Early use of combined exogenous surfactant and inhaled nitric oxide reduces treatment failure in persistent pulmonary hypertension of the newborn: a randomized controlled trial

A Correction to this article was published on 07 September 2020

This article has been updated



To evaluate whether combined surfactant with inhaled nitric oxide (iNO) use will prevent newborns with hypoxemic respiratory failure (HRF) from developing an Oxygenation Index (OI) > 40.


100 term newborns with acute HRF (OI ≥ 20) were randomized to: Surfactant+iNO: received iNO plus up to two doses of surfactant or iNO-Controls: received iNO+placebo. Main outcome was the development of severe HRF (OI > 40) despite iNO use.


Baseline mean ± SD OI was 37.4 ± 14 for the Surfactant+iNO group and 38.2 ± 16 for the controls. Infants receiving surfactant+iNO improved their oxygenation faster, resulting in lower OI at 24 h: 12.9 ± 9 vs 18.7 ± 11 of controls, p < 0.05; and a lower proportion developing OI > 40: 24%(12/50) vs 50%(25/50) of controls, p < 0.02. Fewer infants receiving surfactant+iNO presented the combined outcome of death or ECMO: 16%(8/50) compared to 36%(18/50) of controls, p < 0.05.


Early use of combined surfactant+iNO improves oxygenation preventing the progression to severe HRF. This may reduce mortality and ECMO need.

Trial registration number


Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Consort diagram of eligible study infants.
Fig. 2: Change in Oxygenation Index.

Change history

  • 07 September 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.


  1. 1.

    Morin FC, Stenmark KR. Persistent pulmonary hypertension of the newborn. Am J Respir Crit Care Med. 1995;151:2010–32.

    Article  Google Scholar 

  2. 2.

    Steurer MA, Jelliffe-Pawlowski LL, Baer RJ, Partridge JC, Rogers EE, Keller RL. Persistent pulmonary hypertension of the newborn in late preterm and term infants in California. Pediatrics. 2017;139:e20161165. https://doi.org/10.1542/peds.2016-1165.

    Article  Google Scholar 

  3. 3.

    Mena P, Muhlhausen G, Novoa P, editors. Hypoxic respiratory failure and persistent pulmonary hypertension in the neonate. In: Guias Nacionales de Neonatología. Chilean Ministry of Health Publications, Santiago, Chile, 2005.

  4. 4.

    Steurer MA, Baer RJ, Oltman S, Ryckman KK, Feuer SK, Rogers E, et al. Morbidity of persistent pulmonary hypertension of the newborn in the first year of life. J Pediatr. 2019;213:58–65.

    Article  Google Scholar 

  5. 5.

    The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term infants with hypoxic respiratory failure. N. Engl J Med. 1997;336:597–604.

    Article  Google Scholar 

  6. 6.

    Roberts J, Fineman J, Morin F, Shaul P, Rimar S, Schreiber M, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. N Engl J Med. 1997;336:605–10.

    CAS  Article  Google Scholar 

  7. 7.

    Clark R, Kueser T, Walker M, Southgate WM, Huckaby JL, Perez JA, et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. N Engl J Med. 2000;342:469–74.

    CAS  Article  Google Scholar 

  8. 8.

    Stenmark K, Aldashev A, Orton E, Durmowicz AG, Badesch DB, Parks WC, et al. Cellular adaptation during chronic neonatal hypoxic pulmonary hypertension. Am J Physiol. 1991;261:97–104.

    CAS  Google Scholar 

  9. 9.

    Davey AM, Becker JD, Davis JM. Meconium aspiration syndrome: physiological and inflammatory changes in a newborn piglet model. Pediatr Pulmonol. 1993;16:101–8.

    CAS  Article  Google Scholar 

  10. 10.

    Hallman M, Kankaanoaa K. Evidence of surfactant deficiency in persistent fetal circulation. Eur J Pediatr. 1980;134:129–34.

    CAS  Article  Google Scholar 

  11. 11.

    Hall SB, Notter RH, Smith RJ, Hyde RW. Altered function of pulmonary surfactant in fatty acid lung injury. J Appl Physiol. 1990;69:1143–9.

    CAS  Article  Google Scholar 

  12. 12.

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

    CAS  Google Scholar 

  13. 13.

    Lotze A, Mitchell BR, Bulas DI, Zola EM, Shalwitz RA, Gunkel JH. Multicenter study of surfactant (beractant) use in the treatment of term infants with severe respiratory failure. Survanta in Term Infants Study Group. J Pediatr. 1998;132:40–7.

    CAS  Article  Google Scholar 

  14. 14.

    Konduri G, Solimano A, Sokol G, Singer J, Ehrenkranz RA, Singhal N, et al. A randomized trial of early versus standard inhaled nitric oxide therapy inr term and near term newborn infants with hypoxic respiratory failure. Pediatrics. 2004;113:559–64.

    Article  Google Scholar 

  15. 15.

    González A, Fabres J, D’Apremont I, Urcelay G, Avaca M, Gandolfi C, et al. Randomized controlled trial of early compared with delayed use of inhaled nitric oxide in newborns with a moderate respiratory failure and pulmonary hypertension. J Perinatol. 2010;30:420–4.

