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Surfactant therapy: past, present and future
Early Human Development 89S1 (2013) S22–S24
Contents lists available at ScienceDirect
Early Human Development j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev
Surfactant therapy: past, present and future Christian P. Speer a, *, David G. Sweet b , Henry L. Halliday b a University b Regional
Children’s Hospital, University of W¨ urzburg, W¨ urzburg, Germany Neonatal Unit, Royal Maternity Hospital, Belfast, Northern Ireland, UK
article info
summary
Keywords: Surfactant Respiratory distress syndrome Neonates
Surfactant replacement in preterm infants with respiratory distress syndrome (RDS) has been a major therapeutic breakthrough and the most intensively studied intervention in neonatal medicine. Surfactant whether given prophylactically in the delivery room or in babies with established RDS reduces the severity of RDS, the incidence of air leaks and pneumothorax and, most importantly, neonatal death. Many randomized controlled trials have explored different strategies to optimize the effect of surfactant administration and have further improved neonatal outcome. Whenever indicated, surfactant should be administered as early as possible in the course of the RDS. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction In 1959 Avery and Mead showed that surfactant deficiency was a key feature in the pathogenesis of neonatal RDS. Thirteen years later, Enhorning and Robertson were the first to demonstrate that surfactant treatment in preterm rabbits normalized lung function and histology [1]. In 2001 Fujiwara and colleagues reported that the intratracheal administration of a modified bovine surfactant in preterm infants with severe RDS resulted in a striking improvement in gas exchange [1]. After this sensational report more than 30 randomized controlled trials have shown that administration of natural or synthetic surfactant results in pronounced reduction in the incidence of pneumothorax and neonatal mortality. Most of these studies were performed in an era of low antenatal corticosteroid use [1]. In this brief review we will summarize the pivotal role of natural surfactant therapy in neonatal RDS and where possible show recommendations based on the European guidelines for management of RDS [2]. A more extensive review has been published recently [3]. Surfactant is the first drug developed only for the treatment of neonates.
indicate that larger doses are more effective (see [3]). A phospholipid dose of at least 100 mg/kg is required. With the development of RDS, serum-derived protein inhibitors and inflammatory mediators may inactivate the surfactant system; as a consequence more surfactant is needed to overcome this inhibition [4]. Several small studies have compared the recommended doses of poractant alfa of 200 mg/kg with beractant 100 mg/kg, and a recent meta-analysis suggests a reduction in mortality favouring the higher dose of poractant alfa (typical relative risk [RR] 0.29; 95% confidence interval [CI], 0.10–0.79) [5]. 3. Multiple doses Preterm infants with severe RDS benefit from allowing multiple doses of surfactant rather than limiting to a single dose in terms of reducing mortality and the incidence of pneumothorax (see [3]). Previously, rigid re-dosing protocols were used in many trials; however, in clinical practice retreatment should be individualized and based on the baby’s residual lung disease and oxygen requirement. 4. Timing of initial surfactant administration
2. Initial dose Although the optimal dose of surfactant has not been clearly defined, a number of clinical and pharmacokinetic studies * Corresponding author. Christian P. Speer, MD, FRCPE, Professor of Pediatrics, Director and Chairman, University Children’s Hospital, JosefSchneider-Str. 2, 97080 Wuerzburg, Germany. Tel.: +49 931 201 27830; fax: +49 931 201 27833. E-mail address: [email protected] (C.P. Speer). 0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved.
A number of well-designed trials compared prophylactic surfactant administration within 15 minutes after birth with rescue treatment. The results of individual studies and meta-analysis clearly indicated that prophylactic surfactant administration reduced neonatal mortality as well as the rate of pneumothoraxes and interstitial emphysema when compared with later rescue treatment (see [3]). In particular, very immature preterm infants <28 weeks of gestation were shown to benefit from a prophylactic strategy which has
C.P. Speer et al. / Early Human Development 89S1 (2013) S22–S24
S23
Table 1 Adjusted recommendations of surfactant administration according to the European Guidelines for Management of Neonatal Respiratory Distress Syndrome in Preterm Infants – 2013 update [2] 1.
