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Neonatology pp 933-962 | Cite as

Persistent Pulmonary Hypertension of the Newborn

  • Jason Gien
  • John P. Kinsella
  • Steven H. Abman
Reference work entry

Abstract

Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome, characterized by failure of the pulmonary vasculature resistance to fall after birth, resulting in postnatal maintenance of a fetal circulation, which in the absence of placental gas exchange results in hypoxemia with end organ damage. Nitric oxide produced by the vascular endothelium is primarily responsible for vasodilation after birth. When delivered exogenously, inhaled nitric oxide (iNO) is the mainstay of therapy for PPHN, with clinical studies demonstrating improved survival and decreased need for extracorporeal membrane oxygenation therapy (ECMO) with iNO treatment. However, 25–30% of cases fail to respond to iNO, most commonly in the setting of lung hypoplasia and abnormal development of the pulmonary vasculature in utero. For these infants, alternate therapies are often needed. In this chapter, we discuss the pathophysiology of PPHN, the history of PPHN therapies as they have evolved over time, mechanisms for failed responses to iNO, and the approach to PPHN that occurs in the setting of lung hypoplasia.

References

  1. Abman SH (2001) Bronchopulmonary dysplasia: a “vascular hypothesis”. Am J Respir Crit Care Med 164:1755–1756CrossRefPubMedGoogle Scholar
  2. Abman SH, Accurso FJ (1989) Acute effects of partial compression of ductus arteriosus on fetal pulmonary circulation. Am J Physiol Heart Circ Physiol 26:H626–H634CrossRefGoogle Scholar
  3. Abman SH, Kinsella JP (1995) Inhaled nitric oxide for persistent pulmonary hypertension of the newborn: the physiology matters. Pediatrics 96:1153–1155PubMedGoogle Scholar
  4. Abman SH, Chatfield BA, Hall SL, McMurtry IF (1990) Role of endothelium-derived relaxing factor activity during transition of pulmonary circulation at birth. Am J Physiol (Heart Circ Physiol 28) 259:H1921–H1927CrossRefGoogle Scholar
  5. Abman SH, Griebel JL, Parker DK et al (1994) Acute effects of inhaled nitric oxide in severe hypoxemic respiratory failure in pediatrics. J Pediatr 124:881–888PubMedCrossRefGoogle Scholar
  6. Acute Respiratory Distress Syndrome Network (2000) Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the ARDS. N Engl J Med 342:1301–1308CrossRefGoogle Scholar
  7. Adel Mohamed MD, Nehad Nasef MD, Vibhuti Shah MD, Patrick J, McNamara MD (2014) Vasopressin as a rescue therapy for refractory pulmonary hypertension in neonates: case series. Pediatr Crit Care Med 15:148–154PubMedCrossRefGoogle Scholar
  8. Agrawal A, Singh VK, Varma A, Sharma R (2012) Therapeutic applications of vasopressin in pediatric patients. Indian Pediatr 49:297–305PubMedCrossRefGoogle Scholar
  9. Alano MA, Ngougmna E, Ostrea EM Jr, Konduri GG (2001) Analysis of nonsteroidal antiinflammatory drugs in meconium and its relation to persistent pulmonary hypertension of the newborn. Pediatrics 107(3):519–523PubMedCrossRefGoogle Scholar
  10. Antunes MJ, Greenspan JS, Holt WJ, Vallieu DS, Spitzer AR (1994) Assessment of lung function pre-nitric oxide therapy: a predictor of response? Pediatr Res 35:212AGoogle Scholar
  11. Aslam M, Baveja R, Liang OD, Fernandez-Gonzalez A, Lee C, Mitsialis SA et al (2009) Bone marrow stromal cells attenuate lung injury in a murine model of neonatal chronic lung disease. Am J Respir Crit Care Med 180:1122–1130PubMedPubMedCentralCrossRefGoogle Scholar
  12. Atz AM, Wessel DL (1999) Sildenafil ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology 91:307–310PubMedCrossRefGoogle Scholar
  13. Balasubramaniam V, Le Cras TD, Ivy DD, Kinsella J, Grover TR, Abman SH (2003) Role of platelet-derived growth factor in the pathogenesis of perinatal pulmonary hypertension. Am J Phys Lung Cell Mol Phys 284:L826–L833Google Scholar
  14. Ballard RA, Truog WE, Cnaan A et al (2006) Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. N Engl J Med 205:343–353CrossRefGoogle Scholar
  15. Baumgart S, Paul JJ, Huhta JC, Katz AL, Paul KE, Spettell C et al (1998) Cardiac malposition, redistribution of fetal cardiac output, and left heart hypoplasia reduce survival in neonates with congenital diaphragmatic hernia requiring extracorporeal membrane oxygenation. J Pediatr 133:5762CrossRefGoogle Scholar
  16. Behrman RE (1976) Persistence of the fetal circulation. J Pediatr 89:636–637PubMedCrossRefGoogle Scholar
