Surfactant and surfactant therapy in neonates: from the beginning to the modern features of the application

Surfactant is a secreted surface-active substance that provides the first breath of the newborn by reducing the surface tension of the alveoli. Surfactant preparations were the first and most popular drugs in neonatology, saving the lives of millions of premature babies. Successful treatment with surfactants is preceded by an individual personalized approach to each child and early detection of newborns with surfactant deficiency. Determining the indications for surfactant therapy, choosing an effective method of drug delivery, selecting concomitant respiratory support are current areas of neonatology to this day. The article reflects the history of use, new approaches to surfactant therapy and methods of administration of various surfactant preparations.

1. Hallman M., Herting E. Historical perspective on surfactant therapy: Transforming hyaline membrane disease to respiratory distress syndrome. Semin Fetal Neonatal Med 2023; 28(6): 101493. DOI: 10.1016/j.siny.2023.101493

2. Halliday H.L. Surfactants: past, present and future. J Perinatol 2008; 28 Suppl 1(Suppl 1): S47–56. DOI: 10.1038/jp.2008.50

3. De Luca D., Loi B., Tingay D., Fiori H., Kingma P., Dellacà R. et al. Surfactant status assessment and personalized therapy for surfactant deficiency or dysfunction. Semin Fetal Neonatal Med 2023; 28(6): 101494. DOI: 10.1016/j.siny.2023.101494

4. Ишутина О.В. Сурфактантная система легких. Обзорная-статья. Вестник ВГМУ 2021; 20 (4): 7–17. [Ishutina O.V. Surfactant system of the lungs. Review article. Vestnik VGMU 2021; 20 (4): 7–17. (in Russ.)] DOI: 10.22263/2312–4156.2021.4.7

5. Verder H., Heiring C., Schousboe P. [Surfactant therapy of respiratory distress syndrome]. Ugeskr Laeger 2021; 183(44): V04210322. Danish.

6. Володин Н.Н. Неонатология: Национальное руководство в 2-х томах. Том 1. Н.Н. Володин, Д.Н. Дегтярева. М.: ГЭОТАР-Медиа, 2023;752 [N.N. Volodin. Neonatology: National manual in 2 volumes. Volume 1. N.N. Volodin, D.N. Degtyareva. M.: GEOTAR-Media, 2023; 752. (in Russ.)]

7. Lenyushkina A.A., Andreev A.V., Ionov O.V., Zubkov V.V. Review of recommendations for the management of newborns with respiratory distress syndrome. Neonatologiya: novosti, mneniya, obuchenie. 2024; 12(1): 84–99. (in Russ.) DOI: 10.33029/2308–2402–2024–12–1–84–99

8. Perepelitsa S.A. Acute respiratory distress syndrome in premature newborns (morphological study). Obshchaya reanimatologiya 2020; 16(1): 35–44. (in Russ.) DOI: 10.15360/1813–9779–2020–1–35–44

9. Peers de Nieuwburgh M., Wambach J.A., Griese M., Danhaive O. Towards personalized therapies for genetic disorders of surfactant dysfunction. Semin Fetal Neonatal Med 2023; 28(6): 101500. DOI: 10.1016/j.siny.2023.101500

10. Ramanathan R., Biniwale M., Sekar K., Hanna N., Golombek S., Bhatia J., et al. Synthetic Surfactant CHF5633 Compared with Poractant Alfa in the Treatment of Neonatal Respiratory Distress Syndrome: A Multicenter, Double-Blind, Randomized, Controlled Clinical Trial. J Pediatr 2020; 225: 90–96.e1. DOI: 10.1016/j.jpeds.2020.06.024

11. De Luca D., Yousef N. Pharmaceutical Expenditure Is Unchanged with Ultrasound-Guided Surfactant Administration. Am J Perinatol 2022; 39(5): 562–566. DOI: 10.1055/s-0040–1715821

12. Herting E., Härtel C., Göpel W. Less invasive surfactant administration (LISA): chances and limitations. Arch Dis Child Fetal Neonatal Ed. 2019;104(6):F655–F659. DOI: 10.1136/archdischild-2018–316557.