Preterm infants with RDS should be given a natural surfactant preparation as early as possible.
2.
A policy of early rescue surfactant should be standard but there are occasions when surfactant should be administered in the delivery suite, such as extremely preterm infants in whom the mother has not had antenatal steroids or those who require intubation for stabilization.
3.
Preterm infants with RDS should be given rescue surfactant early in the course of the disease. A suggested protocol would be to treat extremely preterm infants <26 weeks’ gestation when FiO2 requirements >0.30 and babies >26 weeks when FiO2 requirements >0.40.
4.
Poractant alfa in an initial dose of 200 mg/kg is better than 100 mg/kg of poractant alfa or beractant for rescue therapy.
5.
CPAP should be started early, preferably in the delivery suite for infants of gestational age less than 30 weeks.
6.
For those who require mechanical ventilation, aim to ventilate for as short a time as possible, avoiding hyperoxia, hypocapnia and volutrauma.
7.
A second, and sometimes a third dose of surfactant should be administered if there is evidence of ongoing RDS such as a persistent oxygen requirement and need for mechanical ventilation.
become a routine approach in many neonatal units worldwide (see [2,3]). With prophylactic surfactant administration, however, a considerable number of preterm infants may be intubated and receive surfactant unnecessarily, as the degree of lung maturity is unknown. Therefore the issue of timing of surfactant administration has continued to cause debate among neonatologists, particularly as many high-risk babies now benefit from antenatal steroids and immediate initiation of CPAP (continuous positive airway pressure) in the delivery suite. In fact, recent trials which reflect current practice including greater utilization of antenatal steroids demonstrate that early initiation of CPAP and selective surfactant administration is associated with less chronic lung disease and death when compared with prophylactic surfactant [6]. However, it must be borne in mind that in these trials very immature preterm infants were recruited antenatally or included as a selected group of babies who were not primarily intubated after birth. These high-risk babies were either born in optimal condition or had uncomplicated postnatal stabilization. The results of these trials may neither be generalizable to all very immature preterm infants nor to specific situations of individual neonatal intensive care units. Babies who require immediate intubation for stabilization in the delivery suite, should receive surfactant before the diagnosis of RDS is clinically confirmed. The general recommendation is that surfactant replacement therapy should be used as early as possible in the evolution of RDS (see [2,3]). 5. Surfactant administration technique In most clinical trials the standard method of surfactant administration was bolus instillation via an endotracheal tube or a thin catheter inserted into the endotracheal tube. Following surfactant administration the babies were maintained on mechanical ventilation. Nearly 20 years ago, a group of Danish neonatologists impressively demonstrated that immediately after bolus instillation of surfactant extubation to CPAP was possible and well tolerated by many babies [7]. This strategy of “INSURE” (INtubate–SURfactant–Extubate to CPAP) has been studied in a number of small randomized trials and shown to reduce need for mechanical ventilation and rate of BPD (see [2,3]). This technique is especially effective in avoiding mechanical ventilation if the decision to use INSURE is made early in the course of the RDS [8]. Moreover, in resourcelimited institutions use of nasal CPAP and INSURE together with antenatal steroids improved survival of extremely low birth weight infants [9]. More recent data from randomized trials have demonstrated that surfactant can be effectively delivered intratracheally whilst avoiding traditional intubation with an endotracheal tube. Instead, a fine catheter is inserted