    Article  Google Scholar 

  16. 16.

    Kattan J, González A, Becker P, Faunes M, Estay A, Toso P, et al. Survival of newborn infants with severe respiratory failure before and after establishing an ECMO program. Pediatr Crit Care Med. 2013;14:876–83.

    Article  Google Scholar 

  17. 17.

    Chinese Collaborative Study Group for Neonatal Respiratory Diseases. Treatment of severe meconium aspiration syndrome with porcine surfactant: a multicentre, randomized, controlled trial. Acta Pædiatrica. 2005;94:896–902.

    Article  Google Scholar 

  18. 18.

    El Shahed AI, Dargaville PA, Ohlsson A, Soll R. Surfactant for meconium aspiration syndrome in term and late preterm infants. Cochrane Database Syst Rev. 2014;12:CD002054. https://doi.org/10.1002/14651858.CD002054.

  19. 19.

    Kattwinkel J. Surfactant lavage for meconium aspiration: a word of caution. Pediatrics. 2002;109:1167–8.

    Article  Google Scholar 

  20. 20.

    Barrington KJ, Finer N, Pennaforte T, Altit G. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev. 2017;1:CD000399. https://doi.org/10.1002/14651858.CD000399.

  21. 21.

    Kinsella J, Truog W, Walsh W, Goldberg RN, Bancalari E, Mayock D, et al. Randomized, multicenter trial of inhaled nitric oxide and high frequency oscillatory ventilation in severe persistent pulmonary hypertension of the newborn. J Pediatr. 1997;131:55–62.

    CAS  Article  Google Scholar 

  22. 22.

    Dadiz R, Nair J, D’Angio CT, Ryan RM, Lakshminrusimha S. Methemoglobin and the response to inhaled nitric oxide in persistent pulmonary hypertension of the newborn. J Neonatal Perinat Med. 2019;10:3233/NPM-180082. https://doi.org/10.3233/NPM-180082.

    Article  Google Scholar 

  23. 23.

    Afolayan AJ, Eis A, Alexander M, Michalkiewicz T, Teng RJ, Lakshminrusimha S, et al. Decreased endothelial nitric oxide synthase expression and function contribute to impaired mitochondrial biogenesis and oxidative stress in fetal lambs with persistent pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2016;310:L40–49.

    Article  Google Scholar 

  24. 24.

    Issa A, Lappalainen U, Kleinman M, Bry K, Hallman M. Inhaled nitric oxide decreases hyperoxia-induced surfactant abnormality in preterm rabbits. Pediatr Res. 1999;45:247–54.

    CAS  Article  Google Scholar 

  25. 25.

    Gadzinowski J, Kowalska K, Vidyasagar D. Treatment of MAS with PPHN using combined therapy: SLL, bolus surfactant and iNO. J Perinatol. 2008;28:S56–66.

    CAS  Article  Google Scholar 

  26. 26.

    Dargaville PA, Copnell B, Mills JF, Haron I, Lee JK, Tingay DG. on behalf of the lessMAS Trial Study Group et al. Randomized controlled trial of lung lavage with dilute surfactant for meconium aspiration syndrome. J Pediatr. 2011;158:383–9.

    CAS  Article  Google Scholar 

  27. 27.

    Konduri GG, Sokol G, Van Meurs K, Singer J, Ambalavanan N, Lee T, et al. Impact of early surfactant and inhaled nitric oxide therapies on outcomes in term/late preterm neonates with moderate hypoxic respiratory failure. J Perinatol. 2013;33:944–9.

    CAS  Article  Google Scholar 

Download references


We are grateful to Angélica Domínguez for their statistical assistance and for the valuable help of the group of research collaborators of the five centers listed in Appendix 1.


Funded by the Chilean Fund for Health Research (FONIS): Project: SA07I20035.

Author information



Corresponding author

Correspondence to Alvaro González.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Appendix 1: Collaborators

Appendix 1: Collaborators

The following members from the centers are non-author contributors to this study. They contributed with data collection and provided clinical care for study patients:

Hospital Clínico Universidad Católica de Chile, Santiago: Katherine Flores, Rodrigo Lagos, Claudia Miralles, María Eugenia Pérez, Solange Rojas, Angélica Vives.

Hospital Guillermo Grant, Concepción: Lilian Cifuentes, Andrea Saldías, Claudia Aburto.

Hospital Dr. Luis Tisné, Santiago: María Lidia Poblete, Paula Vasquez.

Hospital San José, Santiago: Ana María Pacheco, Paula Ponce.

Hospital Dr. Sótero del Rio, Santiago: Mónica Ahumada, Patricia Mena, Claudia Toro.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

González, A., Bancalari, A., Osorio, W. et al. Early use of combined exogenous surfactant and inhaled nitric oxide reduces treatment failure in persistent pulmonary hypertension of the newborn: a randomized controlled trial. J Perinatol (2020). https://doi.org/10.1038/s41372-020-00777-x

Download citation

Further reading