eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Neonatology

Respiratory Distress Syndrome: Treatment & Medication

Author: Arun K Pramanik, MD, MBBS, Professor of Pediatrics, Director of Neonatal Fellowship, Louisiana State University Health Sciences Center
Contributor Information and Disclosures

Updated: Sep 23, 2009

Treatment

Medical Care

  • Prenatal prevention and prediction of respiratory distress syndrome (RDS)
    • 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.
    • The following has been reported with the use of antenatal corticosteroids:
      • One course of antenatal corticosteroids reduces the risk of respiratory distress syndrome and neonatal death; however, in a recent 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.3 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. However, in contrast, several large clinical trials in which much higher fetal corticosteroid exposure occurred showed benefit with less severe lung disease and no increased risks. 
      • The increased incidence of cerebral palsy in the study from Wapner and associates could be avoided by limiting retreatment to less than 4 weekly treatments.4 The results of the studies from Crowther and colleagues and Wapner and associates are not consistent with the result of the other strategy (ie, a single treatment when delivery is imminent).5 Nevertheless, these weekly retreatment trials demonstrate considerable safety for retreatment. Other trials with different retreatment intervals are in progress.
      • 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.
    • Tests to predict fetal lung maturity are done by estimating the lecithin-to-sphingomyelin ratio and/or by 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.
  • 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, continuous nasal 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.6,7 By avoiding intubation, lung injury may be diminished.
  • Surfactant replacement therapy
    • The mortality rate of respiratory distress syndrome decreased by approximately 50% over the last decade with the advent of surfactant therapy.
    • 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 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 BPD did not differ between the groups.
    • Neonates with respiratory distress syndrome 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.
    • Stevens et al used meta-analysis of 6 studies to assess if early surfactant therapy with extubation to nasal CPAP is associated with a decrease in the need for mechanical ventilation, air leak, and BPD compared with later selective surfactant replacement and continued mechanical ventilation with extubation from low ventilator support.8 They concluded that treatment with surfactant by transient intubation using a low treatment threshold (FIO2 <0.45) is preferable to later, selective surfactant therapy by transient intubation using higher threshold for study entry (FIO2 >0.45) or at the time of respiratory failure and initiation of mechanical ventilation. Extremely premature neonates administered surfactant in the delivery room may have improvement in short-term outcomes and milder BPD.
    • Because surfactant is protective to the immature lungs, several investigators have recommended its prophylactic use after resuscitation in extremely premature neonates (<27 weeks' gestation). Also, 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 synthesis of surfactant by type II cells after oxidant injury.
    • In developing countries, surfactant is expensive and unnecessary in most instances because more than 60% of premature infants do not have surfactant deficiency; they are intubated with its inherent risks. Instead, nasal bubble CPAP has been widely used in recent years to manage respiratory distress syndrome and apnea of prematurity.
    • Premature neonates with surfactant deficiency and respiratory distress syndrome 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-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.
    • 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 using 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.
    • The ideal surfactant preparation to treat premature infants with respiratory distress syndrome and its sequelae has not been identified. 
    • Two large international trials studied the KL4 polypeptide, Surfaxin, which has not yet been approved by the US Food and Drug Administration (FDA).9,10 The studies had several limitations including the following:
      • 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, Surfaxin 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 regarding the range of outcome 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.
    • In 2 reviews, Notter and Kresch et al summarized data from extensive biophysical studies, in vitro and whole-animal biochemical studies, molecular and physiologic studies, and several large international clinical trials.11,12
  • Oxygenation and CPAP
    • CPAP was introduced as the primary therapeutic modality when Gregory et al demonstrated a marked reduction in respiratory distress syndrome mortality.13 Oxygen was the primary therapeutic mode before the introduction of CPAP.
    • Oxygen is administered a hood, nasal canula or in the isolette to treat infants with mild respiratory distress syndrome or after discontinuation of CPAP or assisted ventilation.
    • CPAP keeps the alveoli open at the end of expiration, decreasing the right-to-left pulmonary shunt.
    • CPAP is often administered using nasal prongs. In the Cochrane database review, devices and pressure sources for administration of nasal CPAP were assesed.7 Short binasal-prongs devices were found to be more effective than single prongs and also reduced the rate of reintubation.
    • 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.14
    • In a study of nasal CPAP in infants born at less than 27 weeks' gestation in a retrospective, observational study in one hospital, the probability of an individual baby remaining on nasal CPAP was 66% (95% confidence interval [CI], 46-86%) on day 1 and 80% (95% CI, 60-99%) on day 2.15
    • In a recent trial, 610 infants born at 25-28 weeks' gestation were randomly assigned to CPAP or intubation 5 minutes after birth, their outcomes were assessed at age 28 days, at age 36 weeks, and before discharge.16 These investigators found no reduction in death or BPD with early nasal CPAP; the CPAP group had an increase in the incidence of pneumothorax (9% vs 3%) but also fewer days on ventilator and fewer infants receiving oxygen at age 28 days.
    • Recently, Pillow and her colleagues have suggested that bubble CPAP promotes enhanced airway patency during treatment of acute postnatal respiratory disease in preterm lambs.17 Whether the findings of this animal model of respiratory distress syndrome, wherein the nares length and gas flow pattern is considerably different, can be mirrored to prematurely born infants is unclear. Air leak from nasal prongs may also alter the findings.
    • 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.18
    • CPAP may be used after extubation in individuals with respiratory distress syndrome to prevent atelectasis and prevent apnea in premature infants. A randomized control trial compared postextubation bubble CPAP with infant flow driver CPAP in preterm infants with respiratory distress syndrome;6 although both were equally effective, bubble CPAP is associated with a significantly higher rate of successful extubation and reduced duration of CPAP in infants younger than 14 days.
    • The goal of therapy for patients with respiratory distress syndrome 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.
  • 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.19 Neonatal units in the United States and 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. 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 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.20 Assisted ventilation further decreased respiratory distress syndrome–related morbidity and 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 respiratory distress syndrome. 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 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 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 respiratory distress syndrome 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 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 (HFV)
    • With high-frequency ventilation (HFV), small tidal volumes (less than anatomic dead space) are usually delivered at rapid frequencies, thus eliminating wide pressure swings seen with conventional ventilators. These modes of ventilation received attention because the high tidal volumes, wide pressure swings, and the resultant pulmonary trauma and cardiovascular compromise are believed to be major contributing factors associated with mechanical ventilation.
    • 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.
    • 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-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.
    • The HFV techniques are as follows:
      • High-frequency oscillatory ventilation (10-15 Hz): Because expiration actively occurs, monitor patients for hypocarbia to prevent periventricular leukomalacia (PVL). Controlled trials of HFOV to reduce BPD in infants with respiratory distress syndrome have been controversial because of the varied types of ventilators used, time of recruitment, differences in surfactant treatment, management of 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 and differences in chorioamnionitis; and (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 prefer to use high-frequency jet ventilation to treat infants with pulmonary 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.
  • Nitric oxide (NO)
    • Although inhaled NO (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.
    • It has selective pulmonary vasodilation and, in premature infants, 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 the extent of the infant's lung disease. Results of several clinical trials are summarized in the tables below.
    • Some evidence suggests that low-dose iNO may be safe and effective in reducing the risk of death and BPD for a subset of premature infants with birth weight less than 1000 g. Also, a neuroprotective effect of iNO has been demonstrated in large randomized clinical trials, although its exact relationship and mechanism of action is unclear.
    • Hintz et al reported no improvement in the neurodevelopmental outcome at a mean corrected age of 20 months in premature infants with birth weight less than 1500g and severe respiratory failure enrolled in a randomized, controlled trial of iNO.1 They 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.
    • In 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.
  • 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.
    • Fluids, 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 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 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 CBC count 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 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, 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 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.
  • Summary
    • 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 Respiratory Distress Syndrome With Natural or Synthetic Surfactant Preparations

