It is estimated that 30000 to 40000 infants in the United States are treated for respiratory distress syndrome (RDS) every year. Not all of these infants are sick enough to warrant treatment in level III neonatal intensive care units, and as a result, many are cared for in level II nurseries by practicing pediatricians. This article addresses questions raised by practicing pediatricians who care for such infants and also reviews current and prospective management approaches.
At 1:30 AM, you are aroused from a sound sleep by your on-call beeper. The answering service informs you that Dr Richmond, the local obstetrician and your weekend golfing partner, wishes to speak with you. He would like you to attend the imminent delivery of your daughter's kindergarten teacher, who is currently 31 to 32 weeks gestation.
On your arrival, the baby boy has just been delivered and is vigorous. Apgar scores are 6 at 1 minute and 7 at 5 minutes. The birthweight is 1850 g. The baby is taken to the special care nursery where he develops moderate respiratory distress over the next several hours. In the intervening time, you discover the mother had ruptured her membranes 1 0 hours prior to delivery.
An IV is started, a complete blood cell count and blood culture are obtained, and ampictllin and gentamicin are administered. At 4 hours of age, the infant is in 50% oxygen in a head hood, and his initial capillary blood gas is pH 7.28, P0O2 54, P02 46, and base deficit 4.2. His respiratory rate at that time is in the 70s with grunting and moderate retractions noted on physical examination. A chest radiograph is consistent with respiratory distress syndrome, demonstrating low lung volumes, diffuse granularity, and air broncnograms.
Because of an increase in the oxygen requirement to F1O2 70% in the head hood, a trial of nasopharyngeal continuous positive airway pressure is undertaken. A follow-up capillary blood gas shows a pH of 7.26, PCO7 of 58, and a P02 of 48 with a base deficit of 3.Í Arrangements are made to transfer the infant to a level III neonatal intensive care unit that is 90 minutes away by ground transport. You then attempt to reassure the anxious parents about the impending transfer to the children's hospital neonatal intensive care unit for intubation, mechanical ventilation, and surfactant.
Figure 1. Pathophysiology of respiratory distress syndrome.
The above scenario is repeated nightly throughout the United States with private pediatricians caring for such infants on a regular basis. Fifty percent of infants born between 26 and 28 weeks gestation and 20% to 30% of those born at 30 to 31 weeks gestation are affected.1 Although the incidence of RDS has decreased at each gestational age with improvements in perinatal management, RDS still accounts for significant morbidity and is the leading cause of death in premature infants.
What is respiratory distress syndrome?
Respiratory distress syndrome is a developmental disorder associated with prematurity that results in a relative deficiency of pulmonary surfactant in the airways. It is usually more severe in males at a given gestational age, and the incidence and severity also is increased in infants of diabetic mothers, infants suffering perinatal asphyxia, and those born after maternal hemorrhage. The surfactant-deficient lung is poorly compliant, referring to the high pressure needed to fully inflate the lung and the ease with which the lung collapses. This disease process is complicated further because the premature infant has a compliant chest wall with relatively weak respiratory muscles. These factors together result in progressive atelectasis and subsequent loss of functional residual capacity, alterations in ventilation and perfusion because of the right to left shunt through a collapsed lung, and ultimately hypoxemia and hypercarbia (Figure 1 ).
In 1959, Avery and Meade2 reported that infants weighing <1200 g and those dying of RDS lacked a "surface active" substance in their lungs. The identification of surfactant deficiency as the primary abnormality in RDS sparked a vast amount of research over the ensuing 25 years directed at developing preparations and techniques for providing exogenous surfactant to affected premature infants.
Initial attempts to provide affected infants with an aerosolized preparation were unsuccessful. However, in 1 980, Fujiwara and his colleagues3 reported the first successful treatment of infants with RDS via intratracheal administration of an extract of bovine lung. Numerous multicenter trials followed this initial observation and established that exogenous administration of surfactant decreases mortality and the resultant complications of RDS. No other drug in neonatal medicine has been studied so thoroughly prior to approval by governing agencies.
What is surfactant?
