As surfactant therapy becomes standard practice, patients with RDS can benefit at any age.
Surfactant-replacement therapy is, unquestionably, the single most important advance in neonatal medicine of the past 20 years, and it is responsible for the largest decrease in neonatal mortality during that time.1 Since surfactant deficiency was first implicated in neonatal respiratory distress syndrome (RDS), there have been hundreds of clinical trials and thousands of papers defining surfactant biochemistry and physiology. Not only has a tremendous amount of knowledge on surfactant been amassed, but important clinical lessons have been learned. As a result, some new directions are being taken by surfactant-replacement therapy.
Since normal surfactant function is vital to air-breathing mammals of all ages, not just neonates, a thorough appreciation and understanding of surfactant therapy are essential for all RCPs. In addition, intriguing new data suggest that surfactant therapy is valuable for a variety of respiratory disorders in older pediatric patients and adults as well as neonates. Many of the lessons learned in treating neonates will be invaluable as surfactant-replacement therapy becomes the standard of care for older patients.
Alveolar surfactant is essential for the normal function of the mammalian lung. By reducing and dynamically varying surface tension, alveolar surfactant increases lung compliance and maintains alveolar stability, resulting in decreased work of breathing.2 Surfactant also has numerous (and equally important) functions that are not surface activities, such as regulating its own synthesis, secretion, and uptake, as well as playing a role in the lung’s host-defense system.3 Clinically, however, its most obvious function is to facilitate normal gas exchange, as evidenced by the dramatic respiratory failure that occurs when it is deficient or absent in neonatal RDS.
The alveolar surfactant complex is composed of at least six phospholipids, neutral lipids, and four surfactant-specific proteins.2 Phospholipids make up about 85%f human alveolar surfactant, with saturated phosphatidylcholine being the primary component. Although phosphatidylcholine is the major determinant of surfactant’s surface-tension lowering ability, it is clear that many of its other components contribute to its optimal performance. In particular, the low molecular weight hydrophobic proteins SP-B and SP-C aid the dispersal of surfactant at the air-liquid interface. The much larger hydrophilic proteins SP-A and SP-D, which belong to a family of proteins known as collectins, have been shown to have immunological functions in vitro, as well as in some animal models.4
Understanding the role of alveolar surfactant in determining respiratory mechanics led, in the early 1980s, to the development of exogenous surfactants and to trials of their use in infants with RDS. The evolution of surfactant-replacement therapy from bench to bedside represents one of the most important journeys in neonatal medicine, although a series of missteps resulted in a delay of nearly 30 years between the first definitive evidence of surfactant deficiency as the root cause of RDS and the first successful surfactant-replacement therapy trial.5
Indications for Use
Currently, the single approved clinical indication for surfactant-replacement therapy is neonatal RDS, although additional indications are likely to be approved in the near future. Even if therapy is limited to preterm neonates with suspected or proven surfactant deficiency, however, many questions remain. Should only infants with RDS or all those at risk be treated? Should all infants with RDS or only those with severe disease be treated? Should one, two, or more repeat doses of surfactant be given? Should infants with mild RDS be intubated solely in order to give them surfactant?
Attempts to answer these questions have been based on practical considerations, clinical data, and cost-benefit analyses. It is clear that infants with even mild RDS benefit from surfactant-replacement therapy, and that treatment during the early stages of RDS is better than treatment after severe respiratory failure occurs, particularly if pulmonary air leaks have already developed.6 It is also clear that retreatment at intervals of less than the recommended 4 to 6 hours is of no obvious benefit.6
Since exogenous surfactant can currently be given only by the endotracheal route, treatment is inherently limited to infants who are intubated. This is an important issue because significant controversy exists as to whether infants with mild-to-moderate RDS can be managed without intubation. Infants who are managed without intubation cannot benefit from surfactant-replacement therapy; on the other hand, the benefit of elective intubation solely for the purpose of surfactant administration needs to be weighed against the risks of intubation (including trauma, inappropriate tube placement, and increases in vagal tone and intracranial pressure).7 Certainly, it would seem prudent to minimize these risks, and it follows that such infants are best managed in a controlled situation by highly trained professionals. In most cases, this will mean higher levels of expertise and care than are available at most community hospitals.8
Factors Affecting Response
Although the effect of resuscitation at delivery on the infant’s subsequent response to surfactant-replacement therapy has not been studied, it is unlikely to be of major importance. This is primarily because the route of surfactant administration obviates the need for an intact circulation. It is not known, however, whether the additional seconds of bradycardia or hypoxia imposed by trying to administer surfactant to a poorly resuscitated newborn have any long-term consequences. This is an important consideration, since animal data9 suggest that surfactant administration into a fluid-filled or atelectatic immature lung is more effective than administration into a similar lung inflated with air. There are also data to suggest that even modest inflation of a surfactant-deficient lung compromises the benefit of surfactant-replacement therapy.10 Since clinical trials11 have not suggested a significant benefit attributable to immediate dosing, however, a prudent approach would be to resuscitate the neonate first, taking care not to use excessive inflation pressures.
