Neonatal Med.  2021 Feb;28(1):1-6. 10.5385/nm.2021.28.1.1.

Management of Persistent Pulmonary Hypertension in Preterm Infants

• Lee BS

• KMID: 2513352
• DOI: http://doi.org/10.5385/nm.2021.28.1.1

Abstract

Persistent pulmonary hypertension of the newborn (PPHN) is a consequence of the failure of a decrease in the elevated pulmonary vascular resistance after birth. Pulmonary vasodilators, including inhaled nitric oxide (iNO), have been the mainstream of targeted therapy for PPHN, but no drugs have been proven to be effective in preterm infants with PPHN. The fetus remains hemodynamically stable despite lower arterial oxygen tension and pulmonary blood flow as compared to full-term newborns. This adaptation is due to the lower oxygen requirement and high oxygencarrying capacity of fetal circulation. The immature lungs of preterm infants are more vulnerable to reactive oxygen species, and the response of pulmonary vascular dilatation to blood oxygen tension is blunted in preterm infants. Recently, iNO has been reported to be effective in a selected group of preterm infants, such as those with prolonged preterm rupture of membrane-oligohydramnios-pulmonary hypoplasia sequence. PPHN in preterm infants, along with maximum supportive treatment based on fetal physiology and meticulous assessment of cardiovascular function, is in dire need of new treatment guidelines, including optimal dosing strategies for pulmonary vasodilators.

Keyword

Persistent fetal circulation syndrome; Hypertension, pulmonary; Nitric oxide; Infant, premature; Premature rupture of fetal membrane

Figure

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  Figure 1. The three major pathways involved in pulmonary vascular regulation and Food and Drug Administration-approved medications for the treatment of pulmonary hypertension. Abbreviations: ET, endothelin receptor; eNOS, endothelial nitric oxide synthase; GTP, guanosine triphosphate; sGC, soluble guanylyl cyclase; cGMP, cyclic guanosine monophosphate; GMP, guanosine monophosphate; PDE5, phosphodiesterase 5; COX, cyclooxygenase; PGI2, prostacyclin; PGE1, prostaglandin E1; IP, prostaglandin I2 receptor; EP, prostaglandin E1 receptor; ATP, adenosine triphosphate; AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; AMP, adenosine monophosphate; PDE3, phosphodiesterase 3; ER, endoplasmic reticulum.

Reference

1. Martinho S, Adao R, Leite-Moreira AF, Bras-Silva C. Persistent pulmonary hypertension of the newborn: pathophysiological mechanisms and novel therapeutic approaches. Front Pediatr. 2020; 8:342.

2. Kumar VH, Hutchison AA, Lakshminrusimha S, Morin FC 3rd, Wynn RJ, Ryan RM. Characteristics of pulmonary hypertension in preterm neonates. J Perinatol. 2007; 27:214–9.

3. 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.

4. Jain A, McNamara PJ. Persistent pulmonary hypertension of the newborn: advances in diagnosis and treatment. Semin Fetal Neonatal Med. 2015; 20:262–71.

5. 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.

6. Barrington KJ, Finer N, Pennaforte T. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev. 2017; 1:CD000509.

7. 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.

8. Ha J, Lee EH, Park HK, Choi BM. Clinical status of inhaled nitric oxide treatment in infants with persistent pulmonary hypertension of the newborn in Korea: post-marketing surveillance results. Neonatal Med. 2020; 27:57–64.

9. Suzuki S, Togari H, Potenziano JL, Schreiber MD. Efficacy of inhaled nitric oxide in neonates with hypoxic respiratory failure and pulmonary hypertension: the Japanese experience. J Perinat Med. 2018; 46:657–63.

10. 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.

11. de Waal K, Kluckow M. Prolonged rupture of membranes and pulmonary hypoplasia in very preterm infants: pathophysiology and guided treatment. J Pediatr. 2015; 166:1113–20.

12. Aikio O, Metsola J, Vuolteenaho R, Perhomaa M, Hallman M. Transient defect in nitric oxide generation after rupture of fetal membranes and responsiveness to inhaled nitric oxide in very preterm infants with hypoxic respiratory failure. J Pediatr. 2012; 161:397–403.