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        Table
        Natural Surfactant TreatmentSynthetic Surfactant Treatment
        OutcomeNumber of TrialsRelative Risk (95% CI)
        Relative Difference (95% CI)        		Number of TrialsRelative Risk (95% CI)
        Relative Difference (95% CI)
        Pneumothorax120.43 (0.35, 0.52)
        -17% (-21%, -13%)        		50.64 (0.55, 0.76)
        -9% (-12%, -6%)
        BPD90.94 (0.72, 1.22)
        -2% (-9%, 4%)        		50.75 (0.61, 0.92)
        -4% (-6%, -1%)
        Mortality120.68 (0.57, 0.80)
        -9% (-13%, -5%)        		60.73 (0.61, 0.88)
        -5% (-7%, -2%)
        BPD or death100.76 (0.65, 0.90)
        -14% (-21%, -7%)        		40.73 (0.65, 0.83)
        -8% (-11%, -5%)
        Natural Surfactant TreatmentSynthetic Surfactant Treatment
        OutcomeNumber of TrialsRelative Risk (95% CI)
        Relative Difference (95% CI)        		Number of TrialsRelative Risk (95% CI)
        Relative Difference (95% CI)
        Pneumothorax120.43 (0.35, 0.52)
        -17% (-21%, -13%)        		50.64 (0.55, 0.76)
        -9% (-12%, -6%)
        BPD90.94 (0.72, 1.22)
        -2% (-9%, 4%)        		50.75 (0.61, 0.92)
        -4% (-6%, -1%)
        Mortality120.68 (0.57, 0.80)
        -9% (-13%, -5%)        		60.73 (0.61, 0.88)
        -5% (-7%, -2%)
        BPD or death100.76 (0.65, 0.90)
        -14% (-21%, -7%)        		40.73 (0.65, 0.83)
        -8% (-11%, -5%)
      • Table 2. Results of a Meta-Analysis of Separate Clinical Trials of the Prophylactic Use of Natural or Synthetic Surfactant Preparations

