Neonatal respiratory distress syndrome is a major cause of morbidity and mortality in premature infants. Although the term "hyaline membrane disease" is often considered to be synonymous with the term "respiratory distress syndrome," the eosin-staining material of hyaline membrane disease represents a nonspecific response of the lung to a variety of disorders. Of the approximately 60,000 to 70,000 infants born each year in the United States who have respiratory distress syndrome, 5,000 die. Before 1960, over 25,000 neonates died of respiratory distress syndrome each year.
The decrease in mortality from respiratory distress syndrome is largely a result of improvements in supportive care and mechanical ventilator management. Further advances during the past three decades include better prenatal testing to identify infants at risk for respiratory distress syndrome, antepartum referral of mothers at risk for premature delivery and hastening of lung maturity by antenatal administration of corticosteroids.
Unfortunately, a major consequence of improved ventilator management has been the creation of a new disorder, bronchopulmonary dysplasia. Bronchopulmonary dysplasia is a type of ventilator-associated lung injury resulting from the same therapy that has improved survival. Barotrauma, oxygen toxicity and the degree of prematurity play key roles in the pathogenesis of bronchopulmonary dysplasia. The disorder occurs in more than 10,000 infants in the United States each year. Many of these infants remain in newborn intensive care units for months or even years.
This article focuses on three areas of technologic advances that are at the forefront in the search to improve survival among infants with respiratory distress syndrome: exogenous surfactant replacement therapy, high-frequency ventilation and extracorporeal membrane oxygenation. These new advances may also prevent or mitigate the course of bronchopulmonary dysplasia.
Exogenous Surfactant Therapy
More than 30 years have passed since Avery and Mead documented that infants dying of respiratory distress syndrome were deficient in pulmonary surfactant. During the last trimester of fetal development, the lung enters a terminal sac or alveolar stage. As part of this maturation process, surfactant is synthesized by type II pneumocytes. On release, surfactant spreads over the inner surface of the air sacs.
The major function of surfactant is to maintain alveolar stability by reducing surface tension, thus preventing collapse of the alveoli and lungs. Atelectasis results when inspiratory pressures are not great enough to inflate surfactant-deficient alveoli. The classic radiographic features of respiratory distress syndrome (Figure 1) reflect this diffuse atelectasis. Important risk factors associated with surfactant deficiency include the degree of prematurity, male sex, white race, perinatal asphyxia and maternal diabetes.
Pulmonary surfactant is composed of phospholipids (80 to 90 percent by weight), protein (10 to 15 percent by weight) and cholesterol.[5-12]
Dipalmitoylphosphatidylcholine (DPPC), a phospholipid also known as lecithin, is the most abundant component of surfactant. Three specific surfactant-associated proteins, SAP-A, SAP-B and SAP-C., play a critical role in sufactant function by speeding adsorption at the alveolar surface, enhancing spreading and aiding in surfactant reuptake and metabolism, respectively.
Initial attempts at surfactant replacement in the 1960s and 1970s met with limited success. Preparations used during this period contained only phospholipids, which did not stabilize airways effectively. However, in 1980, Fujiwara and associates used a preparation consisting of modified cow's lung surfactant and synthetic phospholipids in the treatment of respiratory distress syndrome. This treatment improved gas exchange and decreased oxygen requirements.
Since then, more than 30 clinical trials have been undertaken to evaluate the efficacy of various surfactant preparations in the treatment or prevention of respiratory distress syndrome. During treatment (so-called "rescue management") trials, only infants with established respiratory distress syndrome are given surfactant.[8-10] In prevention ("prophylaxis") trials, all high-risk premature infants receive treatment immediately after birth.
TYPES OF SURFACTANT PREPARATIONS
The three categories of surfactant preparations include natural surfactants, modified natural surfactants and synthetic surfactants.
Natural surfactants are derived from human and animal sources. Impressive results have been achieved with an extract derived from human amniotic fluid. However, because of production problems and the fear of potential contamination, this material will probably never be widely used, either clinically or commercially.
Animal-derived natural extracts have also been studied. A porcine material (Curosurf) has been primarily investigated in Europe, while several surfactants derived from calf's lung (such as Infasurf) have been studied extensively in the United States. Following Fujiwara's success with a modified surfactant extract, a similar commercially manufactured substance (Survanta) has been tested in many large collaborative investigations. Survanta has recently been approved by the U.S. Food and Drug Administration for commercial use.
