SpringerLink
Log in

Persistent Pulmonary Hypertension of the Newborn

  • Living reference work entry
  • First Online:
Neonatology

  • 241 Accesses

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

Similar content being viewed by others

References

  • Abman SH (2001) Bronchopulmonary dysplasia: a “vascular hypothesis”. Am J Respir Crit Care Med 164:1755–1756

    Article  CAS  PubMed  Google Scholar 

  • 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–H634

    Google Scholar 

  • Abman SH, Kinsella JP (1995) Inhaled nitric oxide for persistent pulmonary hypertension of the newborn: the physiology matters. Pediatrics 96:1153–1155

    CAS  PubMed  Google Scholar 

  • 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–H1927

    CAS  Google Scholar 

  • Abman SH, Griebel JL, Parker DK et al (1994) Acute effects of inhaled nitric oxide in severe hypoxemic respiratory failure in pediatrics. J Pediatr 124:881–888

    Article  CAS  PubMed  Google Scholar 

  • 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 342:1301–1308

    Article  Google Scholar 

  • 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 15:148–154

    Article  PubMed  Google Scholar 

  • Agrawal A, Singh VK, Varma A, Sharma R (2012) Therapeutic applications of vasopressin in pediatric patients. Indian Pediatr 49:297–305

    Article  PubMed  Google Scholar 

  • 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):519–523

    Article  CAS  PubMed  Google Scholar 

  • 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 35:212A

    Google Scholar 

  • 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 180:1122–1130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Atz AM, Wessel DL (1999) Sildenafil ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology 91:307–310

    Article  CAS  PubMed  Google Scholar 

  • 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–L833

    CAS  Google Scholar 

  • Ballard RA, Truog WE, Cnaan A et al (2006) Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. N Engl J Med 205:343–353

    Article  Google Scholar 

  • 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 133:5762

    Article  Google Scholar 

  • Behrman RE (1976) Persistence of the fetal circulation. J Pediatr 89:636–637

    Article  CAS  PubMed  Google Scholar 

  • 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 92:683–691

    Article  CAS  PubMed  Google Scholar 

  • 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):688–94

    Google Scholar 

  • 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):579–587

    Article  CAS  PubMed  Google Scholar 

  • 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:L318

    CAS  Google Scholar 

  • 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 342:469–474

    Article  CAS  PubMed  Google Scholar 

  • 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):363–369

    Article  PubMed  Google Scholar 

  • 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–H1481

    CAS  Google Scholar 

  • 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 104:1089–1094

    Article  CAS  PubMed  Google Scholar 

  • Cotton EK (1965) The use of priscoline in the treatment of the hypoperfusion syndrome. Pediatrics 36:149

    CAS  PubMed  Google Scholar 

  • 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 101:325–334

    Article  CAS  PubMed  Google Scholar 

  • 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 47:282–290

    Article  PubMed  Google Scholar 

  • 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 103:1241–1245

    Article  CAS  PubMed  Google Scholar 

  • Faraci F, Didion S (2004) Vascular protection: Superoxide dismutase isoforms in the vessel wall. Arterioscler Thromb Vasc Biol 24:1367–1373

    Article  CAS  PubMed  Google Scholar 

  • 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–L987

    Google Scholar 

  • 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):226–233

    Article  CAS  PubMed  Google Scholar 

  • Field DJ (2005) Nitric oxide-still no consensus. Early Hum Dev 81:1–4

    Article  CAS  PubMed  Google Scholar 

  • 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 115:926–936

    Article  CAS  PubMed  Google Scholar 

  • 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–L888

    CAS  Google Scholar 

  • 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–e241

    Article  PubMed  Google Scholar 

  • Finer NN (2005) Inhaled nitric oxide for preterm infants: A therapy in search of an indication? The search continues. J Pediatr 146:301–302

    Article  PubMed  Google Scholar 

  • Finer NN, Etches PC, Kamstra B et al (1994) Inhaled nitric oxide in infants referred for extracorporeal membrane oxygenation: dose response. J Pediatr 124:302–308

    Article  CAS  PubMed  Google Scholar 

  • 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 108:949–955

    Article  CAS  PubMed  Google Scholar 

  • 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):1035–1040

    Article  CAS  PubMed  Google Scholar 

  • Fox WW, Gewitz MH, Dinwiddie R, Drummond WH, Peckham GJ (1977) Pulmonary hypertension in the perinatal aspiration syndromes. Pediatrics 59:205–211

    CAS  PubMed  Google Scholar 

  • Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM (1991) A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 83:2038–2047

    Article  CAS  PubMed  Google Scholar 

  • Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:373–376

    Article  CAS  PubMed  Google Scholar 

  • Geggel RL, Reid LM (1984) The structural basis of PPHN. Clin Perinatol 11:525–549

