • Obstetricians with experience in fetal medicine should care for mothers whose infants are at an increased risk for RDS, preferably at a tertiary perinatal center. Strategies to prevent premature birth (eg, bed rest, tocolytics, appropriate antibiotics) and prudent use of antenatal steroids to help fetal lungs mature may decrease the incidence and severity of RDS. Repeat doses of prenatal corticosteroid, though controversial, may reduce the severity of RDS and the use of surfactant. Repeat doses may be associated with long-term neurologic sequelae, but studies are awaited to resolve its routine use. Borderline premature infants are increasingly being born by means of cesarean delivery, which is an independent risk factor for RDS. The risk was reduced but still elevated with labor before cesarean delivery.
  • Fetal lung maturity should be used to predict fetal lung maturity by estimating the lecithin-to-sphingomyelin ratio and/or the presence of phosphatidylglycerol in the amniotic fluid obtained with amniocentesis. Antenatal diagnosis of SP-B deficiency, a rare genetic disease, can also be diagnosed antenatally by analyzing the amniotic fluid; this diagnostic testing should be undertaken in previously affected siblings.
• Delivery and resuscitation: A neonatologist experienced in the resuscitation and care of premature infants should attend the deliveries of fetuses <28 weeks' gestation. These neonates are at a high risk for maladaptation, which further inhibits surfactant production.
• Surfactant replacement therapy
• • The mortality rate of RDS decreased by approximately 50% during the last decade with the advent of surfactant therapy.
  • Meta-analysis of comparisons of 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 RDS suggested a decrease in pulmonary air leaks and chronic lung disease. Early surfactant therapy in tiny neonates followed by rapid extubation to nasal 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 RDS followed by ventilation. Rates of pulmonary hemorrhage, NEC, retinopathy of prematurity (ROP), IVH, PVL, and BPD did not differ between the groups.
• • Neonates with RDS who require assisted ventilation with a fraction of inspiratory oxygen (FIO₂) of >0.40 should receive intratracheal surfactant as soon as possible, preferably within 2 hours after birth. Recent studies showed that surfactant administration to extremely premature neonates in the delivery room may improve immediate outcomes.
  • Because surfactant is protective of immature lungs, several investigators have recommended its prophylactic use after resuscitation in extremely premature neonates (<27 wk of gestation). Also, pulmonary inflammation leads to leakage of proteins inactivating the surfactant, damaging the surfactant phospholipids and fatty acids, affecting hydrolytic activity on SPs by proteolytic enzymes, and decreasing synthesis of surfactant by type II cells after oxidant injury.
  • In developing countries, surfactant is expensive and unnecessary in most instances because >60% of premature infants do not have surfactant deficiency; they would be intubated with its inherent risks.
  • Premature neonates with surfactant deficiency and RDS have an alveolar pool of about 5 mg/kg. Full-term animal models have pools of 50-100 mg/kg. Recommended dosages of clinically available surfactant preparations are 50-200 mg/kg, approximately the surfactant pool of term newborn lungs. Rapid bolus administration of surfactant after adequate lung recruitment with 3-4 cm 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- to 12-hour intervals were used in several clinical trials. If the patient improves rapidly after 1 dose, he or she most likely does not have RDS. In the converse, in those who have a poor or no response, exclude PDA, pneumonia, and complications of ventilation (air leak), especially before a third and subsequent doses are given.
  • Tables 1-6 summarize some complications from a meta-analysis of several clinical trials conducted worldwide. Clinical trials showed fewer complications and more rapid improvement in the infant's respiratory status protein-containing natural surfactants compared with synthetic surfactants. 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 7 shows the source, composition, and dosages of several surfactant preparations.
  • In 2 reviews, Notter (2002) and Kresch et al (1996) summarized data from extensive biophysical studies, in vitro and whole-animal biochemical studies, molecular and physiologic studies, and several large international clinical trials.
• Oxygenation and CPAP
• • In 1971, CPAP was introduced as the primary therapeutic modality when Gregory et al (1971) demonstrated a marked reduction in RDS mortality. Oxygen was the primary therapeutic mode before the introduction of CPAP.
  • Oxygen given by means of a hood still is used to treat infants with mild RDS.
  • CPAP keeps the alveoli open at the end of expiration, decreasing the right-to-left pulmonary shunt.
  • CPAP may be administered by using a variety of nasal prongs, face masks, head boxes, nasopharyngeal tubes (in large infants), or endotracheal (ET) tubes.
  • 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 recent retrospective study, bubble nasal CPAP was successful in 76% of infants <1250 g and in 50% of infants <750 g.
  • CPAP may be used after extubation in individuals with RDS to prevent atelectasis and/or prevent apnea in premature infants.
  • High-flow oxygen (>2 L/min) has recently been used instead of CPAP in infants with RDS. Further studies are warranted to evaluate its advantages and disadvantages in RDS.
  • The goal of therapy for patients with RDS is to maintain a pH of 7.25-7.4, a PaO₂ of 50-70 mm Hg, and a carbon dioxide pressure (PCO₂) of 40-65 mm Hg, depending on the infant's clinical status.
• Assisted ventilation: Kirby and deLemos introduced assisted ventilation several decades ago. Assisted ventilation further decreased RDS-related mortality; however, early ventilators were associated with complications, such as air leaks, BPD (secondary to barotrauma or volutrauma), airway damage, and intraventricular hemorrhage. 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 RDS. Several investigators suggested that permissive hypercapnia with arterial partial pressure of carbon dioxide (PaCO₂) of 45-55 mm Hg (with adequate lung volume) may facilitate weaning during recovery from RDS. To minimize the complications of conventional intermittent mandatory ventilation, new ventilation techniques have been introduced, as described below.