Artificial lung expanding compound (ALEC), a synthetic surfactant from the United Kingdom, consists of a saline suspension of DPPC and phosphatidylglycerol. Exosurf Neonatal is a synthetic substance that is composed primarily of DPPC but also contains two compounds, hexadecanol and tyloxapol, which are not found in natural surfactant. These agents help spread the surfactant. Exosurf is the exogenous surfactant that has been studied most extensively and was the first substance to be commercially approved by the FDA.
To date, no clear advantages of any single surfactant preparation are apparent. In fact, no comparative studies of the various preparations have been performed in a single investigation. At this time, however, comparative trials of several surfactants are underway. The results of virtually all of the more than 30 clinical trials have indicated decreases in oxygen requirements, as well as decreases in the incidence of air leaks (pneumothoraxes and pulmonary interstitial emphysema) and deaths.[9,11,12] In addition, the incidence of intracranial bleeding and bronchopulmonary dysplasia appears to be decreasing.
QUESTIONS ABOUT SURFACTANT THERAPY
Several questions remain regarding surfactant therapy:
1. What is the optimal treatment strategy--prevention or rescue? The physician must determine whether surfactant should be administered before or after the infant exhibits symptoms of respiratory distress.
2. What is the appropriate dose? The appropriate amount of surfactant varies. Some infants may require a higher concentration of surfactant due to a higher degree of prematurity.
3. Should multiple doses be given? The number of doses of surfactant used in clinical trials has ranged from one to six. The optimal timing and total number of doses have yet to be determined.
4. What is the latest any infant can be effectively treated with surfactant (e.g., 48 hours, one week)? Most infants are treated in the first two days of life. Virtually no data exist regarding infants who have been treated beyond 48 hours of life. Some infants may still be surfactant-deficient beyond 48 hours and may potentially benefit from therapy at that time.
5. How should the surfactant be administered? For some varieties of surfactant, special endotracheal tube adapters with side ports must be used. For others, a catheter must be placed in the endotracheal tube. The duration of instillation may vary; each child needs to be considered individually.
Although in most investigations boluses of the surfactants were administered with a syringe, ongoing studies are examining slow continuous infusion over a 10- to 30-minute period. Finally, data are not sufficient to determine whether nebulized or aerosol forms of surfactant are more efficacious than the bolus liquid forms.
6. What are the adverse effects? During administration of surfactant therapy, some infants may have episodes of desaturation and temporarily need increased ventilatory support. The occurrence of patent ductus arteriosus appears to be higher with both natural and synthetic surfactants. Because lung compliance improves, pulmonary vascular resistance decreases with a concomitant decrease in pulmonary vascular pressure, allowing a left-to-right shunt through the patent ductus arteriosus from the higher systemic pressure in the aorta.
In addition, the incidence of pulmonary hemorrhage appears to be increased in surfactant-treated infants. Such bleeding occurs in as many as 2 to 4 percent of cases. A relationship exists between pulmonary hemorrhage and the presence of more severe illness--as in infants with the lowest birth weight, male sex and, in particular, patent ductus arteriosus. Hemorrhagic pulmonary edema may occur as a result of patent ductus arteriosus. Some authors believe that weaning ventilator settings as rapidly as possible after surfactant administration (as the clinical situation and blood gases permit) will mitigate the occurrence of patent ductus arteriosus and pulmonary hemorrhage.
7. Is the long-term outcome better? Survivors who receive surfactant therapy appear to have a better outcome than survivors who do not receive surfactant therapy. However, since this therapy is fairly new, no data are available regarding outcome in children five years of age or older.
8. Will the price of commercially available surfactant remain high? The two commercially available preparations in the United States cost at least $500 per vial. Larger preterm infants may require two vials per dose. Not infrequently, as many as four doses are needed, and the total cost may be $4,000 or more. However, the cost of alternatives, such as death, a longer hospitalization, bronchopulmonary dysplasia and air leaks, is likely to be far greater.