  17. Brennan LA, Steinhorn RH, Wedgwood S, Mata-Greenwood E, Roark EA, Russell JA, Black SM (2003) Increased superoxide generation is associated with pulmonary hypertension in fetal lambs. A role for NADPH oxidase. Circ Res 92:683–691PubMedCrossRefGoogle Scholar
  18. Byrne FA, Keller RL, Meadows J, Miniati D, Brook MM, Silverman NH et al (2015) Severe left diaphragmatic hernia limits size of fetal left heart more than right diaphragmatic hernia. Ultrasound Obstet Gynecol 46(6):688–94CrossRefGoogle Scholar
  19. Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, Mitchell AA (2006) Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 354(6):579–587PubMedCrossRefGoogle Scholar
  20. Chester M, Tourneux P, Seedorf G, Grover TR, Abman SH (2009) Cinaciguat, a soluble guanylate cyclase activator, causes potent and sustained pulmonary vasodilation in the ovine fetus. Am J Physiol 297:L318Google Scholar
  21. Clark RH, Kueser TJ, Walker MW et al (2000) Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical inhaled nitric oxide research group. N Engl J Med 342:469–474PubMedCrossRefGoogle Scholar
  22. Cole FS, Alleyne C, Barks JD, Boyle RJ, Carroll JL, Dokken D, Edwards WH, Georgieff M, Gregory K, Johnston MV, Kramer M, Mitchell C, Neu J, Pursley DM, Robinson WM, Rowitch DH (2011) NIH consensus development conference statement: inhaled nitric-oxide therapy for premature infants. Pediatrics 127(2):363–369PubMedCrossRefGoogle Scholar
  23. Cornfield DN, Chatfield BA, McQueston JA, McMurtry IF, Abman SH (1992) Effects of birth related stimuli on l-arginine-dependent vasodilation in the ovine fetus. Am J Physiol (Heart Circ Physiol 31) 262:H1474–H1481CrossRefGoogle Scholar
  24. Cornfield DN, Maynard RC, deRegnier RO, Guaing SF, Barbato JE, Milla CE (1999) Randomized, controlled trial of low-dose inhaled nitric oxide in the treatment of term and near-term infants with respiratory failure and pulmonary hypertension. Pediatrics 104:1089–1094PubMedCrossRefGoogle Scholar
  25. Cotton EK (1965) The use of priscoline in the treatment of the hypoperfusion syndrome. Pediatrics 36:149PubMedGoogle Scholar
  26. Davidson D, Barefield ES, Kattwinkel J et al (1998) Inhaled nitric oxide for the early treatment of persistent pulmonary hypertension of the term newborn: a randomized, double-masked, placebo-controlled, dose – response, multicenter study. Pediatrics 101:325–334PubMedCrossRefGoogle Scholar
  27. Deprest J, De CP (2012) Antenatal management of isolated congenital diaphragmatic hernia today and tomorrow: ongoing collaborative research and development. Journal of pediatric surgery lecture. J Pediatr Surg 47:282–290PubMedCrossRefGoogle Scholar
  28. Evora PR, Pearson PJ, Schaff HV (1993) Arginine vasopressin induces endothelium-dependent vasodilation of the pulmonary artery. V1-receptor-mediated production of nitric oxide. Chest 103:1241–1245PubMedCrossRefGoogle Scholar
  29. Faraci F, Didion S (2004) Vascular protection: Superoxide dismutase isoforms in the vessel wall. Arterioscler Thromb Vasc Biol 24:1367–1373CrossRefPubMedGoogle Scholar
  30. Farrow KN, Lakshminrusimha S, Reda WJ, Wedgwood S, Czech L, Gugino SF, Davis JM, Russell JA, Steinhorn RH (2008a) Superoxide dismutase restores eNOS expression and function in resistance pulmonary arteries from neonatal lambs with persistent pulmonary hypertension. Am J Phys Lung Cell Mol Phys 295(6):L979–L987Google Scholar
  31. Farrow KN, Groh BS, Schumacker PT, Lakshminrusimha S, Czech L, Gugino SF, Russell JA, Steinhorn RH (2008b) Hyperoxia increases phosphodiesterase 5 expression and activity in ovine fetal pulmonary artery smooth muscle cells. Circ Res 102(2):226–233PubMedCrossRefGoogle Scholar
  32. Field DJ (2005) Nitric oxide-still no consensus. Early Hum Dev 81:1–4PubMedCrossRefGoogle Scholar
  33. Field D, Elbourne D, Truesdale A et al (2005) Neonatal ventilation with inhaled nitric oxide versus ventilatory support without inhaled nitric oxide for preterm infants with severe respiratory failure: the INNOVO multicentre randomized controlled trial. Pediatrics 115:926–936PubMedCrossRefGoogle Scholar
  34. Fike CD, Slaughter JC, Kaplowitz MR, Zhang Y, Aschner JL (2008) Reactive oxygen species from NADPH oxidase contribute to altered pulmonary vascular responses in piglets with chronic hypoxia-induced pulmonary hypertension. Am J Phys Lung Cell Mol Phys 295(5):L881–L888Google Scholar