The composition of surfactant isolated from the alveoli of healthy mammals is quite consistent across species.4 Surfactant is synthesized and secreted by type II alveolar epithelial cells of the lung and contains 70% phospholipids, 8% neutral lipids, and 8% proteins (Figure 2). The phospholipid components in mature surfactant are primarily responsible for reducing surface tension. The surfactant-associated proteins (SP-A, SP-B, SP-C, and SP-D) are essential for rapid spreading and stability of surfactant as a lipid monolayer in the alveolus. SP-A functions to enhance the biophysical activity of the other surfactant proteins and lipids as well as having a role in regulating secretory and reuptake pathways of surfactant. SP-A also may play a role in lung immune function along with SP-D by functioning as an opsonin, promoting macrophage migration and binding organisms.5 SP-B and SP-C are highly lipophilic and confer surfactant- like activities to phospholipids, and also facilitate the adsorption and spreading of lipid to form the surfactant monolayer.
What will happen to my baby in the level III neonatal intensive care unit?
Returning to the case presented above for discussion, on arrival at the level III neonatal intensive care unit, this child's illness continued to progress, and he required intubation and assisted ventilation, at which time he received surfactant. There are two types of surfactant available commercially in the United States for clinical use. One product is derived from bovine lung, and the other product is totally synthetic. The animal surfactants have phospholipid profiles close to that of natural surfactant and contain the surfactant-associated proteins SP-B and SP-C, but not SP-A or SP-D. The preparation used by Fujiwara et al3 in their initial studies subsequently was tested and approved for use in the United States as Survanta (beractant, Ross Laboratories, Columbus, Ohio). This product is produced by mixing bovine lungs with saline and using organic solvents to extract the lipids, SP-B, and SPC. Synthetic surfactant contains the principal surface active phospholipid, dipalmitoylphosphatidylcholine, as well as other ingrethents to facilitate spreading and adsorption. The synthetic preparation currently available in the United States is Exosurf Neonatal, a mixture of dipalmitoylphosphatidylcholine, hexadecanol, and tyloxapol.
Extensive testing of each preparation has demonstrated that both products are efficacious in preventing and treating RDS and preventing the complications of pulmonary airleak. A recent multicenter trial sponsored by the National Institutes of Health did demonstrate that infants receiving Survanta required lower F1O2 and mean airway pressures in the first 72 hours after treatment compared with infants receiving Exosurf, but this difference did not translate to an advantage in outcome with regard to chronic lung disease or length of hospital stay.6
Can I give surfactant in my level II nursery?
While individuals do administer surfactant presently in a level II setting, this approach has never been studied in a controlled, randomized fashion. However, one aspect of surfactant administration that has been investigated extensively is the timing of the initial dose. Two different strategies have been evaluated: prophylactic administration in the delivery room as part of initial stabilization and resuscitation, and rescue administration after the symptoms of RDS are clearly established. A concern with prophylactic administration has been the unnecessary intratracheal treatment of large numbers of infants who would never develop RDS. However, delay in treatment may expose surfactant-deficient infants to lung injury from mechanical ventilation in the interval before they are able to be treated.
In the largest randomized trial completed to date, the OSIRIS (Open Study of Infants at High Risk of or With Respiratory Insufficiency - The Role of Surfactant) Collaborative Study Group enrolled several thousand babies in a protocol to assess when Exosurf should be administered initially and how often it should be given.7 In that study, 2690 infants judged to be at high risk of developing RDS were randomized in a level III neonatal intensive care unit setting to early administration (<2 hours) or delayed administration (>2 hours) of surfactant. Even though the early administration time was only an hour earlier on average (118 versus 182 minutes median age at administration), the risk of death was 16% lower for the early treatment group. There was also a 32% reduction in risk of pneumothorax in the early administration group.
Similar results with regard to decreased airleak and improved survival to 28 days of life without bronchopulmonary dysplasia were obtained by Soil et al8 when Survanta versus air placebo was administered prophylactically to a group of premature infants weighing 750 to 1250 g. Other studies, however, have not demonstrated an advantage of prophylactic versus rescue surfactant administration.9,10
The OSIRIS study also addressed the question of multiple doses of surfactant.7 Of 3376 infants eligible to receive up to four doses of Exosurf, 45% actually required more than two doses. When compared with the 3381 who received only two doses of Exosurf in a separate arm of the study, there was no significant difference in mortality, long-term oxygen dependence, or other major morbidity.