13. Rasanen J, Wood DC, Weiner S, Ludomirski A, Huhta JC. Role of the pulmonary circulation in the distribution of human fetal cardiac output during the second half of pregnancy. Circulation. 1996; 94:1068–73.

14. Lakshminrusimha S, Saugstad OD. The fetal circulation, pathophysiology of hypoxemic respiratory failure and pulmonary hypertension in neonates, and the role of oxygen therapy. J Perinatol. 2016; 36 Suppl 2:S3–11.

15. Rasanen J, Wood DC, Debbs RH, Cohen J, Weiner S, Huhta JC. Reactivity of the human fetal pulmonary circulation to maternal hyperoxygenation increases during the second half of pregnancy: a randomized study. Circulation. 1998; 97:257–62.

16. Berkelhamer SK, Farrow KN. Developmental regulation of antioxidant enzymes and their impact on neonatal lung disease. Antioxid Redox Signal. 2014; 21:1837–48.

17. Steinhorn RH. Pulmonary vascular development. In : Martin RJ, Fanaroff AA, Walsh MC, editors. Fanaroff and Martin's Neonatal-Perinatal Medicine. 11th ed. Philadelphia: Elsevier;2020. p. 1306–19.

18. Porta NF, Steinhorn RH. Pulmonary vasodilator therapy in the NICU: inhaled nitric oxide, sildenafil, and other pulmonary vasodilating agents. Clin Perinatol. 2012; 39:149–64.

19. Lakshminrusimha S, Swartz DD, Gugino SF, Ma CX, Wynn KA, Ryan RM, et al. Oxygen concentration and pulmonary hemodynamics in newborn lambs with pulmonary hypertension. Pediatr Res. 2009; 66:539–44.

20. Gonzalez 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.

21. 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.

22. 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.

23. Cho JY, Lee BS, Oh MY, Cha T, Jeong J, Jung E, et al. Response to inhaled nitric xxide and clinical outcome in very low birth weight infants with early pulmonary hypertension. Neonatal Med. 2020; 27:133–40.

24. van Kempen LEM, van Teeffelen AS, de Ruigh AA, Oepkes D, Haak MC, van Leeuwen E, et al. Amnioinfusion compared with no intervention in women with second-trimester rupture of membranes: a randomized controlled trial. Obstet Gynecol. 2019; 133:129–36.

25. Roberts D, Vause S, Martin W, Green P, Walkinshaw S, Bricker L, et al. Amnioinfusion in very early preterm prelabor rupture of membranes (AMIPROM): pregnancy, neonatal and maternal outcomes in a randomized controlled pilot study. Ultrasound Obstet Gynecol. 2014; 43:490–9.

26. Committee Opinion No. 684 Summary: delayed umbilical cord clamping after birth. Obstet Gynecol. 2017; 129:232–3.

27. Vali P, Lakshminrusimha S. The fetus can teach us: oxygen and the pulmonary vasculature. Children (Basel). 2017; 4:67.

28. Lakshminrusimha S, Keszler M. Persistent pulmonary hypertension of the newborn. Neoreviews. 2015; 16:e680–92.

29. Nair J, Lakshminrusimha S. Update on PPHN: mechanisms and treatment. Semin Perinatol. 2014; 38:78–91.

30. Qasim A, Jain SK. Milrinone use in persistent pulmonary hypertension of the newborn. Neoreviews. 2020; 21:e165–78.

31. Kelly LE, Ohlsson A, Shah PS. Sildenafil for pulmonary hypertension in neonates. Cochrane Database Syst Rev. 2017; 8:CD005494.

32. James AT, Bee C, Corcoran JD, McNamara PJ, Franklin O, El-Khuffash AF. Treatment of premature infants with pulmonary hypertension and right ventricular dysfunction with milrinone:a case series. J Perinatol. 2015; 35:268–73.

33. Shivanna B, Gowda S, Welty SE, Barrington KJ, Pammi M. Prostanoids and their analogues for the treatment of pulmonary hypertension in neonates. Cochrane Database Syst Rev. 2019; 10:CD012963.

34. Park BY, Chung SH. Treprostinil for persistent pulmonary hypertension of the newborn, with early onset sepsis in preterm infant: 2 case reports. Medicine (Baltimore). 2017; 96:e7303.