9. Should surfactant therapy be considered the standard of care for premature infants with respiratory distress syndrome? The answer appears to be "yes." The benefits have been clearly demonstrated, and the substance is commercially available. However, the general consensus is that surfactant should only be administered by specially trained individuals experienced in making ventilator changes. In nonintensive care nurseries, consideration should be given to administering the substance if it appears there will be an inordinate delay before an infant with respiratory distress syndrome is transferred to a tertiary-care center. However, again, physicians or respiratory therapists must have sufficient skill in giving the medication and making ventilator adjustments. Transport teams of the 1990s will often bring surfactant with them.
10. Can surfactant be used in the treatment of other disorders? According to one anecdotal report, researchers administered calf's lung surfactant extract to 14 full-term infants who had either pneumonia or meconium aspiration syndrome. The infants responded with improved oxygenation. Furthermore, preliminary data suggest improvement after surfactant therapy in patients with adult respiratory distress syndrome.[14,15] Nevertheless, properly designed trials are clearly indicated before this therapy is used for disorders other than neonatal respiratory distress syndrome.
The term "high-frequency ventilation" encompasses a group of techniques that provide mechanical ventilatory support at supraphysiologic rates and low tidal volumes (near or less than dead space volume).[16-19] If conventional ventilation is considered to be analogous to giving an infant a cupful of air 20 times a minute, high-frequency ventilation is similar to administering a thimbleful of air 600 times a minute. High-frequency ventilation research has challenged a fundamental law of respiratory physiology--namely, that tidal volume must be greater than dead space in order for ventilation to occur.
Clearly, the physiologic mechanisms for gas exchange must differ from those of conventional ventilation.[16,18] The supraphysiologic rates on these devices are at least two to four times higher than resting respiratory rates. In neonates, rates of 240 or more breaths per minute are generally used. Some practitioners equate all types of high-frequency ventilation. However, wide ranges exist in design and function of the various devices. Many different strategies for use are employed. Thus, interpretation of the literature is difficult. Results should not be compared when neither the device nor the strategy are similar.
High-frequency ventilation devices fall into three major categories. None of these include the operation of conventional ventilators at unconventionally high rates.
HIGH-FREQUENCY JET VENTILATION
High-frequency jet ventilation consists of a high-pressure gas source, which is periodically directed down a small-bore catheter into the endotracheal tube lumen. The typical high-frequency jet ventilation operating frequency is 200 to 600 breaths per minute. The Bunnell Life Pulse (Bunnell Inc., Salt Lake City) is the only high-frequency jet ventilation approved by the FDA for use in neonates. Its use is indicated as a rescue mode of ventilation for air leaks or respiratory failure, not as the initial primary ventilator for respiratory distress syndrome.
Only one investigation to date has examined the role of high-frequency jet ventilation in the early management of respiratory distress syndrome. Using a prototype high-frequency jet ventilation device (not commercially available), researchers did not find substantial reductions in mortality and morbidity, and numerous problems were apparent with the investigation design. However, a multicenter collaborative investigation is currently being conducted regarding early management of respiratory distress syndrome with the Bunnell Life Pulse.
HIGH-FREQUENCY FLOW INTERRUPTION
High-frequency flow interruption is similar to high-frequency jet ventilation in that a high-pressure gas source is periodically interrupted (typically by solenoid or pneumatic valves). Unlike high-frequency jet ventilation, the gas stream in high-frequency flow interruption devices is delivered directly into the top of a conventional endotracheal tube. The frequencies are generally higher with these devices, from 400 to 750 breaths per minute.
Infant Star (Infrasonics Inc., San Diego) is a commercially available high-frequency flow interruption device. It has been approved by the FDA for the rescue treatment of infants with air leaks and respiratory failure, but not for the initial management of respiratory distress syndrome. No studies have been published regarding the use of the Infant Star high-frequency flow interruption device in a defined population of neonates.
HIGH-FREQUENCY OSCILLATORY VENTILATION
High-frequency oscillatory ventilation is the final category of high-frequency ventilation. This type of ventilation is unique in that it provides an active expiratory phase. In all other types of ventilation (natural, conventional, high-frequency jet ventilation or high-frequency flow interruption), exhalation is passive. However, in high-frequency oscillatory ventilation, a piston or a diaphragm produces a positive inhalation wave as well as a negative stroke during which gas is actually drawn out of the airways. High-frequency oscillatory ventilation devices operate at higher frequencies than high-frequency jet ventilation or high-frequency flow interruption, generally in the 600 to 1,200 breaths per minute range.
