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Response categorization and outcomes in extremely premature infants born at 22–26 weeks gestation that received inhaled nitric oxide for hypoxic respiratory failure

Journal of Perinatology volume 43, pages 324–331 (2023)Cite this article

Subjects

Abstract

Objective

To evaluate the outcomes of extremely premature infants who received inhaled nitric oxide(iNO) for hypoxic respiratory failure(HRF).

Study design

Retrospective analysis of 107 infants born 22–26 weeks gestation who received iNO for HRF at a single institution. Infants were categorized as positive, negative, or no responders based on change in FiO2 or OI. Underlying physiology was determined using Echocardiography/Radiography/Biochemistry.

Results

63% of infants had a positive response; they received iNO earlier and were more likely to have acute pulmonary hypertension(PH). Positive response correlated with decreased incidence of death or grade 3 BPD at 36 weeks postmenstrual age, as compared to a negative response.

Conclusions

Extremely premature infants have a positive response rate to iNO comparable to term infants when used for PH in the transitional period. Infants with a negative response to iNO had worse outcomes, necessitating the determination of the underlying physiology of HRF prior to iNO initiation.

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Fig. 1: Description of the population.
Fig. 2: Proportion of neonates who were classified as positive responders, non-responders, and negative responders by gestational age in the first 96 of life.

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Data availability

Requests to view the included data can be made to the corresponding author.

References

  1. Dani C, Corsini I, Cangemi J, Vangi V, Pratesi S. Nitric oxide for the treatment of preterm infants with severe RDS and pulmonary hypertension. Pediatr Pulmonol. 2017;52:1461–8.

    Article  PubMed  Google Scholar 

  2. Pandya S, Baser O, Wan GJ, Lovelace G, Potenziano J, Pham At, et al. The burden of hypoxic respiratory failure in preterm and term/near-term infants in the United States 2011-2015. J Health Econ Outcomes Res. 2019;6:130–41.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Giesinger RE, More K, Odame J, Jain A, Jankov RP, McNamara PJ. Controversies in the identification and management of acute pulmonary hypertension in preterm neonates. Pediatr Res. 2017;82:901–14.

  4. Seth SA, Soraisham AS, Harabor A. Risk factors and outcomes of early pulmonary hypertension in preterm infants. J Matern Fetal Neonatal Med, 2017;31:1–17.

  5. Nakanishi H, Suenaga H, Uchiyama A, Kusuda S. Neonatal research network Japan, Persistent pulmonary hypertension of the newborn in extremely preterm infants: a Japanese cohort study. Arch Dis Child Fetal Neonatal Ed. 2018;103:F554–61.

    Article  PubMed  Google Scholar 

  6. Kumari S, Braun RK, Tetri LH, Barton GP, Hacker TA, Goss KN. Bimodal right ventricular dysfunction after postnatal hyperoxia exposure: implications for the preterm heart. Am J Physiol Heart Circ Physiol. 2019;317:H1272–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Carey WA, Weaver AL, Mara KC, Clark RH. Inhaled nitric oxide in extremely premature neonates with respiratory distress syndrome. Pediatrics, 2018;141:1–9.

  8. Gaddam Bhoomaiah S, Rasiah SV. Outcomes of inhaled nitric oxide in preterm neonates—a five-year experience in a tertiary neonatal centre. Acta Paediatr. 2015;104:880–2.

    Article  CAS  PubMed  Google Scholar 

  9. Barrington KJ, Finer N, Pennaforte T. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev. 2017;1:Cd000509.

    PubMed  Google Scholar 

  10. Baczynski M, Ginty S, Weisz DE, McNamara PJ, Kelly E, Shah P, et al. Short-term and long-term outcomes of preterm neonates with acute severe pulmonary hypertension following rescue treatment with inhaled nitric oxide. Arch Dis Child Fetal Neonatal Ed. 2017;102:F508–14.

    Article  PubMed  Google Scholar 

  11. Ahmed MS, Giesinger RE, Ibrahim M, Baczynski M, Louis D, McNamara KP, et al. Clinical and echocardiography predictors of response to inhaled nitric oxide in hypoxic preterm neonates. J Paediatr Child Health. 2019;55:753–61.

    PubMed  Google Scholar 

  12. Dani C, Bertini G, Pezzati M, Fillipi L, Cecchi A, Rubaltelli FF. Inhaled nitric oxide in very preterm infants with severe respiratory distress syndrome. Acta Paediatr. 2006;95:1116–23.

    Article  PubMed  Google Scholar 

  13. Van Meurs KP, Wright LL, Ehrenkranz RA, Lemons JA, Ball MB, Poole WK, et al. Inhaled nitric oxide for premature infants with severe respiratory failure. N. Engl J Med. 2005;353:13–22.

    Article  PubMed  Google Scholar 

  14. Wernovsky G, Wypij D, Jonas RA, Mayer JE Jr, Hanley FL, Hickey PR, et al. Postoperative course and hemodynamic profile after the arterial switch operation in neonates and infants. A comparison of low-flow cardiopulmonary bypass and circulatory arrest. Circulation. 1995;92:2226–35.