13. Ovsyannikov D.Yu., KravchukD.A., Nikolaeva D.Yu. Clinical pathophysiology of the respiratory system of premature infants. Neonatologiya: novosti, mneniya, obuchenie. 2018; 6(3): 74–79. (in Russ.) DOI: 10.24411/2308–2402–2018–13003

14. Avery’s diseases of the newborn, eleventh edition. Editors Sawyer T., Gleason C. A. Elsevier, 2023; 1681.

15. Panza R., Laforgia N., Bellos I., Pandita A. Systematic review found that using thin catheters to deliver surfactant to preterm neonates was associated with reduced bronchopulmonary dysplasia and mechanical ventilation. Acta Paediatr 2020; 109(11): 2219–2225. DOI: 10.1111/apa.15374

16. Liggins G.C., Howie R.N. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics. 1972; 50(4): 515–525.

17. Dargaville P.A., Herting E., Soll R.F. Neonatal surfactant therapy beyond respiratory distress syndrome. Semin Fetal Neonatal Med 2023; 28(6): 101501. DOI: 10.1016/j.siny.2023.101501

18. National Institutes of Health Consensus Development Conference Statement. Effect of corticosteroids for fetal maturation on perinatal outcomes. 1994; 12(2): 1–24.

19. McGoldrick E., Stewart F., Parker R., Dalziel S.R. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2020; 12(12): CD004454. DOI: 10.1002/14651858.CD004454.pub4

20. Gaertner V.D., Thomann J., Bassler D., Rüegger C.M. Surfactant Nebulization to Prevent Intubation in Preterm Infants: A Systematic Review and Meta-analysis. Pediatrics 2021; 148(5): e2021052504. DOI: 10.1542/peds.2021–052504

21. Sweet D.G., Carnielli V.P., Greisen G., Hallman M., Klebermass-SchrehofK., Ozek E., et al. European Consensus Guidelines on the Management of Respiratory Distress Syndrome: 2022 Update. Neonatology 2023; 120(1): 3–23. DOI: 10.1159/000528914

22. Hutcheon J.A., Liauw J. Improving the external validity of Antenatal Late Preterm Steroids trial findings. Paediatr Perinat Epidemiol 2023; 37(1): 1–8. DOI: 10.1111/ppe.12856

23. Regiroli G., Loi B., Fortas F., Centorrino R., Mosca F., De Luca D. Effect of inspired gas temperature on lung mechanics and gas exchange in neonates in normothermia or therapeutic hypothermia. Resuscitation 2021; 163: 116–123. DOI: 10.1016/j.resuscitation.2021.04.015

24. Norman M., Jonsson B., Wallström L., Sindelar R. Respiratory support of infants born at 22–24 weeks of gestational age. Semin Fetal Neonatal Med 2022; 27 (2): 101328. DOI: 10.1016/j.siny.2022.101328

25. Mazmanyan P., Kerobyan V., Shankar-Aguilera S., Yousef N., De Luca D. Introduction of point-of-care neonatal lung ultrasound in a developing country. Eur J Pediatr 2020; 179(7): 1131–1137. DOI: 10.1007/s00431–020–03603-w

26. Morley C.J., Bangham A.D., Miller N., Davis J.A. Dry artificial lung surfactant and its effect on very premature babies. Lancet 1981; 1(8211): 64–68. DOI: 10.1016/s0140–6736(81)90002–7

27. Long W., Corbet A., Cotton R., Courtney S., McGuiness G., Walter D., et al. A controlled trial of synthetic surfactant in infants weighing 1250 g or more with respiratory distress syndrome. The American Exosurf Neonatal Study Group I, and the Canadian Exosurf Neonatal Study Group. N Engl J Med 1991; 325(24) :1696–703. DOI: 10.1056/NEJM199112123252404

28. Curstedt T., Jrnvall H., Robertson B., Bergman T., Berggren P. Two hydrophobic low-molecular-mass protein fractions of pulmonary surfactant. Characterization and biophysical activity. Eur J Biochem 1987; 168(2): 255–262. DOI: 10.1111/j.1432–1033.1987.tb13414.x

29. Braide-Moncoeur O., Tran N.T., Long J.R. Peptide-based synthetic pulmonary surfactant for the treatment of respiratory distress disorders. Curr Opin Chem Biol 2016; 32: 22–28. DOI: 10.1016/j.cbpa.2016.02.012

30. Clinical recommendations “Management of newborns with respiratory distress syndrome” [Electronic resource]. Editor N.N. Volodin. 2016. (in Russ.) URL: https://www.raspm.ru/files/0236-rds-br2.pdf / Ссылка активна на 25.02.2025

31. Rosenberg O.A. Pulmonary surfactant preparations and surfactant therapy for ARDS in surgical intensive care (literature review). Kreativnaya hirurgiya i onkologiya 2019; 9(1): 50–65. (in Russ.) DOI: 10.24060/2076–3093–2019–9–1–50–65

