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  • Original Article
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Surfactants: past, present and future

Abstract

In 1929 Kurt von Neergaard performed experiments suggesting the presence of pulmonary surfactant and its relevance to the newborn's first breath. Almost 25 years later, Richard Pattle, John Clements and Chris Macklin, each working on the effects of nerve gases on the lungs, contributed to the understanding of the physiology of pulmonary surfactant. About 5 years later Mary Ellen Avery and Jere Mead published convincing evidence that preterm neonates dying of hyaline membrane disease (respiratory distress syndrome, RDS) had a deficiency of pulmonary surfactant. The first trials of nebulized synthetic (protein-free) surfactant to prevent RDS were published soon after Patrick Bouvier Kennedy (son of President John F Kennedy) died of this disorder after treatment in Boston. These trials were unsuccessful; however, Goran Enhorning and Bengt Robertson in the early 1970s demonstrated that natural surfactants (containing proteins) were effective in an immature rabbit model of RDS. Soon after this Forrest Adams showed that a natural surfactant was also effective in an immature lamb model. Working with him was Tetsuro Fujiwara who 2 years later, after returning to Japan, published the seminal article reporting the responses of 10 preterm infants with RDS to a bolus of modified bovine surfactant. During the 1980s there were numerous randomized controlled trials of many different natural and synthetic surfactants, demonstrating reductions in pulmonary air leaks and neonatal mortality. Subsequently natural surfactants were shown to be superior to the protein-free synthetic products. Recently there have been a number of randomized trials comparing different natural surfactant preparations. Commercially available bovine surfactants may have similar efficacy but there is some evidence that a porcine surfactant used to treat RDS with an initial dose of 200 mg per kg is more effective than a bovine surfactant used in an initial dose of 100 mg per kg. Bovine and porcine surfactants have not been compared in trials of prophylaxis. Very recently a new synthetic surfactant with a surfactant protein mimic has been compared with other commercially available natural and synthetic surfactants in two trials. The new surfactant may be superior to one of the older protein-free synthetic surfactants but there is no evidence of its superiority over established natural products and it is currently not approved for clinical use. A number of other new synthetic surfactants have been tested in animal models or in treatment of adults with ARDS, but so far there have been no reports of treatment of neonatal RDS. Natural surfactants work best if given by a rapid bolus into the lungs but less invasive methods such as a laryngeal mask, pharyngeal deposition or rapid extubation to CPAP have showed promise. Unfortunately, delivery of surfactant by nebulization has so far been ineffective. Surfactant treatment has been tried in a number of other neonatal respiratory disorders but only infants with meconium aspiration seem to benefit although larger and more frequent doses are probably needed to demonstrate improved lung function. A surfactant protocol based upon early treatment and CPAP is suggested for very preterm infants. Earlier treatment may improve survival rates for these infants; however, there is a risk of increasing the prevalence of milder forms of chronic lung disease. Nevertheless, surfactant therapy has been a major contribution to care of the preterm newborn during the past 25 years.

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References

  1. Von Neergaard K . Neue auffassungen uber einen grundbegriff der atemmechanik. Die retraktionskraft der lunge, abhangig von der oberflachenspannung in den alveolen. Z Gesamt Exp Med 1929; 66: 373–394.

    Article  Google Scholar 

  2. Gruenwald P . Surface tension as a factor in the resistance of neonatal lungs to aeration. Am J Obstet Gynecol 1947; 53: 996–1007.

    Article  CAS  Google Scholar 

  3. Pattle RE . Properties, function and origin of the alveolar lining layer. Nature 1955; 175: 1125–1126.

    Article  CAS  Google Scholar 

  4. Clements JA . Dependence of pressure-volume characteristics of lungs on intrinsic surface active material. Am J Physiol 1956; 187: 592.