  35. Filippi L, Gozzini E, Daniotti M, Pagliai F, Catarzi S, Fiorini P (2011) Rescue treatment with terlipressin in different scenarios of refractory hypotension in newborns and infants. Pediatr Crit Care Med 12:e237–e241PubMedCrossRefGoogle Scholar
  36. Finer NN (2005) Inhaled nitric oxide for preterm infants: A therapy in search of an indication? The search continues. J Pediatr 146:301–302PubMedCrossRefGoogle Scholar
  37. Finer NN, Etches PC, Kamstra B et al (1994) Inhaled nitric oxide in infants referred for extracorporeal membrane oxygenation: dose response. J Pediatr 124:302–308PubMedCrossRefGoogle Scholar
  38. Finer NN, Sun JW, Rich W, Knodel E, Barrington KJ (2001) Randomized, prospective study of low-dose versus high-dose inhaled nitric oxide in the neonate with hypoxic respiratory failure. Pediatrics 108:949–955PubMedCrossRefGoogle Scholar
  39. Fornaro E, Li D, Pan J, Belik J (2007) Prenatal exposure to fluoxetine induces fetal pulmonary hypertension in the rat. Am J Respir Crit Care Med 176(10):1035–1040PubMedCrossRefGoogle Scholar
  40. Fox WW, Gewitz MH, Dinwiddie R, Drummond WH, Peckham GJ (1977) Pulmonary hypertension in the perinatal aspiration syndromes. Pediatrics 59:205–211PubMedGoogle Scholar
  41. Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM (1991) A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 83:2038–2047PubMedCrossRefGoogle Scholar
  42. Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:373–376PubMedPubMedCentralCrossRefGoogle Scholar
  43. Geggel RL, Reid LM (1984) The structural basis of PPHN. Clin Perinatol 11:525–549PubMedCrossRefGoogle Scholar
  44. Gerlach H, Rossaint R, Pappert D, Falke KJ (1993) Time-course and dose-response of nitric oxide inhalation for systemic oxygenation and pulmonary hypertension in patients with adult respiratory distress syndrome. Eur J Clin Invest 23:499–502PubMedCrossRefGoogle Scholar
  45. Gersony WM (1984) Neonatal pulmonary hypertension: pathophysiology, classification and etiology. Clin Perinatol 11:517–524PubMedCrossRefGoogle Scholar
  46. Gersony WM, Duc GV, Sinclair JC (1969) “PFC” syndrome (persistence of the fetal circulation). Circulation 40:111Google Scholar
  47. Gien J, Kinsella JP (2015) Differences in preductal and postductal arterial blood gas measurements in infants with severe congenital diaphragmatic hernia. Arch Dis Child Fetal Neonatal Ed 101:F314PubMedCrossRefGoogle Scholar
  48. Goetzman BW, Sunshine P, Johnson JD, Wennberg RP, Hackel A, Merten DF et al (1976) Neonatal hypoxia and pulmonary vasospasm: response to tolazoline. J Pediatr 89:617–621PubMedCrossRefGoogle Scholar
  49. Goldman AP, Tasker RC, Haworth SG, Sigston PE, Macrae DJ (1996) Four patterns of response to inhaled nitric oxide for persistent pulmonary hypertension of the newborn. Pediatrics 98:706–713PubMedGoogle Scholar
  50. Gordon JB, Martinez FR, Keller PA, Tod ML, Madden JA (1993) Differing effects of actue and prolonged alkalosis on hypoxic pulmonary vasoconstriction. Am Rev Respir Dis 148:1651–1656PubMedCrossRefGoogle Scholar
  51. Grover TR, Parker TA, Zenge JP, Markham NE, Abman SH (2003) Intrauterine pulmonary hypertension decreases lung VEGF expression and VEGF inhibition causes pulmonary hypertension in the ovine fetus. Am J Phys 284:L508–L517Google Scholar
  52. Grover TR, Parker TA, Hunt-Peacock C, Markham NE, Abman SH (2005) rhVEGF treatment improves pulmonary vasoreactivity and structure in an experimental model of pulmonary hypertension in fetal sheep. Am J Physiol LCMP 289:L529–L535Google Scholar
  53. Hamon I, Fresson J, Nicolas MB et al (2005) Early inhaled nitric oxide improves oxidative balance in very preterm infants. Pediatr Res 57:637–643PubMedCrossRefGoogle Scholar
  54. Hanson KA, Abman SH, Clarke WR (1996) Elevation of pulmonary PDE5-specific activity in an experimental fetal ovine perinatal pulmonary hypertension model. Pediatr Res 39:334ACrossRefGoogle Scholar
  55. Harrison MR, de Lorimier AA (1981) Congenital diaphragmatic hernia. Surg Clin North Am 61:1023–1035PubMedCrossRefGoogle Scholar
  56. Hascoet JM, Fresson J, Claris O et al (2005) The safety and efficacy of nitric oxide therapy in premature infants. J Pediatr 146:318–323PubMedCrossRefGoogle Scholar
  57. Haworth SG, Reid L (1976) Persistent fetal circulation: newly recognized structural features. J Pediatr 88:614–620PubMedCrossRefGoogle Scholar