    Article  CAS  PubMed  Google Scholar 

  15. Perri A, Riccardi R, Iannotta R, Di Molfetta DV, Arena R, Vento G, et al. Lung ultrasonography score versus chest X-ray score to predict surfactant administration in newborns with respiratory distress syndrome. Pediatr Pulmonol. 2018;53:1231–6.

    Article  PubMed  Google Scholar 

  16. Rios DR, de Freitas Martins F, El-Khuffash A, Weisz DE, Giesinger RE, McNamara PJ. Early role of the atrial-level communication in premature infants with patent ductus arteriosus. J Am Soc Echocardiogr. 2021;34:423–e1.

    Article  PubMed  Google Scholar 

  17. Teixeira LS, Shivananda SP, Stephens D, Van Arsdell GV, McNamara PJ. Postoperative cardiorespiratory instability following ligation of the preterm ductus arteriosus is related to early need for intervention. J Perinatol. 2008;28:803–10.

    Article  CAS  PubMed  Google Scholar 

  18. Jensen EA, Dysart K, Gantz MG, McDonald S, Bamat NA, Keszler M, et al. The diagnosis of bronchopulmonary dysplasia in very preterm infants. an evidence-based approach. Am J Respir Crit Care Med. 2019;200:751–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Backes CH, Rivera BK, Pavlek L, Beer LJ, Ball MK, Zettler ET, et al. Proactive neonatal treatment at 22 weeks of gestation: a systematic review and meta-analysis. Am J Obstet Gynecol. 2021;224:158–74.

    Article  CAS  PubMed  Google Scholar 

  20. Cole FS, Alleyne C, Barks JDE, Boyle RJ, Carroll JL, Dokken D, et al. NIH consensus development conference statement: inhaled nitric-oxide therapy for premature infants. Pediatrics. 2011;127:363–9.

    Article  PubMed  Google Scholar 

  21. Kumar P. Committee on fetus and newborn american academy of pediatrics, use of inhaled nitric oxide in preterm infants. Pediatrics. 2014;133:164–70.

    Article  PubMed  Google Scholar 

  22. Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK, et al. Pediatric pulmonary hypertension: guidelines from the American Heart Association and American Thoracic Society. Circulation. 2015;132:2037–99.

    Article  PubMed  Google Scholar 

  23. Ellsworth MA, Harris MN, Carey WA, Spitzer AR, Clark RH. Off-label use of inhaled nitric oxide after release of NIH consensus statement. Pediatrics. 2015;135:643–8.

    Article  PubMed  Google Scholar 

  24. Manja V, Guyatt G, Lakshminrusimha S, Jack S, Kirpalani H, Zupancic JAF, et al. Factors influencing decision making in neonatology: inhaled nitric oxide in preterm infants. J Perinatol. 2019;39:86–94.

    Article  PubMed  Google Scholar 

  25. Kumar VH, Hutchison AA, Lakshminrusimha S, Morin FC, Wynn RJ, Ryan RM. Characteristics of pulmonary hypertension in preterm neonates. J Perinatol. 2007;27:214–9.

    Article  CAS  PubMed  Google Scholar 

  26. Early compared with delayed inhaled nitric oxide in moderately hypoxaemic neonates with respiratory failure: a randomised controlled trial. The Franco-Belgium Collaborative NO Trial Group. Lancet, 1999;354:1066–71.

  27. Uga N, Ishii T, Kawase Y, Arai H, Tada H. Nitric oxide inhalation therapy in very low-birthweight infants with hypoplastic lung due to oligohydramnios. Pediatr Int. 2004;46:10–4.

    Article  CAS  PubMed  Google Scholar 

  28. Chock VY, Van Meurs KP, Hintz SR, Ehrenkranz RA, Lemons JA, Kendrick DE, et al. Inhaled nitric oxide for preterm premature rupture of membranes, oligohydramnios, and pulmonary hypoplasia. Am J Perinatol. 2009;26:317–22.

    Article  PubMed  Google Scholar 

  29. Su PH, Chen JY. Inhaled nitric oxide in the management of preterm infants with severe respiratory failure. J Perinatol. 2008;28:112–6.

    Article  CAS  PubMed  Google Scholar 

  30. Field D, Elbourne D, Truesdale A, Grieve R, Hardy P, Fenton AC, et al. Neonatal ventilation with inhaled nitric oxide versus ventilatory support without inhaled nitric oxide for preterm infants with severe respiratory failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics. 2005;115:926–36.

    Article  CAS  PubMed  Google Scholar 

  31. Shaul PW. Ontogeny of nitric oxide in the pulmonary vasculature. Semin Perinatol. 1997;21:381–92.

    Article  CAS  PubMed  Google Scholar 

  32. Liu YA, Theis JG, Coceani F. Contractile and relaxing mechanisms in pulmonary resistance arteries of the preterm fetal lamb. Biol Neonate. 2000;77:253–60.