    Google Scholar 

  5. Clements JA . Surface tension of lung extracts. Proc Soc Exp Biol Med 1957; 95: 170–172.

    Article  CAS  Google Scholar 

  6. Macklin CC . The pulmonary alveolar mucoid film and the pneumonocytes. Lancet 1954; i: 1099–1104.

    Article  Google Scholar 

  7. Obladen M . History of surfactant up to 1980. Biol Neonate 2005; 87: 308–316.

    Article  CAS  Google Scholar 

  8. Avery ME, Mead J . Surface properties in relation to atelectasis and hyaline membrane disease. Am J Dis Child 1959; 97: 517–523.

    CAS  Google Scholar 

  9. Robillard E, Alarie Y, Dagenais-Perusse P, Baril E, Guilbeault A . Microaerosol administration of synthetic beta-gamma-dipalmitoyl-L-alpha-lecithin in the respiratory distress syndrome. A preliminary report. Can Med Assoc J 1964; 90: 55–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Chu J, Clements JA, Cotton EK, Klaus MH, Sweet AY, Tooley WH . Neonatal pulmonary ischemia: clinical and physiologic studies. Pediatrics 1967; 40: 709–782.

    Google Scholar 

  11. Enhorning G, Robertson B . Lung expansion in the premature rabbit fetus after tracheal deposition of surfactant. Pediatrics 1972; 50: 58–66.

    CAS  PubMed  Google Scholar 

  12. Enhorning G, Grossmann G, Robertson B . Pharyngeal deposition of surfactant in the premature rabbit fetus. Biol Neonate 1973; 22: 126–132.

    Article  CAS  Google Scholar 

  13. Adams FH, Towers B, Osher AB, Ikegami M, Fujiwara T, Nozaki M . Effects of tracheal instillation of natural surfactant in premature lambs. I. Clinical and autopsy findings. Pediatr Res 1978; 12: 841–848.

    Article  CAS  Google Scholar 

  14. Fujiwara T, Chida S, Watabe YJ, Maeta H, Morita T, Abe T . Artificial surfactant therapy in hyaline membrane disease. Lancet 1980; i: 55–59.

    Article  Google Scholar 

  15. Robertson B, Curstedt T, Johansson J, Jornvall H, Kobayashi T . Structural and functional characterization of porcine surfactant isolated by liquid-gel chromatography. Prog Resp Res 1990; 25: 237–246.

    Article  Google Scholar 

  16. Halliday HL . Overview of clinical trials comparing natural and synthetic surfactants. Biol Neonate 1995; 67 (suppl 1): 32–47.

    Article  Google Scholar 

  17. Merritt TA, Hallman M, Bloom BT, Berry C, Benirschke K, Sahn D et al. Prophylactic treatment of very premature infants with human surfactant. N Engl J Med 1986; 315: 785–790.

    Article  CAS  Google Scholar 

  18. Halliday HL . History of surfactant from 1980. Biol Neonate 2005; 87: 317–322.

    Article  CAS  Google Scholar 

  19. Soll RF . Prophylactic natural surfactant extract for preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev 1997; 4: CD000511.

    Google Scholar 

  20. Soll RF . Prophylactic synthetic surfactant for preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev 1998; 2: CD001079.

    Google Scholar 

  21. Soll RF . Synthetic surfactant for respiratory distress syndrome in preterm infants. Cochrane database. Syst Rev 1998; 3: CD001149.

    Google Scholar 

  22. Soll RF . Multiple versus single dose natural surfactant extract for severe neonatal respiratory distress syndrome. Cochrane Database Syst Rev 1999; 2: CD000141.

    Google Scholar 

  23. Yost CC, Soll RF . Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Cochrane Database Syst Rev 1999; 4: CD001456.

    Google Scholar 

  24. Soll RF, Morley CJ . Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2001; 2: CD000510.

    Google Scholar 

  25. Soll RF, Blanco F . Natural surfactant extract versus synthetic surfactant for neonatal respiratory distress syndrome. Cochrane Database Syst Rev 2001; 2: CD0014444.