into the trachea of spontaneously breathing preterm infants on CPAP and surfactant is administered through it without “bagging” it in. This technique reduced the number of days on mechanical ventilation but no effect on neonatal outcome could be demonstrated [10,11]. Since this strategy needs intensive and long-term training of all personnel involved, it should probably be restricted to centers which are dedicated to further evaluation of this technique in further randomized clinical trials. A possible future alternative to manage babies with RDS on CPAP is surfactant administration by modern membrane nebulizers [12]. 6. Surfactant preparations Several surfactant preparations, both synthetic (which are protein-free) and natural (which are from bovine or porcine origin), have been studied in direct randomized comparative trials and subjected to Cochrane systematic review. The metaanalysis showed an improved outcome of preterm infants with RDS who had been treated with natural surfactants. Natural preparations resulted in fewer pneumothoraxes (RR 0.63; 95% CI 0.53–0.75) and a reduction in mortality (RR 0.87; 95% CI 0.76–0.98) (see [3]). Currently, only three natural surfactant preparations are available in Europe: the bovine preparations beractant and bovactant as well as the porcine preparation poractant alfa. Small trials comparing beractant with poractant alfa as rescue therapy showed a more rapid improvement in oxygenation and a trend towards reduced mortality. Overall there were significant reductions in deaths and need for re-dosing in babies with RDS treated with an initial dose of poractant alfa of 200 mg/kg compared to initial doses of beractant or poractant alfa of 100 mg/kg [5]. 7. Perspective Despite improvements in non-invasive respiratory care of preterm infants, surfactant therapy remains the cornerstone of the successful management of RDS. Practical recommendations for surfactant administration are summarized in Table 1. In the future, a new generation of synthetic surfactants containing protein analogues which are more resistant to inactivation might provide an interesting alternative to natural surfactant preparations. Surfactant inactivation is a key feature in the pathogenesis of respiratory diseases of the newborn such as neonatal pneumonia, meconium aspiration syndrome and other acute respiratory distress syndromes [13]. Surfactant may also be used more extensively as a vehicle to deliver drugs such as corticosteroids directly to the lung. A Taiwanese pilot study of a bovine surfactant preparation containing budesonide demonstrated promising results: a lower incidence of the
S24
C.P. Speer et al. / Early Human Development 89S1 (2013) S22–S24
combined outcome of mortality and BPD and no long-term adverse effects [14]. Moreover, since surfactant preparations demonstrate a variety of anti-inflammatory and immunomodulatory properties, a new generation of synthetic surfactants may be tailored to counteract the injurious inflammatory process in the lung of very immature preterm infants and thus reduce the incidence and severity of BPD [15]. In addition, the pulmonary host defense of very immature infants may benefit from surfactant preparations which are enriched with powerful soluble factors of the innate immune system [16]. Conflict of interest statement C.P. Speer and H.L. Halliday are consultants for Chiesi Farmaceutici S.p.A. (Italy). D.G. Sweet has no conflict of interest. References 1. Halliday HL. History of surfactant from 1980. Biol Neonate 2005;87:317–22. 2. Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Plavka R, et al. European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants – 2013 update. Neonatology 2013;103:353–68. 3. Speer CP, Sweet DG. Surfactant replacement: present and future. In: Bancalari E, editor. The Newborn Lung, 2nd edition. Philadelphia: Elsevier Saunders; 2012, pp. 283–99. 4. Speer CP. Neonatal respiratory distress syndrome (RDS): an inflammatory disease? Neonatology 2011;99:316–9. 5. Singh N, Hawley KL, Viswanathan K. Efficacy of porcine versus bovine surfactants for preterm newborns with respiratory distress syndrome: systematic review and meta-analysis. Pediatrics 2011;128:e1588–95.