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        Table
        Natural ProphylaxisSynthetic Prophylaxis
        OutcomeNumber of TrialsRelative Risk (95% CI)
        Relative Difference (95% CI)        		Number of TrialsRelative Risk (95% CI)
        Relative Difference (95% CI)
        Pneumothorax80.35 (0.26, 0.49)
        -13% (-20% -11%)        		60.67 (0.50, 0.90)
        -5% (-9%, -2%)
        BPD70.93 (0.80, 1.07)
        -4% (-9%, -3%)        		41.06 (0.83, 1.36)
        1% (-4%, 6%)
        Mortality70.60 (0.44, 0.83)
        -7% (-12%, -3%)        		70.70 (0.58, 0.85)
        -7% (-11%, -3%)
        BPD or death70.84 (0.75, 0.93)
        -10% (-16%, -4%)        		40.80 (0.77, 1.03)
        -4% (-10%, 1%)
        Natural ProphylaxisSynthetic Prophylaxis
        OutcomeNumber of TrialsRelative Risk (95% CI)
        Relative Difference (95% CI)        		Number of TrialsRelative Risk (95% CI)
        Relative Difference (95% CI)
        Pneumothorax80.35 (0.26, 0.49)
        -13% (-20% -11%)        		60.67 (0.50, 0.90)
        -5% (-9%, -2%)
        BPD70.93 (0.80, 1.07)
        -4% (-9%, -3%)        		41.06 (0.83, 1.36)
        1% (-4%, 6%)
        Mortality70.60 (0.44, 0.83)
        -7% (-12%, -3%)        		70.70 (0.58, 0.85)
        -7% (-11%, -3%)
        BPD or death70.84 (0.75, 0.93)
        -10% (-16%, -4%)        		40.80 (0.77, 1.03)
        -4% (-10%, 1%)
      • Table 3. Results of a Meta-Analysis of Head-to-Head Trials With Natural Versus Synthetic Surfactants

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        Table
        OutcomeNumber of
        Trials        		Relative Risk
        (95% CI)        		Relative Difference
        (95% CI)
        Pneumothorax50.68 (0.56, 0.83)-4.1% (-6.3%, -2.0%)
        BPD40.97 (0.88, 1.07)-1.2% (-5.4%, -2.9%)
        Mortality70.88 (0.76, 1.02)-2.2% (-4.7%, 0.4%)
        BPD or death20.94 (0.87, 1.01)-3.6% (-8.0%, 0.8%)
        OutcomeNumber of
        Trials        		Relative Risk
        (95% CI)        		Relative Difference
        (95% CI)
        Pneumothorax50.68 (0.56, 0.83)-4.1% (-6.3%, -2.0%)
        BPD40.97 (0.88, 1.07)-1.2% (-5.4%, -2.9%)
        Mortality70.88 (0.76, 1.02)-2.2% (-4.7%, 0.4%)
        BPD or death20.94 (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 Respiratory Distress Syndrome