    Google Scholar 

  26. Stevens TP, Blennow M, Soll RF . Early surfactant treatment with brief ventilation versus selective surfactant and continued mechanical ventilation for preterm infants with or at risk of respiratory distress syndrome. Cochrane Database Syst Rev 2004; 3: CD003063.

    Google Scholar 

  27. Ramanathan R, Rasmussen MR, Gerstman DR, Finer N, Sekar K, North American Study Group et al. A randomized, multicenter masked comparison trial of poractant alfa (Curosurf) versus beractant (Survanta) in the treatment of respiratory distress syndrome in preterm infants. Am J Perinatol 2004; 21: 109–119.

    Article  Google Scholar 

  28. Bloom BT, Kattwinkel J, Hall RT, Delmore PM, Egan EA, Trout JR et al. Comparison of Infasurf (calf lung surfactant extract) to Survanta (beractant) in the treatment and prevention of respiratory distress syndrome. Pediatrics 1997; 100: 31–38.

    Article  CAS  Google Scholar 

  29. Bloom BT, Clark RH, Infasurf Survanta Clinical Trial Group. Comparison of Infasurf (calfactant) and Survanta (beractant) in the prevention and treatment of respiratory distress syndrome. Pediatrics 2005; 116: 392–399.

    Article  Google Scholar 

  30. Van Overmeire B, Jansens J, van Reempts PJ . Comparative evaluation of the respiratory and circulatory responses after instillation of two bovine surfactant preparations. Pediatr Res 1999; 45: 324A (abstract 1912).

    Article  Google Scholar 

  31. Griese M, Dietrich P, Reinhardt D . Pharmacokinetics of bovine surfactant in neonatal respiratory distress syndrome. Am J Respir Crit Care Med 1995; 152: 1050–1054.

    Article  CAS  Google Scholar 

  32. Speer CP, Gefeller O, Groneck P, Laufkötter E, Roll C, Hanssler L et al. Randomised clinical trial of two treatment regimens of natural surfactant preparations in neonatal respiratory distress syndrome. Arch Dis Child Fetal Neonatal Ed 1995; 72: F8–F13.

    Article  CAS  Google Scholar 

  33. Malloy CA, Nicoski P, Muraskas JK . A randomised trial comparing beractant and poractant treatment in neonatal respiratory distress syndrome. Acta Paediatr 2005; 94: 779–784.

    Article  Google Scholar 

  34. Bhatia J, Saunders WB, Friedlich P, Lavin PT, Sekar KC, Ramanathan R . Differences in mortality among infants treated with three different natural surfactants for respiratory distress syndrome. Neonatology 2007; 91: 324.

    Google Scholar 

  35. Moya FR, Gadzinowski J, Bancalari E, Salinas V, Kopelman B, Bancalari A et al. A multicenter, randomised, masked, comparison trial of lucinactant, colfosceril palmitate, and beractant for the prevention of respiratory distress syndrome among very preterm infants. Pediatrics 2005; 115: 1018–1029.

    Article  Google Scholar 

  36. Sinha SK, Lacaze-Masmonteil T, Valls-I-Soler A, Wiswell TE, Gadzinowski J, Hajdu J, Surfaxin Therapy Against Respiratory Distress Syndrome Collaborative Group et al. A multicenter, randomised, controlled trial of lucinactant versus poractant alfa among very premature infants at high risk for respiratory distress syndrome. Pediatrics 2005; 115: 1030–1038.

    Article  Google Scholar 

  37. Halahakoon CW . A study of cerebral function following surfactant treatment for respiratory distress syndrome MD thesis, Queen's University, Belfast, 1999.

  38. Baroutis G, Kaleyias J, Liarou T, Papathoma E, Hatzistmatiou Z, Costalos C . Comparison of three treatment regimens of natural surfactant preparations in neonatal respiratory distress syndrome. Eur J Pediatr 2003; 162: 476–480.