In surfactant-replacement therapy, the relative merits of prophylaxis and rescue application have received much attention. A recent meta-analysis12 suggests that prophylactic treatment is preferred; in fact, its author suggests that prophylaxis, rather than rescue therapy, would result in one less death among every 14 infants treated. Caution is advisable in interpreting such conclusions for several reasons. First, none of the studies in the meta-analysis used the type of surfactant that is currently in use in nearly all US hospitals. Second, these studies were performed before antenatal steroid use became widespread; this practice alone has been shown to reduce neonatal mortality from RDS significantly. Third, the criteria for rescue treatment varied and, in some cases, were more stringent than those commonly used. Fourth, several factors (such as the volume of surfactant given, its rate of administration, and the positioning of the infant) that have significant effects on surfactant-replacement therapy’s efficacy varied significantly among studies. Fifth, the errors inherent in performing meta-analyses have previously been well described.13
Compositional differences in surfactants clearly affect their efficacy. It is generally accepted that natural surfactants are superior to artificial surfactants, and natural surfactants predominate clinically around the world.11 Even among natural surfactants, however, subtle compositional differences can lead to substantial differences in biophysical and physiological activity.14 When compared in the clinical arena, these differences are not as dramatic. Still, they underscore the fact that all surfactants are not created equal, and that availability of various surfactant preparations would only enhance the ability to care for patients with respiratory failure. Unfortunately, legal battles and regulatory hurdles have kept certain preparations out of the United States market. Only one natural surfactant preparation is now approved by the US Food and Drug Administration for general use; with ongoing interest in developing better surfactants, it is to be hoped that this situation will change.
Exogenous surfactant is most effective when it is uniformly distributed within the lung. The optimal distribution can be achieved through complete deflation of the lung followed by reinflation with a volume of surfactant that approximates the functional residual capacity, but this is not clinically practical. In the clinical setting, several factors are important in determining surfactant distribution. These include the volume of surfactant,15 its rate of instillation,16 the positioning of the infant,6 the spreading characteristics of the surfactant,2 and the underlying disease process in the lungs. Of these, the first three are under clinical control, to some extent. The volume of surfactant usually given (3 to 5 mL/kg, depending on the preparation) has been determined partly by consideration of the normal surfactant pool size (approximately 100 mg of phospholipid per kilogram of body weight) and partly by the concern that airway obstruction could occur with the use of larger amounts. The rate of administration is also important; the more slowly the surfactant is instilled, the more likely it is to go to more dependent areas. Repositioning the infant from side to side during and after administration will allow gravity to produce a more uniform distribution, although a two-position method appears equivalent to a four-position approach. Giving surfactant through aerosol dispersion, either as an aqueous suspension, as ultrasonicated liposomes, or as dry powder, has an advantage in that it is not necessary to intubate the infant in order to give the surfactant. In addition, it is generally true that aerosolization will result in more uniform distribution than bolus administration.17 This assumes, though, that the lung is homogeneously aerated, which is not often the case in infants with RDS.
The acute complications of surfactant-replacement therapy result from airway obstruction by the instilled fluid or by mobilized secretions within the lung. Desaturation, bradycardia (produced indirectly by hypoxia or directly by vagal stimulation), blood-pressure changes, increased intracranial pressure, and electroencephalogram changes have all been reported, but can quickly be reversed by interrupting the instillation process.6 Clearly, close monitoring of the patient during surfactant-replacement therapy is important. Equally important is an appreciation of the dramatic changes in lung compliance that follow surfactant-replacement therapy in many patients: in infants supported by pressure-controlled mechanical ventilation, significant overinflation can occur if inspiratory pressures are not reduced appropriately. When surfactant-replacement therapy was first introduced in medical centers, it was not unusual to find a transient increase in air leaks being reported.18 The learning process involved in surfactant-replacement therapy emphasizes the importance of having two or more trained personnel present during therapy so that the infant, cardiorespiratory monitor, and ventilatory waveform can be followed closely, with interventions made as necessary. Surfactant-replacement therapy should be performed by experienced RCPs, nurses, and physicians, preferably within the tertiary care center, where appropriate monitoring and interventions are available.