32. Singh N., Halliday H.L., Stevens T.P., Suresh G., Soll R., Rojas-Reyes M.X. Comparison of animal-derived surfactants for the prevention and treatment of respiratory distress syndrome in preterm infants. Cochrane Database Syst Rev 2015; 2015(12): CD010249. DOI: 10.1002/14651858.CD010249.pub2

33. Schousboe P., Verder H., Jessen T.E., Heiring C., Bender L., Ebbesen F., et al. Predicting respiratory distress syndrome at birth using fast test based on spectroscopy of gastric aspirates. 1. Biochemical part. Acta Paediatr 2020; 109(2): 280–284. DOI: 10.1111/apa.14896

34. Autilio C., Losada-Oliva P., Sánchez Ortiz D., Mingote A., Castejon DiazR., HernandezG., et al. Changes in surface activity of lung surfactant and bronchoalveolar cell profile upon COVID-19-related Acute Respiratory Distress Syndrome. Eur Respir J 2022; 60 (suppl 66): 4435. DOI: 10.1183/13993003.congress-2022.4435

35. De Luca D., Shankar-Aguilera S., Autilio C., Raschetti R., Vedovelli L., Fitting C., et al. Surfactant-secreted phospholipase A2 interplay and respiratory outcome in preterm neonates. Am J Physiol Lung Cell Mol Physiol 2020; 319(1): L95– L104. DOI: 10.1152/ajplung.00462.2019

36. Echaide M., Autilio C., López-Rodríguez E., Cruz A., Pérez-Gil J. In Vitro Functional and Structural Characterization of A Synthetic Clinical Pulmonary Surfactant with Enhanced Resistance to Inhibition. Sci Rep 2020; 10(1): 1385. DOI: 10.1038/s41598–020–58248–4

37. ReynoldsP., BustaniP., DarbyC., FernandezAlvarezJ.R., FoxG., JonesS., et al. Less-Invasive Surfactant Administration for Neonatal Respiratory Distress Syndrome: A Consensus Guideline. Neonatology 2021; 118(5): 586–592. DOI: 10.1159/000518396

38. van Kaam A.H., Niemarkt H.J., Onland W. Timing of surfactant treatment in respiratory distress syndrome. Semin Fetal Neonatal Med 2023; 28(6): 101495. DOI: 10.1016/j.siny.2023.101495

39. Dolma K., Zayek M., Gurung A., Eyal F. Intratracheal Instillation of Budesonide-Surfactant for Prevention of Broncho-pulmonary Dysplasia in Extremely Premature Infants. Am J Perinatol 2024; 41(S 01): e3065–e3073. DOI: 10.1055/s-0043–1776416

40. van Kaam A.H., Niemarkt H.J., Onland W. Timing of surfactant treatment in respiratory distress syndrome. Semin Fetal Neonatal Med 2023; 28(6): 101495. DOI: 10.1016/j.siny.2023.101495

41. Soll R., Ozek E. Multiple versus single doses of exogenous surfactant for the prevention or treatment of neonatal respiratory distress syndrome. Cochrane Database Syst Rev 2009; 1: CD000141. DOI: 10.1002/14651858.CD000141.pub2.

42. Bhandari V., Black R., Gandhi B., Hogue S., Kakkilaya V., Mikhael M. et al. RDS-NExT workshop: consensus statements for the use of surfactant in preterm neonates with RDS. J Perinatol 2023; 43(8): 982–990. DOI: 10.1038/s41372–023–01690–9

43. KalikkotThekkeveedu R., El-Saie A., Prakash V., Katakam L., Shivanna B. Ventilation-Induced Lung Injury (VILI) in Neonates: Evidence-Based Concepts and Lung-Protective Strategies. J Clin Med 2022; 11(3): 557. DOI: 10.3390/jcm11030557

44. Arroyo R., Kingma P.S. Surfactant protein D and broncho-pulmonary dysplasia: a new way to approach an old problem. Respir Res 2021; 22(1): 141. DOI: 10.1186/s12931–021–01738–4

45. Ramaswamy V.V., More K., Roehr C.C., Bandiya P., Nangia S. Efficacy of noninvasive respiratory support modes for primary respiratory support in preterm neonates with respiratory distress syndrome: Systematic review and network meta-analysis. Pediatr Pulmonol 2020; 55(11): 2940–2963. DOI: 10.1002/ppul.25011