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        Table
        OutcomeNumber of
        Trials        		Relative Risk
        (95% CI)        		Relative Difference
        (95% CI)
        Pneumothorax60.62 (0.42, 0.89)-2.1% (-3.7%, -0.55)
        BPD70.95 (0.81, 1.11)-0.9% (-3.5%, 1.7%)
        Mortality60.59 (0.46, 0.76)-4.6% (-6.8%, -2.5%)
        BPD or death70.85 (0.76, 0.95)-4.5% (-7.4%, -1.5%)
        Infants <30 wk of gestation
        Mortality60.60 (0.47, 0.77)-6.5% (-9.6%, -3.4%)
        BPD or death70.86 (0.77, 0.96)-5.5% (-9.6%, -1.5%)
        OutcomeNumber of
        Trials        		Relative Risk
        (95% CI)        		Relative Difference
        (95% CI)
        Pneumothorax60.62 (0.42, 0.89)-2.1% (-3.7%, -0.55)
        BPD70.95 (0.81, 1.11)-0.9% (-3.5%, 1.7%)
        Mortality60.59 (0.46, 0.76)-4.6% (-6.8%, -2.5%)
        BPD or death70.85 (0.76, 0.95)-4.5% (-7.4%, -1.5%)
        Infants <30 wk of gestation
        Mortality60.60 (0.47, 0.77)-6.5% (-9.6%, -3.4%)
        BPD or death70.86 (0.77, 0.96)-5.5% (-9.6%, -1.5%)
      • Table 5. Results of a Meta-Analysis of Early Versus Delayed Treatment of Respiratory Distress

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        Table
        OutcomeNumber of
        trials        		Relative Risk
        (95% CI)        		Relative Difference
        (95% CI)
        Pneumothorax30.70 (0.59, 0.82)-5.2% (-7.5%, -2.9%)
        BPD30.97 (0.88, 1.06)-1.2% (-4.6%, 2.2%)
        Mortality40.87 (0.77, 0.99)-2.8% (-5.5%, 0.0%)
        BPD or death30.94 (0.88, 1.00)-3.7% (-7.2%, 0.0%)
        OutcomeNumber of
        trials        		Relative Risk
        (95% CI)        		Relative Difference
        (95% CI)
        Pneumothorax30.70 (0.59, 0.82)-5.2% (-7.5%, -2.9%)
        BPD30.97 (0.88, 1.06)-1.2% (-4.6%, 2.2%)
        Mortality40.87 (0.77, 0.99)-2.8% (-5.5%, 0.0%)
        BPD or death30.94 (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

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        Table
        OutcomeNumber of
        Trials        		Relative Risk
        (95% CI)        		Relative Difference
        (95% CI)
        Pneumothorax20.51 (0.30, 0.88)-8.7% (-15.4%, -2.0%)
        BPD11.10 (0.63, 1.93)1.2% (-5.8%, 8.3%)
        Mortality20.63 (0.57, 1.11)-7.0% (-14%, 0%)
        BPD or death10.80 (0.57, 1.11)-6.6%, (-16.2%. 3%)
        OutcomeNumber of
        Trials        		Relative Risk
        (95% CI)        		Relative Difference
        (95% CI)
        Pneumothorax20.51 (0.30, 0.88)-8.7% (-15.4%, -2.0%)
        BPD11.10 (0.63, 1.93)1.2% (-5.8%, 8.3%)
        Mortality20.63 (0.57, 1.11)-7.0% (-14%, 0%)
        BPD or death10.80 (0.57, 1.11)-6.6%, (-16.2%. 3%)
      • Table 7. Type, Source, Composition, Dosages, and Other Information for Currently Available Surfactant Preparations