The SensorMedics 3100 (SensorMedics Corporation, Yorba Linda, Calif.) is a commercially available high-frequency oscillatory ventilation device. It is the only device of this kind approved by the FDA for the initial ventilatory management of respiratory distress syndrome. In a controlled trial, neonates managed with high-frequency oscillatory ventilation had a lower incidence of bronchopulmonary dysplasia than other neonates. In this study, the SensorMedics 3100 high-frequency oscillatory ventilation device was documented to be successful in managing air leaks and respiratory failure recalcitrant to conventional therapy. The device has also been approved by the FDA for these indications.
High-frequency ventilation therapy is still in development. Additional properly designed clinical trials are necessary to evaluate various high-frequency ventilation devices, strategies and the specific disease states in which they may be useful.
Extracorporeal Membrane Oxygenation
Extracorporeal membrane oxygenation is a modified prolonged cardiopulmonary bypass procedure used to support infants with respiratory failure who have a high predicted mortality rate (80 percent or higher) on maximal conventional ventilatory support.[17,22] Extracorporeal membrane oxygenation is a temporary support (generally for no longer than 10 to 14 days) used to provide time for the lungs to recover from diverse disorders. Most infants placed on extracorporeal membrane oxygenation have persistent pulmonary hypertension, which is often associated with the meconium aspiration syndrome.
In most medical centers using this technology, venoarterial bypass is employed. Venous blood drains from the infant's right atrium (through an internal jugular catheter) by gravity into a reservoir. The blood is circulated through an artificial membrane lung where gas exchange takes place. The blood is subsequently heated and returned to the infant's aortic arch through a carotid artery cannula. Unfortunately, in most infants, technology limitations require both the right internal jugular vein and the right common carotid artery to be ligated and sacrificed. Although neonates have impressive collateral circulation, there is concern about the long-term neurologic outcome in infants treated with this technique.
Infants placed on extracorporeal membrane oxygenation must be anticoagulated to prevent thromboembolism. Premature infants are at particular risk for intracranial hemorrhage. Even without anticoagulation, 20 to 40 percent of infants at 32 weeks' gestation or less have intracranial hemorrhage. This risk markedly increases if they are placed on extracorporeal membrane oxygenation.
Most extracorporeal membrane oxygenation centers will treat premature infants with respiratory distress syndrome only if their gestational age is 34 weeks or more. However, research is being conducted to produce nonthrombogenic extracorporeal membrane oxygenation circuits. Furthermore, alternate routes of bypass are being investigated (e.g., venovenous perfusion and single cannula techniques). If these efforts are successful, extracorporeal membrane oxygenation may prove to be beneficial in the smallest premature infants with respiratory distress syndrome. To date, neonates with respiratory distress syndrome make up less than 10 percent of infants who are placed on extracorporeal membrane oxygenation.
During the past 25 years, remarkable progress has been made in the management of neonatal respiratory distress syndrome. Congenital malformations have replaced respiratory distress syndrome and its complications as the leading cause of death among neonates. Many "micropremature" infants with birth weights of 500 to 1,000 g are surviving. Nevertheless, respiratory distress syndrome still affects almost 2 percent of liveborn infants. Unremittent respiratory failure recalcitrant to all conventional support often occurs in these infants. Pulmonary air leaks are not infrequent, while infants with bronchopulmonary dysplasia use space and resources in neonatal intensive care units for prolonged periods.
Over the past decade, innovations such as surfactant therapy, high-frequency ventilation and extracorporeal membrane oxygenation have provided hope that the course of respiratory distress syndrome as well as the complications of conventional therapy can be mitigated. Additional research concerning all of these adjunctive modalities is ongoing, providing optimism for continued improvement in the outcome of newborns with respiratory distress syndrome.
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.