• • Synchronous intermittent mandatory ventilation is a technique in which some of the patient's respirations are synchronized with breaths the ventilator deliver. 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%, P < .05). Another study involved neonates born at 28-34 weeks gestational age with RDS who required surfactant with early extubation to synchronous, intermittent positive-pressure ventilation. The duration of intubation was shortened and the need for oxygen was decreased with this strategy compared with conventional 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 RDS.
  • Some physicians use pressure-support ventilation to wean infants who develop chronic lung changes. Further studies are required to evaluate its long-term benefits.
  • With high-frequency ventilation (HFV), small tidal volumes (less than anatomic dead space) are usually delivered at rapid frequencies. HFV was originally designed to treat patients with air leak. Many studies in animal models of RDS demonstrated that HFV promoted uniform lung inflation; improved lung mechanics and gas exchange; and reduced exudative alveolar edema, air leak, and lung inflammation. Early use of high-frequency oscillatory ventilation (HFOV) was clearly superior to conventional ventilation. Several clinical trials showed that prophylactic HFOV may reduce the incidence of chronic lung disease. 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- and long-term respiratory and neurologic outcomes. HFV techniques involve a learning curve, and optimal ventilator strategiesvarywiththestageofRDS.Ventilatorsarelisted below.
  • • High-frequency oscillatory ventilation (10-15 Hz): Because expiration occurs actively, monitor patients for hypocarbia to prevent periventricular leukomalacia. Controlled trials of HFOV to reduce BPD in infants with RDS have been controversial. Perhaps the unfavorable outcome of HFOV in some studies can be 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 and differences in chorioamnionitis; or (4) differences in resuscitation techniques at birth.
    • High-frequency jet ventilation: Its frequency range is 4-11 Hz (usually 7 Hz). This treatment has to be used in tandem with conventional ventilation to provide PEEP and sigh breaths. It decreases air leaks. Because the solenoid valves open intermittently to provide jet breaths, some neonatologists may prefer high-frequency jet ventilation to treat infants with air leaks.
    • High-frequency flow interrupter: Its frequency range is 6-15 Hz, 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 RDS.
  • Inhaled nitric oxide (iNO) was recently used to reduce right-to-left extra pulmonary shunting by decreasing pulmonary vascular resistance. In premature neonates born at <32 weeks' gestation with RDS and hypoxic respiratory failure, low pulmonary blood flow, as determined with Doppler echocardiography, seem to help in determining which patients are likely to benefit from iNO therapy on systemic oxygenation.
• Supportive therapy
• • Temperature regulation: Hypothermia increases oxygen consumption, further compromising neonates with RDS who are born prematurely. Therefore, prevent hypothermia in neonates with RDS 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.
  • Fluids, metabolic, and nutritional support
  • • In infants with RDS, first intravenously administer 5% or 10% dextrose 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 intravenous fluid. Intravenous sodium bicarbonate is often misused and is considered 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 200-300 mL/kg or more because of insensible water loss occurring from their large body surfaces.
    • After the neonate is stable, intravenous 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 intravenous nutritional support is decreased proportionately to maintain adequate fluid and calorie intake. Recent data suggest that 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 is <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 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. Exceptions to the use of antibiotics include the absence of clinical or laboratory findings suggestive of chorioamnionitis, adequate antenatal care, and a recent negative maternal cervical culture for group B beta-hemolytic streptococci or a baby delivered by a mother with intact amniotic membranes.
  • Support of parents and family
  • • Parents often undergo much emotional and/or financial stress with the birth of a critically ill premature baby with RDS 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, provide adequate support for parents and other family members to prevent or minimize these problems.
    • Staff members (preferably a physician and a nurse) should keep the parents well informed by frequently talking to them, especially during the acute stage of RDS. 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.
• Tables 1-6 summarize some of the complications from a meta-analysis of several clinical trials conducted worldwide. Table 7 summarizes features of available surfactant preparations.
  • Table 1. Results of a Meta-Analysis of Separate Clinical Trials of the Treatment of RDS With Natural or Synthetic Surfactant Preparations