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        Table
        TypeSourceCompositionDosingComments
        Beractant (Survanta)Bovine lung minceDipalmitoyl phosphatidylcholine (DPPC), tripalmitin, SP-B <0.5%, SP-C 99% of TP wt/wt4 mL/kg (100 mg/kg), 1-4 doses every 6 hRefrigerate
        Surfactant-TA (Surfacten)
        Bovactant (Alveofact)Bovine lung lavage99% PL, 1% SP-B and SP-C45 mg/mLFrom the Federal Republic of Germany
        Bovine lipid extract surfactant (bLES)Bovine lung lavage75% PC and 1% SP-B and SP-C135 mg/kg/dose (5 mL/kg), 1-4 doses every 12 hCanadian
        InfasurfCalf lung lavageDPPC, tripalmitin, SP-B 290 g/mL, SP-C 360 g/mL3 mL/kg (105 mg/kg), 1-4 doses every 6-12 h6-mL vials, refrigerate
        Calf lung surfactant extract (CLSE)Similar to Infasurf
        Poractant alpha (Curosurf)Minced pig lungPhospholipids (DPPC, PG), neutral lipids, fatty acids; SP-B and SP-C; 80 mg/mL of PL/mL [54 mg PC (30.5 mg DPPC and 1 mg protein includes 0.3 mg of SP-B)]Initially 2.5 mL/kg (200 mg/kg), followed by 1.25 mL (100 mg)/kg1.5 and 3 mL
        Colfosceril Palmitate (Exosurf)Synthetic85% DPPC, 9% hexadecanol, 6% tyloxapol5 mL/kg (67.5 mg/kg),
        1-4 doses every 12 h        		No longer available; lyophilized, dissolve in 8 mL
        Lucinactant (Surfaxin)SyntheticProtein: KL4 (sinapultide) resembles SP-B; Phospholipids: DPPC, POPG175 mg/kg/dose phospholipidNot licensed by FDA; warmed for 15 min at 44 º C on a heating block followed by vigorous shaking until a uniform free-flowing suspension forms
        Artificial lung expanding compound (ALEC)Synthetic70% DPPC, 30% unsaturated phosphatidylglycerolNo dataDiscontinued
        TypeSourceCompositionDosingComments
        Beractant (Survanta)Bovine lung minceDipalmitoyl phosphatidylcholine (DPPC), tripalmitin, SP-B <0.5%, SP-C 99% of TP wt/wt4 mL/kg (100 mg/kg), 1-4 doses every 6 hRefrigerate
        Surfactant-TA (Surfacten)
        Bovactant (Alveofact)Bovine lung lavage99% PL, 1% SP-B and SP-C45 mg/mLFrom the Federal Republic of Germany
        Bovine lipid extract surfactant (bLES)Bovine lung lavage75% PC and 1% SP-B and SP-C135 mg/kg/dose (5 mL/kg), 1-4 doses every 12 hCanadian
        InfasurfCalf lung lavageDPPC, tripalmitin, SP-B 290 g/mL, SP-C 360 g/mL3 mL/kg (105 mg/kg), 1-4 doses every 6-12 h6-mL vials, refrigerate
        Calf lung surfactant extract (CLSE)Similar to Infasurf
        Poractant alpha (Curosurf)Minced pig lungPhospholipids (DPPC, PG), neutral lipids, fatty acids; SP-B and SP-C; 80 mg/mL of PL/mL [54 mg PC (30.5 mg DPPC and 1 mg protein includes 0.3 mg of SP-B)]Initially 2.5 mL/kg (200 mg/kg), followed by 1.25 mL (100 mg)/kg1.5 and 3 mL
        Colfosceril Palmitate (Exosurf)Synthetic85% DPPC, 9% hexadecanol, 6% tyloxapol5 mL/kg (67.5 mg/kg),
        1-4 doses every 12 h        		No longer available; lyophilized, dissolve in 8 mL
        Lucinactant (Surfaxin)SyntheticProtein: KL4 (sinapultide) resembles SP-B; Phospholipids: DPPC, POPG175 mg/kg/dose phospholipidNot licensed by FDA; warmed for 15 min at 44 º C on a heating block followed by vigorous shaking until a uniform free-flowing suspension forms
        Artificial lung expanding compound (ALEC)Synthetic70% DPPC, 30% unsaturated phosphatidylglycerolNo dataDiscontinued
      • Table 8. Inhaled Nitric Oxide Therapy in Preterm Infants and Outcome Measures

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        Table
        StudyNumber EnrolledMean
        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 21 802710003053%75 ppm-15%
        Schreiber et al 22 20127.29701022.5%710 ppm-15%
        Van Meurs et al 23 420268392244%310 ppm-2%
        Ballard et al 24 5872676076%2420 ppm-11%
        Kinsella et al 25 79325792525%145 ppm-4%
        StudyNumber EnrolledMean
        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 21 802710003053%75 ppm-15%
        Schreiber et al 22 20127.29701022.5%710 ppm-15%
        Van Meurs et al 23 420268392244%310 ppm-2%
        Ballard et al 24 5872676076%2420 ppm-11%
        Kinsella et al 25 79325792525%145 ppm-4%

Consultations

  • Premature infants with respiratory distress syndrome are prone to various complications. Appropriate specialists may be consulted as indicated.