[1.] Stark AR, Frantz ID 3d. Respiratory distress syndrome. Pediatr Clin North Am 1986;33:533-44. [2.] Wegman ME. Annual summary of vital statistics-1989. Pediatrics 1990;86:835-47. [3.] Moores RR, Abman SH. Bronchopulmonary dysplasia: persistent cardiopulmonary sequelae of neonatal respiratory distress and its treatment. Semin Respir Med 1990;11:140-51. [4.] Avery M, Mead J. Surface properties in relation to atelectasis and hyaline membrane disease. Am J Dis Child 1959;96:517-23. [5.] Shapiro DL, Notter RH, eds. Surfactant replacement therapy. New York: Liss, 1989. [6.] Jobe A, Ikegami M. Surfactant for the treatment of respiratory distress syndrome. Am Rev Respir Dis 1987;136:1256-75. [7.] Fujiwara T, Maeta H, Chida S, Morita T, Watabe Y, Abe T. Artificial surfactant therapy in hyaline-membrane disease. Lancet 1980;1(8159):55-9. [8.] Hennes HM, Lee MB, Rimm AA, Shapiro DL. Surfactant replacement therapy in respiratory distress syndrome. Meta-analysis of clinical trials of single-dose surfactant extracts. Am J Dis Child 1991;145:102-4. [9.] Soll RF, Lucey JF. Surfactant replacement therapy. Pediatr Rev 1991;12:261-7. [10.] Avery ME. Twenty-five years of progress in hyaline membrane disease. Respir Care 1991;36:283-7. [11.] Golembeski D, Merritt TA. New strategies for prevention of neonatal respiratory distress syndrome: acceleration of fetal lung maturation and exogenous surfactant replacement. Semin Respir Med 1990;11:117-26. [12.] Halliday HL. Surfactant replacement. In: The Year Book of neonatal and perinatal medicine. Chicago: Year Book Medical, 1989:xiii-xxi. [13.] Auten RL, Notter RH, Kendig JW, Davis JM, Shapiro DL. Surfactant treatment of full-term newborns with respiratory failure. Pediatrics 1991;87:101-7. [14.] Nosaka S, Sakai T, Yonekura M, Yoshikawa K. Surfactant for adults with respiratory failure [Letter]. Lancet 1990;336:947-8. [15.] Richman PS, Spragg RG, Robertson B, Merritt TA, Curstedt T. The adult respiratory distress syndrome: first trials with surfactant replacement. Eur Respir J Suppl 1989;3:109S-11S. [16.] Gerstmann DR, deLemos RA, Clark RH. High-frequency ventilation: issues of strategy. Clin Perinatol 1991;18:563-80. [17.] Bui KC, Cornish JD. Innovative therapies for neonatal respiratory failure: high-frequency ventilation and extracorporeal membrane oxygenation. Semin Respir Med 1990;11:127-39. [18.] Bancalari E, Goldberg RN. High-frequency ventilation in the neonate. Clin Perinatol 1987;14:581-97. [19.] Slutsky AS. Nonconventional methods of ventilation. Am Rev Respir Dis 1988;138:175-83. [20.] Carlo WA, Siner B, Chatburn RL, Robertson S, Martin RJ. Early randomized intervention with high-frequency jet ventilation in respiratory distress syndrome. J Pediatr 1990;117:765-70. [21.] Clark RH, Gerstmann DR, Null DM Jr, deLemos RA. Prospective randomized comparison of high-frequency oscillatory and conventional ventilation in respiratory distress syndrome. Pediatrics 1992;89:5-12. [22.] Keszler M, Siva Subramanian KN. Reversing respiratory failure in newborns. Contemp Obstet Gynecol 1991;36:99-112. [23.] Mendoza JC, Shearer LL, Cook LN. Lateralization of brain lesions following extracorporeal membrane oxygenation. Pediatrics 1991;88:1004-9.
THOMAS E. WISWELL, LTC, MC, USA is chief of the neonatology service at Walter Reed Army Medical Center, Washington, D.C., and associate professor of pediatrics at the F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Md. Dr. Wiswell graduated from the University of Pennsylvania School of Medicine, Philadelphia, and completed a residency in pediatrics and a fellowship in neonatology at Tripler Army Medical Center, Honolulu.
JOE MENDIOLA, JR., M.D. is a staff neonatologist at McAllen (Tex.) Hospital. He was formerly assistant chief of the neonatology service at Walter Reed Army Medical Center. Dr. Mendiola graduated from the University of Texas Medical School at San Antonio and completed a pediatric residency at that institution. In addition, he completed a fellowship in neonatology at the University of Texas Medical School at Houston.
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