6. Rojas-Reyes MX, Morley CJ, Soll R. Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2012;(3):CD000510. 7. Verder H, Robertson B, Greisen G, Ebbesen F, Albertsen P, Lundstrøm K, et al. Surfactant therapy and nasal continuous positive airway pressure for newborns with respiratory distress syndrome. Danish–Swedish Multicenter Study Group. N Engl J Med 1994;331(16):1051–5. 8. Rojas MA, Lozano JM, Rojas MX, Laughon M, Bose CL, Rondon MA, et al.; Colombian Neonatal Research Network. Very early surfactant without mandatory ventilation in premature infants treated with early continuous positive airway pressure: a randomized, controlled trial. Pediatrics 2009;123: 137–42. 9. Kirsten GF, Kirsten CL, Henning PA, Smith J, Holgate SL, Bekker A, et al. The outcome of ELBW infants treated with NCPAP and INSURE in a resourcelimited institution. Pediatrics 2012;129:e952–9. 10. Gopel ¨ W, Kribs A, Ziegler A, Laux R, Hoehn T, Wieg C, et al.; German Neonatal Network. Avoidance of mechanical ventilation by surfactant treatment of spontaneously breathing preterm infants (AMV): an open-label, randomised, controlled trial. Lancet 2011;378:1627–34. 11. Dargaville PA. Innovation in surfactant therapy I: surfactant lavage and surfactant administration by fluid bolus using minimally invasive techniques. Neonatology 2012;101(4):326–36. 12. Pillow JJ, Minocchieri S. Innovation in surfactant therapy II: surfactant administration by aerosolization. Neonatology 2012;101(4):337–44. 13. Wirbelauer J, Speer CP. The role of surfactant treatment in preterm infants and term newborn with acute respiratory distress syndrome (ARDS). J Perinatol 2009;29:S18–22. 14. Kuo HT, Lin HC, Tsai CH, Chouc IC, Yeh TF. A follow-up study of preterm infants given budesonide using surfactant as a vehicle to prevent chonic lung disease in preterm infants. J Pediatr 2010;156:537–41. 15. Bersani I, Kunzmann S, Speer CP. Immunomodulatory properties of surfactant preparations. Expert Rev Anti Infect Ther 2013;11(1):99–110. 16. Bersani I, Speer CP, Kunzmann S. Surfactant protein A and D in pulmonary diseases of preterm infants. Expert Rev Anti Infect Ther 2012;10(5):573–84.
Contents lists available at ScienceDirect
Early Human Development j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev
Surfactant therapy: past, present and future Christian P. Speer a, *, David G. Sweet b , Henry L. Halliday b a University b Regional
Children’s Hospital, University of W¨ urzburg, W¨ urzburg, Germany Neonatal Unit, Royal Maternity Hospital, Belfast, Northern Ireland, UK
article info
summary
Keywords: Surfactant Respiratory distress syndrome Neonates
Surfactant replacement in preterm infants with respiratory distress syndrome (RDS) has been a major therapeutic breakthrough and the most intensively studied intervention in neonatal medicine. Surfactant whether given prophylactically in the delivery room or in babies with established RDS reduces the severity of RDS, the incidence of air leaks and pneumothorax and, most importantly, neonatal death. Many randomized controlled trials have explored different strategies to optimize the effect of surfactant administration and have further improved neonatal outcome. Whenever indicated, surfactant should be administered as early as possible in the course of the RDS. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction In 1959 Avery and Mead showed that surfactant deficiency was a key feature in the pathogenesis of neonatal RDS. Thirteen years later, Enhorning and Robertson were the first to demonstrate that surfactant treatment in preterm rabbits normalized lung function and histology [1]. In 2001 Fujiwara and colleagues reported that the intratracheal administration of a modified bovine surfactant in preterm infants with severe RDS resulted in a striking improvement in gas exchange [1]. After this sensational report more than 30 randomized controlled trials have shown that administration of natural or synthetic surfactant results in pronounced reduction in the incidence of pneumothorax and neonatal mortality. Most of these studies were performed in an era of low antenatal corticosteroid use [1]. In this brief review we will summarize the pivotal role of natural surfactant therapy in neonatal RDS and where possible show recommendations based on the European guidelines for management of RDS [2]. A more extensive review has been published recently [3]. Surfactant is the first drug developed only for the treatment of neonates.