The American Academy of Pediatrics has published recommendations for surfactant replacement therapy.11 These recommendations require administration by a qualified individual and adequate support personnel and equipment for optimal management of the infant following surfactant administration."
Do all babies respond to surfactant?
Nogee et al12 recently identified a group o( infants with a defect in the gene for the surfactant-associated protein, SP-B. These infants were all born at term with signs and symptoms consistent with RDS. While such infants respond briefly to administration of SP-B (as Survanta), these infants all ultimately succumbed to this gene defect. Many of these infants have been treated with ECMO and subsequently died. If such a diagnosis is entertained, samples of tracheal lavage should be evaluated for the presence of SP-B and a novel metabolite of SP-C that has only been observed in infants Svith this gene defect and therefore is diagnostic of this disorder.13
Are there other treatment modalities I can use in a level II setting?
The infant with RDS has a poorly compliant and unstable lung that is difficult to inflate and collapses readily during expiration. The spontaneously breathing infant with this disorder who is grunting is attempting to prevent airway collapse. Breathing against a closed glottis prevents complete lung emptying, thereby maintaining a larger functional residual capacity and improving oxygenation. Continuous positive airway pressure is therefore an effective means of treating some infants with RDS.
Continuous positive airway pressure was first introduced in the 1930s as "continuous distending pressure" and was applied in the treatment of pulmonary edema and asthma.14 Continuous positive airway pressure eventually was replaced by mechanical ventilation, which became a more established treatment modality. In 1968, Gregory and associates15 reintroduced the concept of continuous distending pressure in the treatment of neonates with RDS and coined the term continuous positive airway pressure. Continuous positive airway pressure works primarily by increasing the mean airway pressure, which reduces the ventilation/perfusion mismatch characteristic of the atelectatic lungs in RDS and thus improves oxygenation (Figure 1). Continuous positive airway pressure also prevents terminal airway closure by uniformly distributing transpulmonary pressure, thus recruiting collapsed alveoli by decreasing the opening pressure necessary to inflate the alveoli and ultimately reducing the work of breathing.
Continuous positive airway pressure often is initiated as first-line "pressure support" in the infant with RDS, with a head hood oxygen requirement of >Fi02 50% to 70% and with a Pcc>2 in the 50s, or in an infant demonstrating significant work of breathing. Continuous positive airway pressure also is used earlier in more preterm infants whose poor chest wall compliance is such that the resting lung volume is near the collapsed lung volume because of minimal elastic recoil of the thoracic wall. Early intervention with continuous positive airway pressure in infants with RDS may decrease the requirement for high F1O2 and the need for endotracheal intubation, but its prophylactic use does not prevent the occurrence of RDS or improve outcome.16
While continuous positive airway pressure generally is considered less hazardous than mechanical ventilation, its use still requires the same medical and nursing expertise as full mechanical ventilation. Continuous positive airway pressure administration may result in lung overdistention with subsequent increase in ventilation/perfusion mismatch, increased risk of airleak phenomenon, CO2 retention, and increased work of breathing. While the risk of airleak in infants receiving continuous positive airway pressure is increased relative to those not receiving it, the incidence of pnemothorax is reported to be three times lower than in infants receiving mechanical ventilation.17 Potential hazards of continuous positive airway pressure include mucous plugging or mechanical obstruction of the tubing, gastroesophageal reflux and pulmonary aspiration, and local trauma to the nasal mucosa.
How can I tell if I'm in over my head?
When continuous positive airway pressure is not sufficient respiratory support, an infant with RDS requires intubation and positive pressure ventilation. While absolute criteria exist for intubation and ventilation, other criteria also are used. Thus, an infant requiring F1O2 100% in a head hood or an infant who is on continuous positive airway pressure and remains hypoxemic requires tracheal intubation and ventilation. Similarly, an infant with a PCO2 approaching 60 to 70 mm Hg also requires intubation. However, the practicing pediatrician needs to be able to anticipate which infants will require intubation and take appropriate measures before that point is reached. Returning to the case scenario described above, this infant had evidence of an increasing O? requirement and CO2 retention in the first 12 hours of life. Remembering that RDS severity peaks on day 2 to 3 of life, the practicing pediatrician should be able to anticipate which infants will require further intervention. For example, if an infant is requiring F1O2 50% shortly after birth, and 8 hours later requires F1O2 80% as a result of RDS, one may anticipate this infant will need intubation and ventilation sometime in the next 24 hours. However, an infant who requires F1O2 50% by head hood on day 2 of life and subsequently F1O2 80% on day 3 when the illness should be at maximal severity may escape without requiring more aggressive intervention.