  58. Hibbs AM, Walsh MC, Martin RJ, Truog WE, Lorch SA, Alessandrini E, Cnaan A, Palermo L, Wadlinger SR, Coburn CE, Ballard PL, Ballard RA (2008) One-year respiratory outcomes of preterm infants enrolled in the nitric oxide (to prevent) chronic lung disease trial. J Pediatr 153(4):525–529PubMedPubMedCentralCrossRefGoogle Scholar
  59. Higenbottam T, Pepke-Zaba J, Scott J, Woolman P, Coutts C, Wallwork J (1988) Inhaled “endothelium-derived relaxing factor” (EDRF) in primary hypertension (PPH). Am Rev Respir Dis 137:107SGoogle Scholar
  60. Hintz SR, Van Meurs KP, Perritt R, Poole WK, Das A, Stevenson DK, Ehrenkranz RA, Lemons JA, Vohr BR, Heyne R, Childers DO, Peralta-Carcelen M, Dusick A, Johnson YR, Morris B, Dillard R, Vaucher Y, Steichen J, Adams-Chapman I, Konduri G, Myers GJ, de Ungria M, Tyson JE, Higgins RD, NICHD Neonatal Research Network (2007) Neurodevelopmental outcomes of premature infants with severe respiratory failure enrolled in a randomized controlled trial of inhaled nitric oxide. J Pediatr 151(1):16–22PubMedPubMedCentralCrossRefGoogle Scholar
  61. Hoffman AM, Paxson JA, Mazan MR, Davis AM, Tyagi S, Murthy S et al (2011) Lung-derived mesenchymal stromal cell post-transplantation survival, persistence, paracrine expression, and repair of elastase-injured lung. Stem Cells Dev 20:1779–1792PubMedPubMedCentralCrossRefGoogle Scholar
  62. Ichinose F, Erana-Garcia J, Hromi J, Raveh Y, Jones R, Krim L, Clark MWH, Winkler JD, Bloch KD, Zapol WM (2001) Nebulized sildenafil is a selective pulmonary vasodilator in lambs with acute pulmonary hypertension. Crit Care Med 29:1000–1005PubMedCrossRefGoogle Scholar
  63. Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G (1987) Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A 84:9265–9269PubMedPubMedCentralCrossRefGoogle Scholar
  64. Ivy DD, Ziegler JW, Dubus MF, Fox JJ, Kinsella JP, Abman SH (1996) Chronic intrauterine pulmonary hypertension alters endothelin receptor activity in the ovine fetal lung. Pediatr Res 39:435–442PubMedCrossRefGoogle Scholar
  65. Ivy DD, Parker TA, Ziegler JW, Galan HL, Kinsella JP, Tuder RM, Abman SH (1997) Prolonged endothelin A receptor blockade attenuates pulmonary hypertension in the ovine fetus. J Clin Invest 99:1179–1186PubMedPubMedCentralCrossRefGoogle Scholar
  66. Ivy DD, Le Cras TD, Horan MP, Abman SH (1998) Increased lung preproET-1 and decreased ETB-receptor gene expression in fetal pulmonary hypertension. Am J Phys 274(4 Pt 1):L535–L541Google Scholar
  67. Jani J, Valencia C, Cannie M, Vuckovic A, Sellars M, Nicolaides KH (2011) Tracheal diameter at birth in severe congenital diaphragmatic hernia treated by fetal endoscopic tracheal occlusion. Prenat Diagn 31:699–704PubMedCrossRefGoogle Scholar
  68. Kamath BD, Fashaw L, Kinsella JP (2010) Adrenal insufficiency in newborns with congenital diaphragmatic hernia. J Pediatr 156:495–497PubMedPubMedCentralCrossRefGoogle Scholar
  69. Kelly LK, Porta NF, Goodman DM, Carroll CL, Steinhorn RH (2002) Inhaled prostacyclin for term infants with persistent pulmonary hypertension refractory to inhaled nitric oxide. J Pediatr 141:830–832PubMedCrossRefGoogle Scholar
  70. Kinsella JP, Abman SH (1995) Recent developments in the pathophysiology and treatment of persistent pulmonary hypertension of the newborn. J Pediatr 126:853–864PubMedCrossRefGoogle Scholar
  71. Kinsella JP, Abman SH (2000) Clinical approach to inhaled nitric oxide therapy in the newborn with hypoxemia. J Pediatr 136:717–726PubMedGoogle Scholar
  72. Kinsella JP, McQueston JA, Rosenberg AA, Abman SH (1992a) Hemodynamic effects of exogenous nitric oxide in ovine transitional pulmonary circulation. Am J Phys 262:H875–H880Google Scholar
  73. Kinsella JP, Neish SR, Shaffer E, Abman SH (1992b) Low-dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 340:819–820PubMedCrossRefGoogle Scholar
  74. Kinsella JP, Neish SR, Ivy DD, Shaffer E, Abman SH (1993) Clinical responses to prolonged treatment of persistent pulmonary hypertension of the newborn with low doses of inhaled nitric oxide. J Pediatr 123:103–108PubMedCrossRefGoogle Scholar
  75. Kinsella JP, Truog WE, Walsh WF et al (1997) Randomized, multicenter trial of inhaled nitric oxide and high frequency oscillatory ventilation in severe persistent pulmonary hypertension of the newborn. J Pediatr 131:55–62PubMedCrossRefGoogle Scholar
  76. Kinsella JP, Walsh WF, Bose CL et al (1999) Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: a randomised controlled trial. Lancet 354:1061–1065PubMedCrossRefGoogle Scholar