    Article  CAS  PubMed  Google Scholar 

  33. Skimming JW, DeMarco VG, Cassin S. The effects of nitric oxide inhalation on the pulmonary circulation of preterm lambs. Pediatr Res. 1995;37:35–40.

    Article  CAS  PubMed  Google Scholar 

  34. Rallis D, DeierlA, Atreja G, Chaban B, Banerjee J. The efficacy of inhaled nitric oxide treatment in premature infants with acute pulmonary hypertension. Early Hum Dev. 2018;127:1–5.

    Article  CAS  PubMed  Google Scholar 

  35. 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.

    PubMed  Google Scholar 

  36. Bussmann N, El-Khuffash A, Breatnach CR, McCallion N, Franklin O, Singh GK, et al. Left ventricular diastolic function influences right ventricular—Pulmonary vascular coupling in premature infants. Early Hum Dev. 2019;128:35–40.

    Article  PubMed  Google Scholar 

  37. Hasan SU, Potenziano J, Konduri GG, Perez JA, Van Meurs KP, Walker MW, et al. Effect of inhaled nitric oxide on survival without bronchopulmonary dysplasia in preterm infants: a randomized clinical trial. JAMA Pediatr. 2017;171:1081–9.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Mercier JC, Hummler H, Durrmeyer X, Sanchez-Luna M, Carnielli V, Field D, et al. Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial. Lancet. 2010;376:346–54.

    Article  CAS  PubMed  Google Scholar 

  39. Jiang Q, Gao X, Liu C, Chen D, Lin X, Xia S, et al. Early inhaled nitric oxide in preterm infants <34 weeks with evolving bronchopulmonary dysplasia. J Perinatol. 2016;36:883–9.

    Article  PubMed  Google Scholar 

  40. Ballard RA, Truog WE, Cnaan A, Martin RJ, Ballard PL, Merrill JD, et al. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. N. Engl J Med. 2006;355:343–53.

    Article  CAS  PubMed  Google Scholar 

  41. Kinsella JP, Cutter GR, Walsh WF, Gerstmann DR, Bose CL, Hart C, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N. Engl J Med. 2006;355:354–64.

    Article  CAS  PubMed  Google Scholar 

  42. ter Horst SA, Walther FJ, Poorthuis BJHM, Hiemstra PS, Wagenaar GTM. Inhaled nitric oxide attenuates pulmonary inflammation and fibrin deposition and prolongs survival in neonatal hyperoxic lung injury. Am J Physiol Lung Cell Mol Physiol. 2007;293:L35–44.

    Article  PubMed  Google Scholar 

  43. Tourneux P, Markham N, Seedorf G, Balasubramaniam V, Abman SH. Inhaled nitric oxide improves lung structure and pulmonary hypertension in a model of bleomycin-induced bronchopulmonary dysplasia in neonatal rats. Am J Physiol Lung Cell Mol Physiol. 2009;297:L1103–11.

    Article  CAS  PubMed  Google Scholar 

  44. Laube M, Amann E, Uhlig U, Yang Y, Fuchs HW, Zemlin M, et al. Inflammatory mediators in tracheal aspirates of preterm infants participating in a randomized trial of inhaled nitric oxide. PLoS One. 2017;12:e0169352.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Watkins PL, Dagle JM, Bell EF, Colaizy TT. Outcomes at 18 to 22 months of corrected age for infants born at 22 to 25 weeks of gestation in a center practicing active management. J Pediatr. 2020;217:52–58.e1.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatrics, University of Iowa, Iowa City, IA, USA

    Timothy J. Boly, John M. Dagle, Jonathan M. Klein, Danielle R. Rios, Patrick J. McNamara & Regan E. Giesinger

  2. Department of Biochemistry, University of Iowa, Iowa City, IA, USA

    John M. Dagle

  3. Department of Internal Medicine, University of Iowa, Iowa City, IA, USA

    Patrick J. McNamara

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Contributions

TJB designed the study, acquired data, drafted the initial manuscript, revised the manuscript, and approved the final version of the manuscript. JMD acquired data, revised the manuscript, and approved the final version of the manuscript. JMK acquired data, revised the manuscript, and approved the final version of the manuscript. DRR acquired data, revised the manuscript, and approved the final version of the manuscript. PMJ contributed to the design of the study, acquired data, revised the manuscript, and approved the final version of the manuscript. REG conceptualized and designed the study, analyzed and interpreted data, revised the manuscript, and approved the final version of the manuscript. All authors agree to be accountable for all aspects of the work.

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Correspondence to Regan E. Giesinger.

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Boly, T.J., Dagle, J.M., Klein, J.M. et al. Response categorization and outcomes in extremely premature infants born at 22–26 weeks gestation that received inhaled nitric oxide for hypoxic respiratory failure. J Perinatol 43, 324–331 (2023). https://doi.org/10.1038/s41372-022-01582-4

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