    	Natural Surfactant Treatment		Synthetic Surfactant Treatment
    Outcome	No. of Trials	Relative Risk (95% CI) Relative Difference (95% CI)	No. 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%)
    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%)

    Note.—CI indicates confidence interval.
  • Table 2. Results of a Meta-Analysis of Separate Clinical Trials of the Prophylactic Use of Natural or Synthetic Surfactant Preparations

    	Natural Prophylaxis		Synthetic Prophylaxis
    Outcome	No. ofTrials	Relative Risk (95% CI) Relative Difference (95% CI)	No. 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 3. Results of a Meta-Analysis of Head-to-Head Trials With Natural Versus Synthetic Surfactants

    Outcome	No. 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 4. Meta-Analysis of Clinical Trials Comparing Prophylactic Use of Surfactant Versus Rescue Treatment of Infants With RDS

    Outcome	No. 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 5. Results of a Meta-Analysis of Early Versus Delayed Treatment of RDS

    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%)
    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%)

  • Table 6. Results of a Meta-Analysis of Clinical Trials to Compare Multiple Doses With a Single Dose of Surfactant

    Outcome	No. 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%)

  • Table 7. Type, Source, Composition, Dosages, and Other Information for Currently Available Surfactant Preparations

    Type	Source	Composition	Dosing	Comments
    Survanta	Bovine lung mince	DPPC, tripalmitin, SP-B <0.5%, SP-C 99% of TP wt/wt	4 mL/kg (100 mg/kg), 1-4 doses every 6 h	Refrigerate
    Surfactant TA
    Alveofact	Bovine lung lavage	99% PL, 1% SP-B and SP-C	45 mg/mL	From the Federal Republic of Germany
    Bovine lipid extract surfactant (bLES)	Bovine lung lavage	75% PC and 1% SP-B and SP-C	No data	Canadian
    Infasurf	Calf lung lavage	DPPC, tripalmitin, SP-B 290 g/mL, SP-C 360 g/mL	3 mL/kg (105 mg/kg), 1-4 doses every 6-12 h	6-mL vials, refrigerate
    Calf lung surfactant extract (CLSE)	Similar to Infasurf
    Curosurf	Minced pig lung	DPPC, SP-B and SP-C (unknown amount)	2.5 mL/kg (200 mg/kg),Þ1.25 mL (100 mg)/kg	1.5 and 3 mL
    Exosurf	Synthetic	85% DPPC, 9% hexadecanol, 6% tyloxapol	5 mL/kg (67.5 mg/kg), 1-4 doses every 12 h	Lyophilized, dissolve in 8 mL
    Surfaxan (KL4)	Synthetic	DPPC, synthetic peptide	No data	No data
    Artificial lung expanding compound (ALEC)	Synthetic	70% DPPC, 30% unsaturated phosphatidylglycerol	No data	Possibly discontinued

Consultations

Premature infants with RDS are prone to various complications. Appropriate specialists may be consulted as indicated.

Diet

See fluids, metabolism, and nutrition in the Medical Care section.

MEDICATION

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The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Drug Category: Lung surfactants

Exogenous surfactant can be helpful in treating airspace disease (eg, RDS). After inhaled administration of these agents, surface tension is reduced, and alveoli are stabilized to decrease the work of breathing and increasing lung compliance.

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, BPD, and mortality.

In recent years, 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, 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 repeat arginine-lysine (R-L) motif (RL4).

FOLLOW-UP

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Further Inpatient Care

• See the Treatment section.

Further Outpatient Care

• See the Treatment section.

In/Out Patient Meds

• See the Medication section.

Transfer

• Transfer the following patients to a tertiary care center:
• • Mothers with high-risk pregnancy
  • Mothers in premature labor
  • Newborn infants with respiratory failure

Deterrence/Prevention

• See Medical Care section.