  77. Kinsella JP, Parker TA, Ivy DD, Abman SH (2003) Noninvasive delivery of inhaled nitric oxide therapy for late pulmonary hypertension in newborn infants with congenital diaphragmatic hernia. J Pediatr 142:397–401PubMedCrossRefGoogle Scholar
  78. Kinsella JP, Ivy DD, Abman SH (2005) Pulmonary vasodilator therapy in congenital diaphragmatic hernia: acute, late, and chronic pulmonary hypertension. Semin Perinatol 29:123–128PubMedCrossRefGoogle Scholar
  79. Kinsella JP, Cutter GR, Walsh WF et al (2006) Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med 205:354–364CrossRefGoogle Scholar
  80. Konduri GG, Ou J, Shi Y, Pritchard KA Jr (2003) Decreased association of HSP90 impairs endothelial nitric oxide synthase in fetal lambs with persistent pulmonary hypertension. Am J Physiol Heart Circ Physiol 285(1):H204–H211PubMedCrossRefGoogle Scholar
  81. Konduri GG, Solimani A, Sokol GM, Singer J, Ehrenkranz RA, Singhal N, Wright LL, Van Meurs K, Stork E, Kirpalani H, Peliowski A, Group NINOS (2004) A randomized trial of early versus standard inhaled nitric oxide therapy in term and near-term newborn infants with hypoxic respiratory failure. Pediatrics 113:559–564PubMedCrossRefGoogle Scholar
  82. Konduri GG, Bakhutashvili I, Eis A, Pritchard KA (2007) Oxidant stress from uncoupled nitric oxide synthase impairs vasodilation in fetal lambs with persistent pulmonary hypertension. Am J Physiol Heart Circ Physiol 292:H1812–H1820PubMedCrossRefGoogle Scholar
  83. Korones SB, Eyal FB (1975) Succesful treatment of “persistent fetal circulation” with tolazoline. Pediatr Res 9:367Google Scholar
  84. Laffey JG, Engelberts D, Kavanaugh BP (2000) Inurious effects of hypocapnic alkalosis in the isolated lung. Am J Respir Crit Care Med 162:399–405PubMedCrossRefGoogle Scholar
  85. Lakshminrusimha S, Russell JA, Wedgwood S, Gugino SF, Kazzaz JA, Davis JM, Steinhorn RH (2006a) Superoxide dismutase improves oxygenation and reduces oxidation in neonatal pulmonary hypertension. Am J Respir Crit Care Med 174(12):1370–1377. Epub 2006 Sep 1328PubMedPubMedCentralCrossRefGoogle Scholar
  86. Lakshminrusimha S, Russell JA, Steinhorn RH, Ryan RM, Gugino SF, Morin FC 3rd, Swartz DD, Kumar VH (2006b) Pulmonary arterial contractility in neonatal lambs increases with 100% oxygen resuscitation. Pediatr Res 59(1):137–141. Epub 2005 Dec 2002PubMedPubMedCentralCrossRefGoogle Scholar
  87. Lakshminrusimha S, Russell JA, Steinhorn RH, Swartz DD, Ryan RM, Gugino SF, Wynn KA, Kumar VH, Mathew B, Kirmani K, Morin FC 3rd (2007) Pulmonary hemodynamics in neonatal lambs resuscitated with 21%, 50%, and 100% oxygen. Pediatr Res 62:313–318PubMedPubMedCentralCrossRefGoogle Scholar
  88. Le LD, Keswani SG, Biesiada J, Lim FY, Kingma PS, Haberman BE et al (2012) The congenital diaphragmatic hernia composite prognostic index correlates with survival in left-sided congenital diaphragmatic hernia. J Pediatr Surg 47:57–62PubMedCrossRefGoogle Scholar
  89. Lees MH (1970) Cyanosis of the newborn. J Pediatr 77:484–498PubMedCrossRefGoogle Scholar
  90. Levin DL, Heymann MA, Kitterman JA, Gregory GA, Phibbs RH, Rudolph AM (1976) Persistent pulmonary hypertension of the newborn infant. J Pediatr 89:626–630PubMedCrossRefGoogle Scholar
  91. Levin DL, Hyman AI, Heymann MA, Rudolph AM (1978) Fetal hypertension and the development of increased pulmonary vascular smooth muscle: a possible mechanism for persistent pulmonary hypertension of the newborn infant. J Pediatr 92:265–269PubMedCrossRefGoogle Scholar
  92. Lipshutz GS, Albanese CT, Feldstein VA, Jennings RW, Housley HT, Beech R et al (1997) Prospective analysis of lung-to-head ratio predicts survival for patients with prenatally diagnosed congenital diaphragmatic hernia. J Pediatr Surg 32:1634–1636PubMedCrossRefGoogle Scholar
  93. Luccini B, Bimonetti GD, Ceschi A, Lava SA, Fare PB, Bianchetti MG (2013) Severe signs of hyponatremia secondary to desmopressin treatment for enuresis: a systematic review. J Pediatr Urol 9:1049–1053CrossRefGoogle Scholar
  94. Lusk LA, Wai KC, Moon-Grady AJ, Steurer MA, Keller RL (2015) Persistence of pulmonary hypertension by echocardiography predicts short-term outcomes in congenital diaphragmatic hernia. J Pediatr 166:251–256PubMedCrossRefGoogle Scholar
  95. Martin RJ, Walsh MC (2005) Inhaled nitric oxide for preterm infants – who benefits? N Engl J Med 353:82–84PubMedCrossRefGoogle Scholar