    Article  CAS  Google Scholar 

  39. Collaborative European Multicenter Study Group. Surfactant replacement therapy for severe neonatal respiratory distress syndrome: an international randomized clinical trial. Pediatrics 1988; 82: 683–691.

    Google Scholar 

  40. Curstedt T, Johannson J . New synthetic surfactant—how and when? Biol Neonate 2006; 89: 336–339.

    Article  Google Scholar 

  41. Walther FJ, Hernandez-Juviel JM, Gordon LM, Waring AJ, Stenger P, Zasadzinski JA . Comparison of three lipid formulations for synthetic surfactant with a surfactant protein B analog. Exp Lung Res 2005; 31: 563–579.

    Article  CAS  Google Scholar 

  42. Walther FJ, Waring AJ, Sherman MA, Zasadzinski JA, Gordon LM . Hydrophobic surfactant proteins and their analogues. Neonatology 2007; 91: 303–310.

    Article  CAS  Google Scholar 

  43. Spragg RG, Lewis JF, Walmrath HD, Johannigman J, Bellingan G, Laterre PF et al. Effect of recombinant surfactant protein C-based surfactant on the acute respiratory distress syndrome. N Engl J Med 2004; 351: 884–892.

    Article  CAS  Google Scholar 

  44. Kattwinkel J . Synthetic surfactants: the search goes on. Pediatrics 2005; 115: 1075–1076.

    Article  Google Scholar 

  45. Phibbs RH, Ballard RA, Clements JA, Heilbron DC, Phibbs CS, Schlueter MA et al. Initial clinical trial of Exosurf, protein-free synthetic surfactant, for the prophylaxis and early treatment of hyaline membrane disease. Pediatrics 1991; 88: 1–9.

    CAS  PubMed  Google Scholar 

  46. Long W, Thompson T, Sundell H, Schumacher R, Volberg F, Guthrie R . Effects of two rescue doses of a synthetic surfactant on mortality rate and survival without bronchopulmonary dysplasia in 700–1350-gram infants with respiratory distress syndrome. J Pediatr 1991; 118: 595–605.

    Article  CAS  Google Scholar 

  47. Valls-i-Soler A, Fernandez-Ruanova B, Lopez-Heredia Y, Goya J, Roman-Etxebarral L, Rodriguez-Soriano J et al. A randomised comparison of surfactant dosing via a dual-lumen endotracheal tube in respiratory distress syndrome. Pediatrics 1998; 101: E4.

    Article  CAS  Google Scholar 

  48. Berggren P, Liljedahl M, Winblath B, Andreasson B, Curstedt T, Robertson B et al. Pilot study of nebulized surfactant therapy for neonatal respiratory distress syndrome. Acta Paediatr 2000; 89: 460–464.

    Article  CAS  Google Scholar 

  49. Verder H, Albertsen P, Ebbesen F, Greisen G, Robertson B, Bertelsen A et al. Nasal continuous positive airway pressure and early surfactant therapy for respiratory distress syndrome in newborns of <30 weeks’ gestation. Pediatrics 1999; 103: E24.

    Article  CAS  Google Scholar 

  50. Kattwinkel J, Robinson M, Bloom BT, Delmore P, Ferguson JE . Technique for intrapartum administration of surfactant without requirement for an endotracheal tube. J Perinatol 2004; 24: 360–365.

    Article  CAS  Google Scholar 

  51. Trevisanuto D, Grazzina N, Ferrarese P, Micaglio M, Verghese C, Zanardo V . Laryngeal mask airway used as a delivery conduit for the administration of surfactant to preterm infants with respiratory distress syndrome. Biol Neonate 2005; 87: 217–220.

    Article  CAS  Google Scholar 

  52. Findlay RD, Taeusch HW, Walther FJ . Surfactant replacement therapy for meconium aspiration syndrome. Pediatrics 1996; 97: 48–52.

    CAS  PubMed  Google Scholar 

  53. Herting E, Gefeller O, Land M, van Sonderen L, Harms K, Robertson B . Surfactant treatment of neonates with respiratory failure and group B streptococcal infection. Pediatrics 2000; 106: 957–964.