indicate that larger doses are more effective (see [3]). A phospholipid dose of at least 100 mg/kg is required. With the development of RDS, serum-derived protein inhibitors and inflammatory mediators may inactivate the surfactant system; as a consequence more surfactant is needed to overcome this inhibition [4]. Several small studies have compared the recommended doses of poractant alfa of 200 mg/kg with beractant 100 mg/kg, and a recent meta-analysis suggests a reduction in mortality favouring the higher dose of poractant alfa (typical relative risk [RR] 0.29; 95% confidence interval [CI], 0.10–0.79) [5]. 3. Multiple doses Preterm infants with severe RDS benefit from allowing multiple doses of surfactant rather than limiting to a single dose in terms of reducing mortality and the incidence of pneumothorax (see [3]). Previously, rigid re-dosing protocols were used in many trials; however, in clinical practice retreatment should be individualized and based on the baby’s residual lung disease and oxygen requirement. 4. Timing of initial surfactant administration
2. Initial dose Although the optimal dose of surfactant has not been clearly defined, a number of clinical and pharmacokinetic studies * Corresponding author. Christian P. Speer, MD, FRCPE, Professor of Pediatrics, Director and Chairman, University Children’s Hospital, JosefSchneider-Str. 2, 97080 Wuerzburg, Germany. Tel.: +49 931 201 27830; fax: +49 931 201 27833. E-mail address: [email protected] (C.P. Speer). 0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved.
A number of well-designed trials compared prophylactic surfactant administration within 15 minutes after birth with rescue treatment. The results of individual studies and meta-analysis clearly indicated that prophylactic surfactant administration reduced neonatal mortality as well as the rate of pneumothoraxes and interstitial emphysema when compared with later rescue treatment (see [3]). In particular, very immature preterm infants <28 weeks of gestation were shown to benefit from a prophylactic strategy which has
C.P. Speer et al. / Early Human Development 89S1 (2013) S22–S24
S23
Table 1 Adjusted recommendations of surfactant administration according to the European Guidelines for Management of Neonatal Respiratory Distress Syndrome in Preterm Infants – 2013 update [2] 1.
Preterm infants with RDS should be given a natural surfactant preparation as early as possible.
2.
A policy of early rescue surfactant should be standard but there are occasions when surfactant should be administered in the delivery suite, such as extremely preterm infants in whom the mother has not had antenatal steroids or those who require intubation for stabilization.
3.
Preterm infants with RDS should be given rescue surfactant early in the course of the disease. A suggested protocol would be to treat extremely preterm infants <26 weeks’ gestation when FiO2 requirements >0.30 and babies >26 weeks when FiO2 requirements >0.40.
4.
Poractant alfa in an initial dose of 200 mg/kg is better than 100 mg/kg of poractant alfa or beractant for rescue therapy.
5.
CPAP should be started early, preferably in the delivery suite for infants of gestational age less than 30 weeks.
6.
For those who require mechanical ventilation, aim to ventilate for as short a time as possible, avoiding hyperoxia, hypocapnia and volutrauma.
7.
A second, and sometimes a third dose of surfactant should be administered if there is evidence of ongoing RDS such as a persistent oxygen requirement and need for mechanical ventilation.