Data from the early trials of synthetic surfactant suggested that surfactant-replacement therapy was associated with increased incidence rates for patent ductus arteriosus pulmonary hemorrhage. A recent review19 of several clinical trials suggests that these increases are not seen with the use of natural surfactants.
Other concerns that have been raised, particularly for natural surfactants, include sensitization to foreign proteins, transmission of infectious particles (prions), and induction of an inflammatory response.11 After decades of use and intense scrutiny, however, no such evidence has accumulated.
Use in Other Neonatal Respiratory Disorders
Surfactant deficiency or dysfunction has been implicated in a variety of neonatal disorders other than RDS. In some conditions, such as congenital diaphragmatic hernia and pulmonary hypoplasia, it may be a primary deficiency; in others, such as bacterial pneumonia, pulmonary hemorrhage, meconium aspiration syndrome, and bronchopulmonary dysplasia, inactivation of native surfactant occurs. In either situation, there are substantial in vitro and in vivo data to support surfactant-replacement therapy. To date, there have been at least two controlled trials20,21 in full-term infants with severe respiratory failure showing a beneficial effect for surfactant-replacement therapy. The first study20 was limited to infants with meconium aspiration and showed significant reductions in complications, including air leaks. A recent large, multicenter study21 of full-term infants with respiratory failure from a variety of causes found no difference between surfactant-replacement therapy and placebo in regard to complications such as air leaks, intracranial hemorrhage, and chronic lung disease, but did find a significant reduction in the need for extracorporeal membrane oxygenation. Average age at entry was greater than 24 hours, suggesting that surfactant-replacement therapy, even late in the disease process, is still beneficial.
In congenital diaphragmatic hernia, pulmonary hypoplasia, and bronchopulmonary dysplasia, there have been some encouraging animal data and clinical case reports, but controlled clinical evaluations of surfactant-replacement therapy showing significant benefit have not yet been reported.22
Despite the heterogeneity of insults that can lead to adult respiratory distress syndrome (ARDS), it is becoming increasingly clear that surfactant dysfunction plays a central role in the respiratory failure that is the hallmark of this disorder. Thus, it was a disappointment that an early, large controlled trial23 of surfactant-replacement therapy in ARDS showed no discernible benefit, but careful analysis of this study revealed at least two possible explanations for its negative results. First, a synthetic surfactant was used that lacks the surfactant-associated proteins necessary to overcome inhibition by alveolar edema fluid. Second, surfactant-replacement therapy was performed via aerosolization, which probably resulted in very little deposition of surface-active material; another study24 using the same aerosolization system found that less than 55of the aerosolized surfactant actually reached the lung parenchyma.
Clinicians were encouraged to pursue surfactant-replacement therapy in ARDS following several studies in animal models of ARDS (and occasional case reports) showing significant benefit. To date, there have been at least three controlled trials, two25,26 in adults and one27 in children with RDS, showing significant improvement in gas exchange and clinical outcome. While surfactant-replacement therapy will probably become a standard therapy in ARDS, several issues still need to be resolved. These include the relatively large volume of surfactant that must be given and the probable need for repeat doses, both of which make surfactant-replacement therapy with currently available preparations a costly treatment.
Studies in animals have suggested that native surfactant is altered following the ischemia-reperfusion injury induced by lung transplantation. Recent animal studies28,29 have found that graft rejection is reduced by treating the recipient with surfactant and that treatment of lung donors prior to graft storage was associated with less severe lung injury following transplantation.
It has been suggested that some forms of obstructive airway disease, such as asthma or viral bronchiolitis, are associated with both compositional and functional surfactant deficiencies.30 No controlled trials of surfactant-replacement therapy have been conducted for these conditions, but a recent controlled trial31 of surfactant-replacement therapy in adults with chronic bronchitis showed beneficial effects. It is likely that additional trials will be seen for patients with obstructive airway diseases in the near future, particularly as better aerosolization methods for surfactant delivery are developed.
