Intratracheal Administration of Budesonide-instilled Surfactant for Prevention of Bronchopulmonary Dysplasia: A Randomized Controlled Clinical Trial

Document Type : Original Article


1 Department of Pediatrics, Child Growth and Development Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.

2 Department of Nursing, Nursing and Midwifery Sciences Development Research center, Najafabad Branch, Islamic Azad University, Najafabad, Iran.

3 Isfahan University of Medical Sciences, Isfahan, Iran.

4 Shahid Beheshti Hospital, Isfahan University of Medical Sciences, Isfahan, Iran.

5 Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran.

6 Department of Epidemiology and Biostatistics, School of Health, Isfahan University of Medical Sciences, Isfahan, Iran


Background: Despite numerous clinical strategies performed over the years, Bronchopulmonary dysplasia (BPD) still remains a common disease with considerable long-term adverse effects in very premature infants. This study investigated the effect of budesonide-instilled surfactant on the incidence of BPD in preterm infants.
Methods: In this clinical trial, a total of 190 neonates with a gestational age of less than 30 weeks, who were identified as candidates for surfactant therapy, were randomly assigned to two groups. The control group (S) received surfactant at a dosage of 200 mg/kg for the initial dose and 100 mg/kg for subsequent doses. In cases where it was deemed necessary (n=95), the intervention group (BS) received surfactant along with budesonide, instilled once at a dose of 0.25 mg/kg (n=95). The primary outcome was the occurrence of BPD, and the combined incidence of BPD and death Secondary outcomes encompassed other complications related to prematurity and adverse effects associated with corticosteroid use.
Results: Demographic characteristics of the neonates were comparable between the two groups.  Although a slight reduction was seen in the incidence of BPD in the group receiving budesonide, BPD rates remained statistically unchanged after the intervention (48.4% in the BS group vs 50.5% in the S group, P value = 0.772). The combined outcome of BPD and death was insignificantly different between the two groups (61.1% in the BS group vs. 63.2% in the S group, P value = 0.765). The addition of budesonide resulted in an increased incidence of sepsis and pneumothorax in the control group. However, secondary outcomes such as IVH (Inra ventricular Hemorrhage(, retinopathy of prematurity, necrotizing enterocolitis, patent ductus arteriosus, and hyperglycemia were unaffected. Duration of total parenteral nutrition and hospitalization time were longer in the BS group than in the S group.
Conclusion: The addition of budesonide to surfactant in very premature neonates at gestational age <30 weeks who were candidates for surfactant therapy did not prevent BPD. Conversely, it led to an increase in certain secondary morbidities such as sepsis and pneumothorax. Furthermore, it extended the duration of hospitalization.