become a routine approach in many neonatal units worldwide (see [2,3]). With prophylactic surfactant administration, however, a considerable number of preterm infants may be intubated and receive surfactant unnecessarily, as the degree of lung maturity is unknown. Therefore the issue of timing of surfactant administration has continued to cause debate among neonatologists, particularly as many high-risk babies now benefit from antenatal steroids and immediate initiation of CPAP (continuous positive airway pressure) in the delivery suite. In fact, recent trials which reflect current practice including greater utilization of antenatal steroids demonstrate that early initiation of CPAP and selective surfactant administration is associated with less chronic lung disease and death when compared with prophylactic surfactant [6]. However, it must be borne in mind that in these trials very immature preterm infants were recruited antenatally or included as a selected group of babies who were not primarily intubated after birth. These high-risk babies were either born in optimal condition or had uncomplicated postnatal stabilization. The results of these trials may neither be generalizable to all very immature preterm infants nor to specific situations of individual neonatal intensive care units. Babies who require immediate intubation for stabilization in the delivery suite, should receive surfactant before the diagnosis of RDS is clinically confirmed. The general recommendation is that surfactant replacement therapy should be used as early as possible in the evolution of RDS (see [2,3]). 5. Surfactant administration technique In most clinical trials the standard method of surfactant administration was bolus instillation via an endotracheal tube or a thin catheter inserted into the endotracheal tube. Following surfactant administration the babies were maintained on mechanical ventilation. Nearly 20 years ago, a group of Danish neonatologists impressively demonstrated that immediately after bolus instillation of surfactant extubation to CPAP was possible and well tolerated by many babies [7]. This strategy of “INSURE” (INtubate–SURfactant–Extubate to CPAP) has been studied in a number of small randomized trials and shown to reduce need for mechanical ventilation and rate of BPD (see [2,3]). This technique is especially effective in avoiding mechanical ventilation if the decision to use INSURE is made early in the course of the RDS [8]. Moreover, in resourcelimited institutions use of nasal CPAP and INSURE together with antenatal steroids improved survival of extremely low birth weight infants [9]. More recent data from randomized trials have demonstrated that surfactant can be effectively delivered intratracheally whilst avoiding traditional intubation with an endotracheal tube. Instead, a fine catheter is inserted
into the trachea of spontaneously breathing preterm infants on CPAP and surfactant is administered through it without “bagging” it in. This technique reduced the number of days on mechanical ventilation but no effect on neonatal outcome could be demonstrated [10,11]. Since this strategy needs intensive and long-term training of all personnel involved, it should probably be restricted to centers which are dedicated to further evaluation of this technique in further randomized clinical trials. A possible future alternative to manage babies with RDS on CPAP is surfactant administration by modern membrane nebulizers [12]. 6. Surfactant preparations Several surfactant preparations, both synthetic (which are protein-free) and natural (which are from bovine or porcine origin), have been studied in direct randomized comparative trials and subjected to Cochrane systematic review. The metaanalysis showed an improved outcome of preterm infants with RDS who had been treated with natural surfactants. Natural preparations resulted in fewer pneumothoraxes (RR 0.63; 95% CI 0.53–0.75) and a reduction in mortality (RR 0.87; 95% CI 0.76–0.98) (see [3]). Currently, only three natural surfactant preparations are available in Europe: the bovine preparations beractant and bovactant as well as the porcine preparation poractant alfa. Small trials comparing beractant with poractant alfa as rescue therapy showed a more rapid improvement in oxygenation and a trend towards reduced mortality. Overall there were significant reductions in deaths and need for re-dosing in babies with RDS treated with an initial dose of poractant alfa of 200 mg/kg compared to initial doses of beractant or poractant alfa of 100 mg/kg [5]. 