Since surfactant disperses rapidly within the lung, it may also serve as a way to deliver other agents evenly throughout the lung epithelium. This premise has recently been tested in animals receiving somatic gene transfer with a recombinant adenovirus vector. When used as the carrier vehicle, surfactant was much better than saline at achieving uniform distribution of transgenic expression.32
Role of the RCP
Surfactant-replacement therapy is spreading rapidly. Already a mainstay of neonatal respiratory care, it is becoming increasingly important in pediatric and adult critical care. This therapeutic explosion carries with it new challenges for the RCP.
A thorough appreciation of surfactant physiology and administration can be gleaned from decades of experience in neonates. Although neonates should never be viewed as miniature adults, much has been learned from our tiniest patients that can be applied to older patients as well. If these lessons are heeded, RCPs can optimize the benefits of surfactant-replacement therapy and avoid complications. There is still much to learn about the pathophysiology of respiratory failure and the role that the surfactant system may play in certain disorders. Keeping abreast of new insights and opportunities for surfactant-replacement therapy will ensure that patients continue to get the very best respiratory care.
New opportunities for surfactant-replacement therapy emerge as new insights into the role of the surfactant system in various disorders are gained. Newer surfactants, including recombinant products, may be tailored for specific disorders. For example, by altering the protein content of an exogenous surfactant preparation, it may be made more resistant to inactivation when given to patients with proteinaceous alveolar edema (as seen in ARDS). In many ways, the future of surfactant-replacement therapy is already here, and new applications continue to arise.
Surfactant-replacement therapy has secured its place in the armamentarium of respiratory critical care. No single advance in this area has had as spectacular an effect on patient outcomes. Originally designed for neonates, surfactant-replacement therapy is being applied to a variety of diseases in patients of all ages, and exciting new indications continue to arise. No longer are patients simply being supported on ventilators in the hope that the healing process will prevail. A new tool to reverse the disease process in many critically ill patients, and to improve their outcomes dramatically, is available. N
James J. Cummings, MD, is professor of pediatrics and physiology at East Carolina University School of Medicine and director of neonatology at Pitt County Memorial Hospital, both in Greenville, NC.
1. Lee K, Khoshnood B, Wall S, Chang Y, Hsieh H, Singh J. Trend in mortality from respiratory distress syndrome in the United States, 1970-1995. J Pediatr. 1999;134:434-440.
2. Possmayer F. Physicochemical aspects of pulmonary surfactant. In: Polin R, Fox W, eds. Fetal and Neonatal Physiology. 2nd ed. Philadelphia, Pa: W.B. Saunders; 1998:1259-1275.
3. Rooney S. Regulation of surfactant-associated phospholipid synthesis and secretion. In: Polin R, Fox W, eds. Fetal and Neonatal Physiology. 2nd ed. Philadelphia, Pa: W.B. Saunders; 1998:1283-1299.
4. Whitsett J. Composition of pulmonary surfactant lipids and proteins. In: Polin R, Fox W, eds. Fetal and Neonatal Physiology. 2nd ed. Philadelphia, Pa: W.B. Saunders; 1998:1251-1259.
5. Enhorning G, Shennan A, Possmayer F, Dunn M, Chen CP, Milligan J. Prevention of neonatal respiratory distress syndrome by tracheal instillation of surfactant: a randomized clinical trial. Pediatrics. 1985;76:145-153.
6. Robertson B, Halliday H. Principles of surfactant replacement. Biochim Biophys Acta. 1998;408:346-361.
7. Verder H, Robertson B, Greisen G, et al. Surfactant therapy and nasal continuous positive airway pressure for newborns with respiratory distress syndrome. N Engl J Med. 1994;331:1051-1055.
8. American Academy of Pediatrics, Committee on Fetus and Newborn. Surfactant replacement therapy for respiratory distress syndrome. Pediatrics. 1991;87:946-947.
9. Cummings J, Holm B, Nickerson P, Ferguson W, Egan E. Pre versus post-ventilatory surfactant treatment in surfactant-deficient preterm lambs. Reprod Fertil Dev. 1995;7:1-6.
10. Bjorklund L, Ingimarsson J, Curstedt T, et al. Manual ventilation with a few large breaths at birth compromises the therapeutic effect of subsequent surfactant replacement in immature lambs. Pediatr Res. 1997;42:348-355.