Diet

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

Medication

The goals of pharmacotherapy in respiratory distress syndrome (RDS) are to reduce morbidity and prevent complications.

Lung surfactants

Exogenous surfactant can be helpful in treating airspace disease (eg, respiratory distress syndrome [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, bronchopulmonary dysplasia (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).


Beractant (Survanta, Alveofact)

Natural/modified bovine lung extract that lowers surface tension on alveolar surfaces during respiration and stabilizes alveoli against collapse at resting transpulmonary pressures. For ET use only. Survanta contains 10% SP-B.

Adult

Pediatric

ET: 4 mL/kg (100 mg/kg) divided in 4 aliquots administered at least 6 h apart for 1-4 doses within the first 48 h.
Swirl vial gently if settling occurs. Do not shake. Warm in room temperature for 20 min or by holding the vial in the hand for 8 min. Do not use artificial warming methods. For prevention, begin warming prior to birth. Do not let sit outside the refrigerator for longer than 24 h. Only warm to room temperature once, otherwise discard.
The tip of the catheter should be positioned just beyond the end of the ET tube above the carina. Do not instill into the mainstem bronchus. Administration works best with 2 people, one positions the infant while the other administers the dose.

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Must be warmed to room temperature; administer only under carefully supervised conditions because of risk of acute airway obstruction
Marked improvement in oxygenation may occur after administration; hence, decrease oxygen and ventilator pressures (expired tidal volume) as blood gases suggest; monitor systemic oxygenation to avoid hyperoxia or hypoxia; surfactant may reflux into ET tube (hence, administer rapidly followed by positive-pressure ventilation); monitor heart rate and blood pressure; because ET tube becomes occluded in rare cases, suction infant's ET tube (preferably by using closed suction system) before administering surfactant; pulmonary hemorrhage may occur in extremely premature infants (exclude PDA); apnea and nosocomial sepsis may occur


Lucinactant (Surfaxin)

US Food and Drug Administration (FDA) approval pending. ATI-02;KL4-surfactant. Mixture of sinapultide (peptide that mimics action of human SP-B), colfosceril palmitate, sodium palmitoyloleaylphosphatidyl glycerol, and palmitic acid. Contains 30 mg phospholipids per milliliter. Lowers surface tension on alveolar surfaces during respiration and stabilizes alveoli against collapse at resting transpulmonary pressures.
In phase III clinical trial versus colfosceril palmitate and beractant, RDS-related mortality significantly decreased through day 14 (Mayo, 2005).

Adult

Pediatric

100-200 mg/kg based on phospholipid content ET; may repeat q6h if infant requires FIO2 >0.40 and if PDA with significant left-to-right shunt is excluded

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Must be warmed to room temperature; administer only under carefully supervised conditions because of risk of acute airway obstruction
Marked improvement in oxygenation may occur after administration, hence, decrease oxygen and ventilator pressures (expired tidal volume) as blood gases suggest; monitor systemic oxygenation to avoid hyperoxia or hypoxia; surfactant may reflux into ET tube (hence, administer rapidly followed by positive-pressure ventilation); monitor heart rate and blood pressure; because ET tube becomes occluded in rare cases, suction infant's ET tube (preferably by using closed suction system) before administering surfactant; pulmonary hemorrhage may occur in extremely premature infants (exclude PDA); apnea and nosocomial sepsis may occur


Calfactant (Infasurf)

Natural calf lung extract containing phospholipids, fatty acids, and surfactant-associated proteins B (260 mcg/mL) and C (390 mcg/mL). For ET use only.