  1. Bancalari E, Jain D. Bronchopulmonary Dysplasia: 50 Years after the Original Description. 2019;115(4):384–91.
  2. Principi N, Di Pietro GM, Esposito S. Bronchopulmonary dysplasia: clinical aspects and preventive and therapeutic strategies. J Transl Med. 2018 Feb 20;16(1):1-3.
  3. Thébaud B, Goss KN, Laughon M, Whitsett JA, Abman SH, Steinhorn RH, et al. Bronchopulmonary Nature reviews Disease primers [Internet]. 2019;5(1):78. Available from:
  4. Holzfurtner L, Shahzad T, Dong Y, Rekers L, Selting A, Staude B, et al. When inflammation meets lung development—an update on the pathogenesis of bronchopulmonary dysplasia. Mol Cell Pediatr. 2022;9(1):1-2.
  5. Doyle LW, Cheong JL, Hay S, Manley BJ, Halliday HL, Soll R. Early (< 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst Rev. 2021;11:1-136.
  6. Maas C, Poets CF, Bassler D. Survey of Practices Regarding Utilization of Inhaled Steroids in 223 German Neonatal Units. Neonatology. 2010; 98(4):404–8.
  7. Shinwell ES, Portnov I, Meerpohl JJ, Karen T, Bassler D. Inhaled Corticosteroids for Bronchopulmonary Dysplasia: A Meta-analysis. Pediatrics. 2016;138(6): e20162511–1.
  8. Bassler D, Plavka R, Shinwell ES, Hallman M, Jarreau PH, Carnielli V, et al. Early Inhaled Budesonide for the Prevention of Bronchopulmonary Dysplasia. N Engl J Med. 2015;373(16):1497–506.
  9. Doyle LW. Postnatal Corticosteroids to Prevent or Treat Bronchopulmonary Dysplasia. Neonatology. 2021;118(2):244–51.
  10. Shah VS, Ohlsson A, Halliday HL, Dunn M. Early administration of inhaled corticosteroids for preventing chronic lung disease in very low birth weight preterm neonates. Cochrane Database Syst Rev. 2017;1:1-58
  11. Yang CF, Lin CH, Chiou SY, Yang YC, Tsao PC, Lee YS, et al. Intratracheal budesonide supplementation in addition to surfactant improves pulmonary outcome in surfactant-depleted newborn piglets. Pediatr Pulmonol. 2012;48(2):151–9.
  12. Borchard G, Cassará ML, Roemelé PEH, Florea BI, Junginger HE. Transport and local metabolism of budesonide and fluticasone propionate in a human bronchial epithelial cell line (Calu‐3). J Pharm Sci. 2002;91(6):1561–7.
  13. Kothe TB, Kemp MW, Schmidt A, Royse E, Salomone F, Clarke MW, et al. Surfactant plus budesonide decreases lung and systemic inflammation in mechanically ventilated preterm sheep. Am J Physiol Lung Cell Mol Physiol. 2019;316(5):L888–93.
  14. Mokra D, Mokry J, Drgova A, Petraskova M, Bulikova J, Calkovska A. Intratracheally administered corticosteroids improve lung function in meconium-instilled rabbits. J Physiol Pharmacol. 2007; 58(Suppl 5):389-98.
  15. Chen CM, Chang CH, Chao CH, Wang MH, Yeh TF. Biophysical and chemical stability of surfactant/ budesonide and the pulmonary distribution following intra-tracheal administration. Drug Deliv. 2019;26(1):604–11.
  16. Venkataraman R, Kamaluddeen M, Hasan SU, Robertson HL, Lodha A. Intratracheal Administration of Budesonide-Surfactant in Prevention of Bronchopulmonary Dysplasia in Very Low Birth Weight Infants: A Systematic Review and Meta-Analysis. Pediatr Pulmonol. 2017;52(7):968–75.
  17. Moraes LHA, Coelho RMD, Neves dos Santos Beozzo GP, Yoshida R de AM, de Albuquerque Diniz EM, de Carvalho WB. Use of budesonide associated with a pulmonary surfactant to prevent bronchopulmonary dysplasia in premature newborns – A systematic review. J Pediatr. 2023;99:105-11.
  18. Tang W, Chen S, Shi D, Ai T, Zhang L, Huang Y, et al. Effectiveness and safety of early combined utilization of budesonide and surfactant by airway for bronchopulmonary dysplasia prevention in premature infants with RDS: A meta‐analysis. Pediatr Pulmonol. 2021;57(2):455–69.
  19. 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 Chronic Lung Disease in Preterm Infants. J Pediatr. 2010; 156(4):537–41.
  20. Yeh TF, Chen CM, Wu SY, Husan Z, Li TC, Hsieh WS, et al. Intratracheal Administration of Budesonide/ Surfactant to Prevent Bronchopulmonary Dysplasia. Am J Respir Crit Care Med. 2016;193(1):86–95.
  21. Manley BJ, Kamlin OF, Donath S, Huang L, Birch P, Cheong JLY, et al. Intratracheal budesonide mixed with surfactant to increase survival free of bronchopulmonary dysplasia in extremely preterm infants: study protocol for the international, multicenter, randomized PLUSS trial. Trials. 2023;24(1):1-8.
  22. Jobe A, Bancalari E. Bronchopulmonary Dysplasia. Am J Respir Crit Care Med. 2001;163(7):1723–9.
  23. Moschino L, Nardo D, Bonadies L, Stocchero M, Res G, Priante E, et al. Intra‐tracheal surfactant/ budesonide versus surfactant alone: Comparison of two consecutive cohorts of extremely preterm infants. Pediatr Pulmonol. 2021;56(7):2114-24.
  24. Heo M, Jeon GW. Intratracheal administration of budesonide with surfactant in very low birth weight infants to prevent bronchopulmonary dysplasia. Turk J Pediatr. 2020;62(4):551-59.
  25. Yeh TF, Lin HC, Chang CH, Wu TS, Su BH, Li TC, et al. Early Intratracheal Instillation of Budesonide Using Surfactant as a Vehicle to Prevent Chronic Lung Disease in Preterm Infants: A Pilot Study. Pediatrics. 2008;121(5):e1310–8.
  26. Gharehbaghi M, Ganji S, Mahallei M. A Randomized Clinical Trial of Intratracheal Administration of Surfactant and Budesonide Combination in Comparison to Surfactant for Prevention of Bronchopulmonary Dysplasia. Oman Med J. 2021;36(4):e289–9.
  27. Kothe TB, Sadiq FH, Burleyson N, Williams HL, Anderson C, Hillman NH. Surfactant and budesonide for respiratory distress syndrome: an observational study. Pediatr Res. 2019;87(5):940–5.