  96. McNamara PJ, Laique F, Muang-In S, Whyte HE (2006) Milrinone improves oxygenation in neonates with severe persistent pulmonary hypertension of the newborn. J Crit Care 21(2):217–222PubMedCrossRefGoogle Scholar
  97. McQueston JA, Cornfield DN, McMurtry IF, Abman SH (1993) Effects of oxygen and exogenous l-arginine on EDRF activity in fetal pulmonary circulation. Am J Physiol Heart Circ Physiol 264:865–871CrossRefGoogle Scholar
  98. McQueston JA, Kinsella JP, Ivy DD, McMurtry IF, Abman SH (1995) Chronic pulmonary hypertension in utero impairs endothelium-dependent vasodilation. Am J Physiol Heart Circ Physiol 268:H288–H294CrossRefGoogle Scholar
  99. Mercier JC, Hummler H, Durrmeyer X, Sanchez-Luna M, Carnielli V, Field D, Greenough A, Van Overmeire B, Jonsson B, Hallman M, Baldassarre J, EUNO Study Group (2010) Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial. Lancet 376(9738):346–354PubMedCrossRefGoogle Scholar
  100. Mestan KK, Marks JD, Hecox K et al (2005) Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N Engl J Med 353:23–32PubMedCrossRefGoogle Scholar
  101. Meurs KP, Rhine WD, Asselin JM, Duran DJ (1997) Response of premature infants with severe respiratory failure to inhaled nitric oxide. Preemie NO collaborative group. Pediatr Pulmonol 24:319–323PubMedCrossRefGoogle Scholar
  102. Mohamed WA, Ismail M (2012) A randomized, double-blind, placebo-controlled, prospective study of bosentan for the treatment of persistent pulmonary hypertension of the newborn. J Perinatol 32(8):608–613PubMedCrossRefGoogle Scholar
  103. Morin FC III, Eagan EA (1989) The effect of closing the ductus arteriosus on the pulmonary circulation of the fetal sheep. J Dev Physiol 11:245–250Google Scholar
  104. Murphy J, Aronovitz M, Reid L (1986) Effects of chronic in utero hypoxia on the pulmonary vasculature of the newborn guinea pig. Pediatr Res 20:292–295PubMedCrossRefGoogle Scholar
  105. Neonatal Inhaled Nitric Oxide Study Group (1997) Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med 336:597–604CrossRefGoogle Scholar
  106. Olson E, Lusk LA, Fineman JR, Robertson L, Keller RL (2015) Short-term treprostinil use in infants with congenital diaphragmatic hernia following repair. J Pediatr 167:762–764PubMedPubMedCentralCrossRefGoogle Scholar
  107. Palmer RMJ, Ferrige AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327:524–526CrossRefPubMedGoogle Scholar
  108. Parker TA, Ivy DD, Kinsella JP, Torielli F, Ruyle SZ, Thilo EH, Abman SH (1997) Combined therapy with inhaled nitric oxide and intravenous prostacyclin in an infant with alveolar-capillary dysplasia. Am J Respir Crit Care Med 155:743–746PubMedPubMedCentralCrossRefGoogle Scholar
  109. Patterson K, Kapur SP, Chandra RS (1988) PPHN: pulmonary pathologic effects. In: Rosenberg HS, Berstein J (eds) Cardiovascular diseases, perspectives in pediatric pathology, vol 12. Karger, Basel, pp 139–154Google Scholar
  110. Pearson DL, Dawling S, Walsh WF, Haines JL, Christman BW, Bazyk A, Scott N, Summar ML (2001) Neonatal pulmonary hypertension-urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function. N Engl J Med 344(24):1832–1838PubMedCrossRefGoogle Scholar
  111. Peliowski A, Finer NN, Etches PC, Tierney AJ, Ryan CA (1995) Inhaled nitric oxide for premature infants after prolonged rupture of the membranes. J Pediatr 126:450–453PubMedCrossRefGoogle Scholar
  112. Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D, Wallwork J (1991) Inhaled nitric oxide as a cause of selective pulmonary vasodilation in pulmonary hypertension. Lancet 338:1173–1174PubMedCrossRefGoogle Scholar
  113. Pierro M, Thebaud B (2014) Understanding and treating pulmonary hypertension in congenital diaphragmatic hernia. Semin Fetal Neonatal Med 19:357–363PubMedCrossRefGoogle Scholar
  114. Radicioni M, Troiani S, Camerini PG (2012) Effects of terlipressin on pulmonary artery pressure in a septic cooled infant: an echocardiographic assessment. J Perinatol 32:893–895PubMedCrossRefGoogle Scholar
  115. Roberton NRC, Hallidie-Smith DA, Davis JA (1967) Severe respiratory distress syndrome mimicking cyanotic heart disease in term babies. Lancet 2:1108–1110PubMedCrossRefGoogle Scholar
  116. Roberts JD, Polaner DM, Lang P et al (1992) Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 340:818–819PubMedCrossRefGoogle Scholar
  117. Roberts JD, Chen TY, Kawai N et al (1993) Inhaled nitric oxide reverses pulmonary vasoconstriction in the hypoxic and acidotic newborn lamb. Circ Res 72:246–254PubMedCrossRefGoogle Scholar