46. Berggren E., Liljedahl M., Winbladh B., Andreasson B., Curstedt T., Robertson B., et al. Pilot study of nebulized surfactant therapy for neonatal respiratory distress syndrome. Clinical Trial Acta Paediatr 2000; 89(4): 460–464. DOI: 10.1080/080352500750028195

47. Härtel C., Glaser K., Speer C.P. The Miracles of Surfactant: Less Invasive Surfactant Administration, Nebulization, and Carrier of Topical Drugs. Neonatology 2021; 118(2): 225–234. DOI: 10.1159/000516106

48. Ho J.J., Subramaniam P., Davis P.G. Continuous positive airway pressure (CPAP) for respiratory distress in preterm infants. Cochrane Database Syst Rev 2020; 10 (10): CD002271. DOI: 10.1002/14651858.CD002271.pub3

49. Methodological letter of the Ministry of Health of Russia “Primary and resuscitation care for newborn children” dated April 21, 2010 No. 15–4/10/2–3204. (in Russ.) https://static-0.minzdrav.gov.ru/system/attachments/attaches/000/018/647/original/metod_primary_intensive_care_newborns_2010.pdf?1390393892. / Ссылка активна на 26.02.2025

50. Sk H., Saha B., Mukherjee S., Hazra A. Premedication with Fentanyl for Less Invasive Surfactant Application (LISA): A Randomized Controlled Trial. J Trop Pediatr 2022; 68(2): fmac019. DOI: 10.1093/tropej/fmac019

51. Cao Z.L., Pan J.J., Shen X., Zhou X.Y., Cheng R., Zhou X.G., et al. Less invasive surfactant administration in preterm infants with respiratory distress syndrome-an updated meta-analysis. J Chin Med Assoc 2020; 83(2): 170–179. DOI: 10.1097/JCMA.0000000000000228

52. De Luca D., Cogo P., Kneyber M.C., Biban P., Semple M.G., Perez-Gil J., et al. Surfactant therapies for pediatric and neonatal ARDS: ESPNIC expert consensus opinion for future research steps. Crit Care 2021; 25(1): 75. DOI: 10.1186/s13054–021–03489–6

53. Peers de Nieuwburgh M., Wambach J.A., Griese M., Danhaive O. Towards personalized therapies for genetic disorders of surfactant dysfunction. Semin Fetal Neonatal Med 2023; 28(6): 101500. DOI: 10.1016/j.siny.2023.101500

54. Ovsyannikov D.Yu., Zhestkova M.A., Strelnikova V.A., Averin A.P., Atipaeva M.A., Brunova O.Yu. et al. Genetic dysfunctions of the surfactant system in children: results of a multicenter study. Doctor.ru 2023; 22(3): 22–31. (in Russ.) DOI: 10.31550/1727–2378–2023–22–3–22–31

55. Hamouda S., Trabelsi I., de Becdelièvre A., Boussetta K. Difficulties in the treatment of an infant survivor with inherited surfactant protein-B deficiency in Tunisia. Ann Thorac Med 2022; 17(2): 132–135. DOI: 10.4103/atm.atm_445_21

56. Kang M.H., van Lieshout L.P., Xu L., Domm J.M., Vadivel A., Renesme L., et al. A lung tropic AAV vector improves survival in a mouse model of surfactant B deficiency. Nat Commun 2020; 11(1): 3929. DOI: 10.1038/s41467–020–17577–8

57. Peca D., Boldrini R., Johannson J., Shieh J.T., Citti A., Petrini S., et al. Clinical and ultrastructural spectrum of diffuse lung disease associated with surfactant protein C mutations. Eur J Hum Genet 2015; 23(8): 1033–1041. DOI: 10.1038/ejhg.2015.45

58. Alapati D., Zacharias W.J., Hartman H.A., Rossidis A.C., Stratigis J.D., Ahn N.J., et al. In utero gene editing for monogenic lung disease. Sci Transl Med 2019;11(488):eaav8375. DOI: 10.1126/scitranslmed.aav8375

59. Kinting S., Höppner S., Schindlbeck U., Forstner M.E., Harfst J., Wittmann T., et al. Functional rescue of misfolding ABCA3 mutations by small molecular correctors. Hum Mol Genet 2018; 27(6): 943–953. DOI: 10.1093/hmg/ddy011

60. Hamvas A., Deterding R.R., Wert S.E., White F.V., Dishop M.K., Alfano D.N., et al. Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2–1. Chest 2013; 144(3): 794–804. DOI: 10.1378/chest.12–2502