11. Walti H, Monset-Couchard M. A risk-benefit assessment of natural and synthetic exogenous surfactants in the management of neonatal respiratory distress syndrome. Drug Saf. 1998;118:321-337.
12. Morley C. Systematic review of prophylactic vs rescue surfactant. Arch Dis Child. 1997;77:F70-74.
13. LeLorier J, Gregoire G, Benhaddad A, Lapierre J, Derderian E. Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med. 1997;337:536-542.
14. Cummings JJ, Holm BA, Hudak ML, Hudak BB, Ferguson WH, Egan EA. A controlled clinical comparison of four different surfactant preparations in surfactant-deficient preterm lambs. Am Rev Respir Dis. 1992;145:999-1004.
15. van der Bleek J, Plotz F, van Overbeek F, et al. Distribution of exogenous surfactant in rabbits with severe respiratory failure: the effect of volume. Pediatr Res. 1993;134:154-158.
16. Segerer H, Gekder WV, Angenent F, et al. Pulmonary distribution and efficacy of exogenous surfactant in lung-lavaged rabbits are influenced by the instillation technique. Pediatr Res. 1993;134:490-494.
17. Henry M, Rebello C, Ikegami M, et al. Ultrasonic nebulized in comparison with instilled surfactant treatment of preterm lambs. Am J Respir Crit Care Med. 1996;154:366-375.
18. Gormally S, Clarke T, Krishman A, et al. Surfactant therapy in respiratory distress syndrome: the effect of a learning curve in improving outcome. Ir J Med Sci. 1993;162:458-461.
19. Braun K, Davidson K, Henry M, Nielsen H. Severe pulmonary hemorrhage in the premature newborn infant: analysis of presurfactant and surfactant eras. Biol Neonate. 1999;75:18-30.
20. Findlay R, Taeusch H, Walther F. Surfactant replacement therapy for meconium aspiration syndrome. Pediatrics. 1996;97:48-52.
21. Lotze A, Mitchell B, Bulas D, Zola E, Shalwitz R, Gunkel J. Multicenter study of surfactant (Beractant) use in the treatment of term infants with severe respiratory failure. J Pediatr. 1998;132:40-47.
22. Dekowski S, Holtzman R. Surfactant replacement therapy. An update on applications. Pediatr Clin North Am. 1998;45:549-572.
23. Anzueto A, Baughman RP, Guntupalli KK, et al. Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. N Engl J Med. 1996;334:1417-1421.
24. MacIntyre N, Coleman R, Schuller F, Zaccardelli D, Pattishall E. Efficiency of the delivery of aerosolized artificial surfactant in intubated patients with adult respiratory distress syndrome. Am J Respir Crit Care Med. 1994;149:A125.
25. Gregory TJ, Steinberg KP, Spragg R, et al. Bovine surfactant therapy for patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 1997;155:1309-1315.
26. Walmrath D, Gunther A, Ghofrani
HA, et al. Bronchoscopic surfactant administration in patients with severe adult respiratory distress syndrome and sepsis. Am J Respir Crit Care Med. 1996;154:57-62.
27. Willson D, Bauman L, Zaritsky A, et al. Instillation of calf lung surfactant extract (Calfactant) is beneficial in pediatric acute hypoxemic respiratory failure. Crit Care Med. 1999. In press.
28. Erasmus M, Petersen A, Hofstede G, et al. Surfactant treatment before reperfusion improves the immediate function of lung transplants in rats. Am J Respir Crit Care Med. 1996;153:665-670.
29. Novick RJ, MacDonald J, Veldhuizen RAW, et al. Evaluation of surfactant treatment strategies after prolonged graft storage in lung transplantation. Am J Respir Crit Care Med. 1996;154:98-104.
30. Hohlfeld J, Fabel H, Hamm H. The role of pulmonary surfactant in obstructive airways disease. Eur Respir J. 1997;10:482-91.
31. Anzueto A, Jubran A, Ohar J, et al. Effects of aerosolized surfactant in patients with stable chronic bronchitis: a prospective randomized controlled trial. JAMA. 1997;278:1426-1431.
32. Katkin J, Husser R, Langston C, Welty S. Exogenous surfactant enhances the delivery of recombinant adenoviral vectors to the lung. Hum Gene Ther. 1997;8:171-176. r