Complications

• Acute complications
• • Alveolar rupture: Suspect an air leak (eg, pneumomediastinum, pneumopericardium, interstitial emphysema, pneumothorax [see Tables 1-6]) when an infant with RDS suddenly deteriorates with hypotension, apnea, or bradycardia or when metabolic acidosis is persistent.
  • Infection: Infections may complicate the management of RDS and may manifest in a variety of ways, including failure to improve, sudden deterioration, or a change in 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 increased incidence of septicemia secondary to staphylococcal epidermidis and/or candidal infection. When septicemia is suspected, obtain blood cultures from 2 sites and start appropriate antibiotics until culture results are obtained.
  • Intracranial hemorrhage and periventricular leukomalacia: Intraventricular hemorrhage is observed in 20-40% of premature infants with greater frequency in infants with RDS who require mechanical ventilation. Cranial ultrasonography is performed in the first week and thereafter as indicated in premature neonates younger than 32 weeks' gestation. Prophylactic indomethacin therapy and antenatal steroids have decreased the frequency of intracranial hemorrhage in these patients with RDS. Hypocarbia and chorioamnionitis are associated with an increase in periventricular leukomalacia.
  • PDA with increasing left-to-right shunt: This shunt may complicate the course of RDS, especially in infants weaned rapidly after surfactant therapy. Suspect 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. Treat PDA with indomethacin, which can be repeated during the first 2 weeks if the PDA reopens. In refractory incidents of RDS or in infants in whom indomethacin is contraindicated, surgically close the PDA.
  • Pulmonary hemorrhage: The occurrence of pulmonary hemorrhage increases in tiny premature infants, especially after surfactant therapy. Increase 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 necrotizing enterocolitis and/or GI perforation in any infant with abnormal abdominal findings on physical examination. A radiograph of the abdomen assists in confirming their presence. Spontaneous perforation (not necessarily as part of necrotizing enterocolitis) 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 (theophylline, caffeine) and CPAP or assisted ventilation in refractory incidents. Exclude septicemia, seizures, gastroesophageal reflux, and metabolic and other causes in infants with apnea of prematurity.
• Chronic complications
• • 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.
    • Clinical studies have demonstrated various incidences of BPD, which has been attributed to increased survival of small and ill infants with RDS after the introduction of the therapies discussed above (see Tables 1-6). 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.
  • ROP: Infants with RDS and a PaO₂ >100 mm Hg are at increased risk for ROP. Hence, closely monitor PaO₂ and maintain it at 50-70 mm 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.
  • 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. They may develop a specific learning disability and aberrant behavior. Therefore, periodically follow up these infants to detect those with neurologic impairment, and undertake appropriate interventions.
  • Familial psychopathology
  • • Infants with RDS 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 infants with RDS in a separate room before discharge, especially if the parents are at high social risk (eg, teenagers) who also have extremely premature infants.
    • 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 RDS 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.

Prognosis

• See Tables 1-6.

Patient Education

• Because the risk of prematurity and RDS is increased for subsequent pregnancies, counsel the parents.
• Promptly manage high-risk factors, such as diabetes, hypertension, incompetent cervix, and chorioamnionitis.
• Educating and counseling of the parents, caregivers, and families of premature infants must be undertaken as part of discharge planning. They should be advised of the potential problems infants with RDS may encounter during and after their nursery stay. Audiovisual aids and handouts supplement such education.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Trained and experienced professionals at a tertiary care facility should treat infants with RDS whenever possible, because complications of premature births, RDS, and the procedures performed on infants with RDS are associated with an increase in medicolegal action against health care professionals and institutions.
• To minimize such actions, adequately document the infant's clinical progress, including discussions with the families and/or caregivers.
• Obtain written informed consent before transport, elective procedures, or administration of blood products.

MULTIMEDIA

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Media file 1:  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.
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Media file 2:  Microscopic appearance of lungs of an infant with respiratory distress syndrome. Hematoxylin and eosin stain shows hyaline membranes (pink areas).
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Media file 3:  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.
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Media type:  Graph

Media file 4:  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.
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Media type:  Graph

Media file 5:  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, possibly in the form of small vesicles, apparently by a specific pathway that involves endosomes, and probably transported for storage into lamellar bodies for recycling. Alveolar macrophages also take up some surfactant in the liquid layer. A single transit of the phospholipid components of surfactant through the alveolar lumen normally requires a few hours. The phospholipid in the lumen is taken back into type II cell and is reused 10 times before being degraded. Surfactant proteins are synthesized in polyribosomes and extensively modified in the endoplasmic reticulum, Golgi apparatus, and multivesicular bodies. Surfactant proteins are detected in lamellar bodies or secretory vesicles closely associated with lamellar bodies before they are secreted into the alveolus.
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Media type:  Image

Media file 6:  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.
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Media type:  X-RAY

REFERENCES

Section 11 of 11

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