Adult

Pediatric

ET: 3 mL/kg (105 mg/kg) q6-12h for 1-4 doses

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Administer only under carefully supervised conditions because of risk of acute airway obstruction
Marked improvement in oxygenation may occur in minutes, hence, wean infant's inspired oxygen and/or ventilator pressure (expired tidal volume) as blood gases indicate; monitor systemic oxygenation with pulse oximetry to avoid hypoxia and/or hyperoxia; surfactant may reflux into ET tube (hence, administer rapidly followed by positive-pressure ventilation); cyanosis, bradycardia, or changes in blood pressure have occurred during dosing procedures; because ET tube becomes occluded in rare cases, suction infant's tube (preferably by using closed system) before administering surfactant


Poractant (Curosurf)

Lowers surface tension on alveolar surfaces during respiration and stabilizes alveoli against collapse at resting transpulmonary pressures. Indicated to treat RDS in premature infants. For ET use only. Curosurf has SP-B content of 30%.

Adult

Pediatric

ET: 2.5 mL/kg (200 mg/kg); then 1.25 mL/kg (100 mg/kg) at 12-h intervals prn in 2 subsequent doses

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Correction of acidosis, hypotension, anemia, hypoglycemia, and hypothermia recommended before administration; marked improvement in oxygenation may occur in minutes; monitor systemic oxygenation to avoid hyperoxia


Colfosceril (Exosurf Neonatal)

Lowers surface tension on alveolar surfaces during respiration and stabilizes alveoli against collapse at resting transpulmonary pressures. For ET use only.

Adult

Pediatric

ET: 5 mL/kg (67.5 mg/kg) q12h for 1-4 doses

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Rapidly affects oxygenation and lung compliance; only for instillation into trachea; surfactant may reflux into ET tube, hence, administer rapidly followed by ventilation; because ET becomes blocked in rare cases, suction ET tube (preferably by using closed suction system) before administering surfactant; pulmonary hemorrhage may occur in infants <700 g; nosocomial sepsis and apnea may occur

More on Respiratory Distress Syndrome

Overview: Respiratory Distress Syndrome
Differential Diagnoses & Workup: Respiratory Distress Syndrome
Treatment & Medication: Respiratory Distress Syndrome
Follow-up: Respiratory Distress Syndrome
Multimedia: Respiratory Distress Syndrome
References
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Further Reading

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Keywords

respiratory distress syndrome, RDS, HMD, hyaline membrane disease, premature infant, surfactant therapy, mechanical ventilation, continuous positive airway pressure, CPAP, inhaled nitric oxide, patent ductus arteriosus, prematurity, septicemia, bronchopulmonary dysplasia, BPD, necrotizing enterocolitis, NEC, retinopathy of prematurity, ROP, hypertension, failure to thrive, intraventricular hemorrhage, periventricular leukomalacia, group B streptococcus, , influenza virus, adenovirus, respiratory syncytial virus, RSV, metabolic acidosis, chronic lung disease, congenital diaphragmatic hernia, pulmonary hypoplasia, meconium aspiration pneumonia, hypothermia, hypoglycemia, anemia, polycythemia, jaundice, transient tachypnea of newborn, aspiration syndrome, pneumothorax, interstitial emphysema, pneumomediastinum, pneumopericardium, chylothorax, treatment, diagnosis

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Contributor Information and Disclosures

Author

Arun K Pramanik, MD, MBBS, Professor of Pediatrics, Director of Neonatal Fellowship, Louisiana State University Health Sciences Center
Arun K Pramanik, MD, MBBS is a member of the following medical societies: American Academy of Pediatrics, American Thoracic Society, National Perinatal Association, and Southern Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

Steven M Donn, MD, Professor of Pediatrics, University of Michigan Medical School; Director, Division of Neonatal-Perinatal Medicine, Department of Pediatrics, CS Mott Children's Hospital, University of Michigan Health System
Steven M Donn, MD is a member of the following medical societies: American Pediatric Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

David A Clark, MD, Chairman, Professor, Department of Pediatrics, Albany Medical College
David A Clark, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Pediatric Society, Christian Medical & Dental Society, Medical Society of the State of New York, New York Academy of Sciences, and Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Carol L Wagner, MD, Professor of Pediatrics, Medical University of South Carolina
Carol L Wagner, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American Medical Women's Association, American Public Health Association, American Society for Bone and Mineral Research, American Society for Clinical Nutrition, Massachusetts Medical Society, National Perinatal Association, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Ted Rosenkrantz, MD, Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine
Ted Rosenkrantz, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Pediatric Society, Connecticut State Medical Society, Eastern Society for Pediatric Research, and Society for Pediatric Research
Disclosure: Nothing to disclose.

 
 
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