Mechanical ventilation for RDS came into widespread use in the early 1970s. Initial strategies that often used very high peak airway pressure to maintain oxygenation resulted in significant morbidity and mortality secondary to bronchopulmonary dysplasia. Although the best way to ventilate an infant with RDS is still open to question, "gentler" approaches that attempt to limit the use of high pressures and reduce barotrauma currently are favored.
Some clinicians prefer the use of high frequencies and lower peak inspiratory pressures, while others advocate low frequencies with higher peak inspiratory pressures and longer inspiratory time. Most neonates are ventilated with pressure-limited time-cycled ventilators. These ventilators are rather simple in design, making them cost effective and easy to operate.
Newer ventilators are being designed with a synchronous mode. Previously, synchronous ventilation in neonates was limited by the inability of available equipment to accurately judge a baby's spontaneous respiration. As technology has been developed to overcome this limitation, the advocates of this method of ventilation claim decreased duration of ventilation and oxygen therapy and decreased complications of extrapulmonary airleak and intraventricular hemorrhage.18
Another ventilatory strategy termed high-frequency ventilation that uses very low volumes and supraphysiologic rates has been shown to provide adequate gas exchange at lower peak inspiratory pressures by mechanisms not completely understood. Theoretically, this approach should decrease barotrauma to the lung. High-frequency ventilators in current use are classified as high-frequency positive pressure ventilators, high-frequency jet ventilators, high-frequency flow interrupters, or high-frequency oscillatory ventilators. Although the characteristics of these ventilators overlap, there is as yet no standard strategy for their clinical application. There have been numerous clinical trials using high-frequency ventilation in the management of RDS. A large multicenter trial sponsored by the National Institutes of Health failed to demonstrate any improvement in outcome in infants managed with high-frequency ventilators versus conventional ventilation.19 Currently used by many centers as rescue therapy for extrapulmonary airleak and failed conventional ventilation, further investigation will be necessary to determine if highfrequency technology will replace current clinical respiratory management using conventional ventilators.
Should a mother be given steroids to prevent RDS?
The significant improvement in morbidity and mortality in preterm infants with RDS certainly can be attributed to improvement in respiratory management and the advent of surfactant therapy. Further reductions in morbidity and mortality have been clearly demonstrated with the antenatal administration of glucocorticoids. First reported by Liggins and Howie20 in 1972, a significant decrease in RDS was noted in infants born to mothers who had been given betamethasone therapy prior to delivery. Since that time, multiple clinical trials have substantiated the results of this study and further demonstrated reduction in other morbidity associated with prematurity, such as intraventricular hemorrhage and necrotizing entercolitis. In early March 1994, a National Institutes of Health consensus development conference was held on the use of antenatal steroids. The recommendations of this consensus conference included antenatal treatment with corticosteroids of all fetuses delivered between 24 and 34 weeks gestation at risk of preterm delivery. The consensus conference further noted that the use of antenatal steroids should not be altered by fetal race or gender or the availability of surfactant replacement therapy. Patients eligible for therapy with tocolytics also should be considered eligible for treatment with antenatal steroids.21
In summary, the incidence and natural history of RDS as a consequence of preterm delivery have been altered by modern interventions in obstetric and neonatal care. Obstetricians have been responsible for improvements in pregnancy surveillance, appropriate use of tocolytics and antenatal steroids, and judicious maternal transfer to high-risk obstetric services where appropriate. Coupled with advances in neonatology in respiratory management, surfactant replacement therapy, nutritional support, and environmental regulation, improved outcomes in preterm deliveries have resulted. The role of the practicing pediatrician in management of such infants should not be minimized. Prompt recognition and treatment of the infant with RDS along with appropriate transfer to a level HI neonatal intensive care unit when appropriate have resulted in further marked improvement in the outcome of prematurely delivered babies.
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