7. Perspective Despite improvements in non-invasive respiratory care of preterm infants, surfactant therapy remains the cornerstone of the successful management of RDS. Practical recommendations for surfactant administration are summarized in Table 1. In the future, a new generation of synthetic surfactants containing protein analogues which are more resistant to inactivation might provide an interesting alternative to natural surfactant preparations. Surfactant inactivation is a key feature in the pathogenesis of respiratory diseases of the newborn such as neonatal pneumonia, meconium aspiration syndrome and other acute respiratory distress syndromes [13]. Surfactant may also be used more extensively as a vehicle to deliver drugs such as corticosteroids directly to the lung. A Taiwanese pilot study of a bovine surfactant preparation containing budesonide demonstrated promising results: a lower incidence of the
S24
C.P. Speer et al. / Early Human Development 89S1 (2013) S22–S24
combined outcome of mortality and BPD and no long-term adverse effects [14]. Moreover, since surfactant preparations demonstrate a variety of anti-inflammatory and immunomodulatory properties, a new generation of synthetic surfactants may be tailored to counteract the injurious inflammatory process in the lung of very immature preterm infants and thus reduce the incidence and severity of BPD [15]. In addition, the pulmonary host defense of very immature infants may benefit from surfactant preparations which are enriched with powerful soluble factors of the innate immune system [16]. Conflict of interest statement C.P. Speer and H.L. Halliday are consultants for Chiesi Farmaceutici S.p.A. (Italy). D.G. Sweet has no conflict of interest. References 1. Halliday HL. History of surfactant from 1980. Biol Neonate 2005;87:317–22. 2. Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Plavka R, et al. European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants – 2013 update. Neonatology 2013;103:353–68. 3. Speer CP, Sweet DG. Surfactant replacement: present and future. In: Bancalari E, editor. The Newborn Lung, 2nd edition. Philadelphia: Elsevier Saunders; 2012, pp. 283–99. 4. Speer CP. Neonatal respiratory distress syndrome (RDS): an inflammatory disease? Neonatology 2011;99:316–9. 5. Singh N, Hawley KL, Viswanathan K. Efficacy of porcine versus bovine surfactants for preterm newborns with respiratory distress syndrome: systematic review and meta-analysis. Pediatrics 2011;128:e1588–95.
6. Rojas-Reyes MX, Morley CJ, Soll R. Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2012;(3):CD000510. 7. Verder H, Robertson B, Greisen G, Ebbesen F, Albertsen P, Lundstrøm K, et al. Surfactant therapy and nasal continuous positive airway pressure for newborns with respiratory distress syndrome. Danish–Swedish Multicenter Study Group. N Engl J Med 1994;331(16):1051–5. 8. Rojas MA, Lozano JM, Rojas MX, Laughon M, Bose CL, Rondon MA, et al.; Colombian Neonatal Research Network. Very early surfactant without mandatory ventilation in premature infants treated with early continuous positive airway pressure: a randomized, controlled trial. Pediatrics 2009;123: 137–42. 9. Kirsten GF, Kirsten CL, Henning PA, Smith J, Holgate SL, Bekker A, et al. The outcome of ELBW infants treated with NCPAP and INSURE in a resourcelimited institution. Pediatrics 2012;129:e952–9. 10. Gopel ¨ W, Kribs A, Ziegler A, Laux R, Hoehn T, Wieg C, et al.; German Neonatal Network. Avoidance of mechanical ventilation by surfactant treatment of spontaneously breathing preterm infants (AMV): an open-label, randomised, controlled trial. Lancet 2011;378:1627–34. 11. Dargaville PA. Innovation in surfactant therapy I: surfactant lavage and surfactant administration by fluid bolus using minimally invasive techniques. Neonatology 2012;101(4):326–36. 12. Pillow JJ, Minocchieri S. Innovation in surfactant therapy II: surfactant administration by aerosolization. Neonatology 2012;101(4):337–44. 13. Wirbelauer J, Speer CP. The role of surfactant treatment in preterm infants and term newborn with acute respiratory distress syndrome (ARDS). J Perinatol 2009;29:S18–22. 14. Kuo HT, Lin HC, Tsai CH, Chouc IC, Yeh TF. A follow-up study of preterm infants given budesonide using surfactant as a vehicle to prevent chonic lung disease in preterm infants. J Pediatr 2010;156:537–41. 15. Bersani I, Kunzmann S, Speer CP. Immunomodulatory properties of surfactant preparations. Expert Rev Anti Infect Ther 2013;11(1):99–110. 16. Bersani I, Speer CP, Kunzmann S. Surfactant protein A and D in pulmonary diseases of preterm infants. Expert Rev Anti Infect Ther 2012;10(5):573–84.