  118. Roberts JD, Fineman JR, Morin FC et al (1997) Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. N Engl J Med 336:605–610PubMedCrossRefGoogle Scholar
  119. Rosenberg AA, Kennaugh J, Koppenhafer SL, Loomis M, Chatfield BA, Abman SH (1993) Elevated immunoreactive endothelin-1 levels in newborn infants with persistent pulmonary hypertension. J Pediatr 123:109–114PubMedCrossRefGoogle Scholar
  120. Rossaint R, Falke KJ, Lopez F et al (1993) Inhaled nitric oxide for the adult respiratory distress syndrome. NEJM 328:399–405PubMedCrossRefGoogle Scholar
  121. Ruano R, Yoshisaki CT, da Silva MM, Ceccon ME, Grasi MS, Tannuri U et al (2012) A randomized controlled trial of fetal endoscopic tracheal occlusion versus postnatal management of severe isolated congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 39:20–27PubMedCrossRefGoogle Scholar
  122. Rudolph AM (1980) High pulmonary vascular resistance after birth: pathophysiologic considerations and etiologic classification. Clin Pediatr 19:585–590CrossRefGoogle Scholar
  123. Rudolph AM, Drorbraugh JE, Auld PAM, Rudolph AJ, Nadas AS, Smith CA, Hubbell JP (1961) Studies in the circulation in the neonatal period. The circulation in the respiratory distress syndrome. Pediatrics 27:551–556PubMedGoogle Scholar
  124. Russ RD, Walker BR (1992) Role of nitric oxide in vasopressinergic pulmonary vasodilatation. Am J Phys 262:H743–H747CrossRefGoogle Scholar
  125. Scheurer MA, Scott MB, Atz AM (2005) Vasopressin to attenuate pulmonary hypertension and improve systemic blood pressure after correction of obstructed total anomalous pulmonary venous return. J Thorac Cardiovasc Surg 129:464–466PubMedCrossRefGoogle Scholar
  126. Schreiber MD, Gin-Mestan K, Marks JD et al (2003) Inhaled nitric oxide in premature infants with the respiratory distress syndrome. N Engl J Med 349:2099–2107PubMedCrossRefGoogle Scholar
  127. Share L (1988) Role of vasopressin in cardiovascular regulation. Physiol Rev 68:1248–1284PubMedCrossRefGoogle Scholar
  128. Shaul PW, Yuhanna IS, German Z, Chen Z, Steinhorn RH, Morin FC III (1997) Pulmonary endothelial NO synthase gene expression is decreased in fetal lambs with pulmonary hypertension. Am J Phys Lung Cell Mol Phys 272:L1005–L1012Google Scholar
  129. Shekerdemian L, Ravn H, Penny D (2002) Intravenous sildenafil lowers pulmonary vascular resistance in a model of neonatal pulmonary hypertension. Am J Respir Crit Care Med 165:1098–2002PubMedCrossRefGoogle Scholar
  130. Shekerdemian LS, Ravn HB, Penny DJ (2004) Interaction between inhaled nitric oxide and intravenous sildenafil in a porcine model of meconium aspiration syndrome. Pediatr Res 55(3):413–418. Epub 2004 Jan 2007PubMedCrossRefGoogle Scholar
  131. SIassi B, Goldberg SJ, Emmanouilides GC, Higashimo SM, Lewis E (1971) Persistent pulmonary vascular obstruction in newborn infants. J Pediatr 78:610–615PubMedCrossRefGoogle Scholar
  132. Stahlman M (1964) Treatment of cardiovascular diseases of the newborn. Pediatr Clin N Am 11:363–400CrossRefGoogle Scholar
  133. Steinhorn RH, Russell JA, Morin FC III (1995) Disruption of cyclic GMP production in pulmonary arteries isolated from fetal lambs with pulmonary hypertension. Am J Physiol Heart Circ Physiol 268:H1483–H1489CrossRefGoogle Scholar
  134. Steinhorn RH, Kinsella JP, Butrous G, Dilleen M, Oakes M, Wessel DL (2007) Open-label, multicentre, pharmacokinetic study of IV sildenafil in the treatment of neonates with persistent pulmonary hypertension of the newborn (PPHN). Circulation 116:II–614Google Scholar
  135. Stevenson DK, Kasting DS, Darnall RA et al (1979) Refractory hypoxemia associated with neonatal pulmonary disease: the use and limitations of tolazoline. J Pediatr 95:595–599PubMedCrossRefGoogle Scholar
  136. Storme L, Rairigh RL, Parker TA, Kinsella JP, Abman SH (1999) Acute intrauterine pulmonary hypertension impairs endothelium dependent vasodilation in the ovine fetus. Pediatr Res 45:575–581PubMedCrossRefGoogle Scholar
  137. Subhedar NV, Ryan SW, Shaw NJ (1997) Open randomised controlled trial of inhaled nitric oxide and early dexamethasone in high risk preterm infants. Arch Dis Child 77:F185–F190CrossRefGoogle Scholar
  138. Taira Y, Yamataka T, Miyazaki E, Puri P (1998) Comparison of the pulmonary vasculature in newborns and stillborns with congenital diaphragmatic hernia. Pediatr Surg Int 14:30–35PubMedCrossRefGoogle Scholar