    Article  CAS  Google Scholar 

  54. Bos AP, Tibboel D, Hazelrock FW, Malenaar JC, Lachmann B, Gommes D . Surfactant replacement therapy in high-risk congenital diaphragmatic hernia. Lancet 1991; 338: 1279.

    Article  CAS  Google Scholar 

  55. Lotze A, Knight GR, Martin GR, Bulas DI, Hull WM, O’Donnell RM et al. Improved pulmonary outcome after exogenous surfactant therapy for respiratory failure in term infants requiring extracorporeal membrane oxygenation. J Pediatr 1993; 122: 261–268.

    Article  CAS  Google Scholar 

  56. Khammash H, Perlman M, Wojtulewicz J, Dunn M . Surfactant therapy in full-term neonates with severe respiratory failure. Pediatrics 1993; 92: 135–139.

    CAS  PubMed  Google Scholar 

  57. Pandit PB, Dunn MS, Kelly EN, Perlman M . Surfactant replacement in neonates with early chronic lung disease. Pediatrics 1995; 96: 851–854.

    Google Scholar 

  58. Pandit PB, O’Brien K, Asztalos E, Colucci E, Dunn MS . Outcome following pulmonary haemorrhage in very low birthweight neonates treated with surfactant. Arch Dis Child Fetal Neonatal Ed 1999; 81: F40–F44.

    Article  CAS  Google Scholar 

  59. Yeh TF, Su BH, Chang CH, Lin HC, Tsai CH, Pyati S et al. Early intratracheal instillation of budesonide by using surfactant (Survanta) as a vehicle to preterm infants at risk for chronic lung disease. PAS Meeting, San Francisco (3724. 1). 2006.

  60. Egberts J, Brand R, Walti H, Bevilacqua G, Breart G, Gardini F . Mortality, severe respiratory distress syndrome and chronic lung disease of the newborn are reduced more after prophylactic than therapeutic administration of the surfactant Curosurf. Pediatrics 1997; 100: E4.

    Article  CAS  Google Scholar 

  61. Walti H, Paris-Llado J, Egberts J, Brand R, Bevilacqua G, Gardini F et al. Prophylactic administration of porcine-derived lung surfactant is a significant factor in reducing the odds for peri-intraventricular haemorrhage in premature infants. Biol Neonate 2002; 81: 182–187.

    Article  CAS  Google Scholar 

  62. Sweet D, Bevilacqua G, Carnielli V, Greisen G, Plavka R, Saugstad OD et al. European consensus guidelines on the management of neonatal respiratory distress syndrome. J Perinat Med 2007; 35: 175–186.

    Article  Google Scholar 

  63. Horbar JD, Carpenter JH, Buzas J, Soll RF, Suresh G, Bracken MB et al. Collaborative quality improvement to promote evidence based surfactant for preterm infants: a cluster randomised trial. BMJ 2004; 329: 1004–1007.

    Article  Google Scholar 

  64. O’Neill CP, Sweet DG, Halliday HL . Changing pattern of surfactant use for extremely preterm infants over the past decade in Belfast. Biol Neonate 2005; 87: 357.

    Google Scholar 

  65. Sinn JKH, Ward MC, Henderson-Smart DJ . Developmental outcome of preterm infants after surfactant therapy: systematic review of randomised controlled trials. J Paediatr Child Health 2002; 38: 597–600.

    Article  CAS  Google Scholar 

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Correspondence to H L Halliday.

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This paper was supported from a grant from Dey, L.P. Dr. Halliday has received consultancy fees from Chiesi Farmaceutici for giving advice and has received honoraria for lecturing from Abbott, Burroughs-Wellcome, Dey and Chiesi. He also holds equity.

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Halliday, H. Surfactants: past, present and future. J Perinatol 28 (Suppl 1), S47–S56 (2008). https://doi.org/10.1038/jp.2008.50

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