  139. The Franco – Belgium Collaborative NO Trial Group (1999) Early compared with delayed inhaled nitric oxide in moderately hypoxaemic neonates with respiratory failure: a randomised controlled trial. Lancet 354:1066–1071CrossRefGoogle Scholar
  140. The Neonatal Inhaled Nitric Oxide Study Group (NINOS) (1997) Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics 99:838–845CrossRefGoogle Scholar
  141. Tiktinsky MH, Morin FC (1993) Increasing oxygen tension dilates fetal pulmonary circulation via endothelium-derived relaxing factor. Am J Phys 265:H376–H380Google Scholar
  142. Tzao C, Nickerson PA, Russell JA, Gugino SF, Steinhorn RH (2001) Pulmonary hypertension alters soluble guanylate cyclase activity and expression in pulmonary arteries isolated from fetal lambs. Pediatr Pulmonol 31:97–105PubMedCrossRefGoogle Scholar
  143. van der Cammen-van Zijp MH, Janssen AJ, Raets MM, van Rosmalen J, Govaert P, Steiner K, Gischler SJ, Tibboel D, van Heijst AF (2014) IJsselstijn H; Dutch ECMO follow-up team. Motor performance after neonatal extracorporeal membrane oxygenation: a longitudinal evaluation. Pediatrics 134(2):e427–e435PubMedCrossRefGoogle Scholar
  144. Van Marter LJ, Leviton A, Allred EN (1996) PPHN and smoking and aspirin and nonsteroidal antiinflammatory drug consumption during pregnancy. Pediatrics 97:658–663PubMedGoogle Scholar
  145. Van Meurs KP, Wright LL, Ehrenkranz RA et al (2005) Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med 353:13–22PubMedCrossRefGoogle Scholar
  146. Villamor E, LeCras TD, Horan MP, Halbower AC, Tuder RM, Abman SH (1997) Chronic intrauterine pulmonary hypertension impairs endothelial nitric oxide synthase in the ovine fetus. Am J Phys Lung Cell Mol Phys 272:L1013–L1020Google Scholar
  147. Walsh MC, Hibbs AM, Martin CR, Cnaan A, Keller RL, Vittinghoff E, Martin RJ, Truog WE, Ballard PL, Zadell A, Wadlinger SR, Coburn CE, Ballard RA, NO CLD Study Group (2010) Two-year neurodevelopmental outcomes of ventilated preterm infants treated with inhaled nitric oxide. J Pediatr 156(4):556–61.e1.  https://doi.org/10.1016/j.jpeds.2009.10.011. Epub 2010 Feb 6CrossRefPubMedPubMedCentralGoogle Scholar
  148. Walsh-Sukys MC, Tyson JE, Wright LL, Bauer CR, Korones SB, Stevenson DK, Verter J, Stoll BJ, Lemons JA, Papile LA, Shankaran S, Donovan EF, Oh W, Ehrenkranz RA, Fanaroff AA (2000) Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics 105:14–20PubMedCrossRefGoogle Scholar
  149. Wedgwood S, Black SM (2003) Role of reactive oxygen species in vascular remodeling associated with pulmonary hypertension. Antioxid Redox Signal 5(6):759–769PubMedCrossRefGoogle Scholar
  150. Wedgwood S, Steinhorn RH, Bunderson M, Wilham J, Lakshminrusimha S, Brennan LA, Black SM (2005) Increased hydrogen peroxide downregulates soluble guanylate cyclase in the lungs of lambs with persistent pulmonary hypertension of the newborn. Am J Phys Lung Cell Mol Phys 289(4):L660–L666. Epub 2005 Jun 2003Google Scholar
  151. Weimann J, Ullrich R, Hromi J, Fujino Y, Clark MWH, Bloch KD, Zapol WM (2000) Sildenafil is a pulmonary vasodilator in awake lambs with acute pulmonary hypertension. Anesthesiology 92:1702–1712PubMedCrossRefGoogle Scholar
  152. Wessel DL, Adatia I, Van Marter LJ et al (1997) Improved oxygenation in a randomized trial of inhaled nitric oxice for persistent pulmonary hypertension of the newborn. Pediatrics 100:e7PubMedCrossRefGoogle Scholar
  153. Wynn J, Krishnan U, Aspelund G, Zhang Y, Duong J, Stolar CJ et al (2013) Outcomes of congenital diaphragmatic hernia in the modern era of management. J Pediatr 163:114–119PubMedPubMedCentralCrossRefGoogle Scholar
  154. Yuniartha R, Alatas FS, Nagata K, Kuda M, Yanagi Y, Esumi G et al (2014) Therapeutic potential of mesenchymal stem cell transplantation in a nitrofen-induced congenital diaphragmatic hernia rat model. Pediatr Surg Int 30:907–914PubMedCrossRefGoogle Scholar
  155. Ziegler JW, Ivy DD, Wiggins JW, Kinsella JP, Clarke WR, Abman SH (1998) Effects of dipyridamole and inhaled nitric oxide in pediatric patients with pulmonary hypertension. Am J Respir Crit Care Med 158:1388–1395PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Jason Gien
    • 1
  • John P. Kinsella
    • 2
  • Steven H. Abman
    • 3
  1. 1.University of Colorado DenverDenverUSA
  2. 2.University of DenverDenverUSA
  3. 3.University of Colorado Denver – Anschutz Medical CampusDenverUSA

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