    CAS  PubMed  Google Scholar 

  • 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 23:499–502

    Article  CAS  PubMed  Google Scholar 

  • Gersony WM (1984) Neonatal pulmonary hypertension: pathophysiology, classification and etiology. Clin Perinatol 11:517–524

    CAS  PubMed  Google Scholar 

  • Gersony WM, Duc GV, Sinclair JC (1969) “PFC” syndrome (persistence of the fetal circulation). Circulation 40:111

    Google Scholar 

  • 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:F314

    Article  PubMed  Google Scholar 

  • 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 89:617–621

    Article  CAS  PubMed  Google Scholar 

  • 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 98:706–713

    CAS  PubMed  Google Scholar 

  • 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 148:1651–1656

    Article  CAS  PubMed  Google Scholar 

  • 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–L517

    CAS  Google Scholar 

  • 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–L535

    Google Scholar 

  • Hamon I, Fresson J, Nicolas MB et al (2005) Early inhaled nitric oxide improves oxidative balance in very preterm infants. Pediatr Res 57:637–643

    Article  CAS  PubMed  Google Scholar 

  • Hanson KA, Abman SH, Clarke WR (1996) Elevation of pulmonary PDE5-specific activity in an experimental fetal ovine perinatal pulmonary hypertension model. Pediatr Res 39:334A

    Article  Google Scholar 

  • Harrison MR, de Lorimier AA (1981) Congenital diaphragmatic hernia. Surg Clin North Am 61:1023–1035

    Article  CAS  PubMed  Google Scholar 

  • Hascoet JM, Fresson J, Claris O et al (2005) The safety and efficacy of nitric oxide therapy in premature infants. J Pediatr 146:318–323

    Article  CAS  PubMed  Google Scholar 

  • Haworth SG, Reid L (1976) Persistent fetal circulation: newly recognized structural features. J Pediatr 88:614–620

    Article  CAS  PubMed  Google Scholar 

  • 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):525–529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 137:107S

    Google Scholar 

  • 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):16–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 20:1779–1792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 29:1000–1005

    Article  CAS  PubMed  Google Scholar 

  • 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 84:9265–9269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 39:435–442

    Article  CAS  PubMed  Google Scholar 

  • 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 99:1179–1186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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–L541

    CAS  Google Scholar 

  • 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 31:699–704

    Article  CAS  PubMed  Google Scholar 

  • Kamath BD, Fashaw L, Kinsella JP (2010) Adrenal insufficiency in newborns with congenital diaphragmatic hernia. J Pediatr 156:495–497

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 141:830–832

    Article  CAS  PubMed  Google Scholar 

  • Kinsella JP, Abman SH (1995) Recent developments in the pathophysiology and treatment of persistent pulmonary hypertension of the newborn. J Pediatr 126:853–864

    Article  CAS  PubMed  Google Scholar 

  • Kinsella JP, Abman SH (2000) Clinical approach to inhaled nitric oxide therapy in the newborn with hypoxemia. J Pediatr 136:717–726

    CAS  PubMed  Google Scholar 

  • 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–H880

    Google Scholar 

  • Kinsella JP, Neish SR, Shaffer E, Abman SH (1992b) Low-dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 340:819–820

    Article  CAS  PubMed  Google Scholar 

  • 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 123:103–108

    Article  CAS  PubMed  Google Scholar 

  • 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 131:55–62

    Article  CAS  PubMed  Google Scholar 

  • 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 354:1061–1065

    Article  CAS  PubMed  Google Scholar 

  • 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 142:397–401

    Article  CAS  PubMed  Google Scholar 

  • Kinsella JP, Ivy DD, Abman SH (2005) Pulmonary vasodilator therapy in congenital diaphragmatic hernia: acute, late, and chronic pulmonary hypertension. Semin Perinatol 29:123–128

    Article  PubMed  Google Scholar 

  • Kinsella JP, Cutter GR, Walsh WF et al (2006) Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med 205:354–364

    Article  Google Scholar 

  • 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–H211

    Article  CAS  PubMed  Google Scholar 

  • 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 113:559–564

    Article  PubMed  Google Scholar 

  • 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–H1820

    Article  CAS  PubMed  Google Scholar 

  • Korones SB, Eyal FB (1975) Succesful treatment of “persistent fetal circulation” with tolazoline. Pediatr Res 9:367

    Google Scholar 

  • Laffey JG, Engelberts D, Kavanaugh BP (2000) Inurious effects of hypocapnic alkalosis in the isolated lung. Am J Respir Crit Care Med 162:399–405

    Article  CAS  PubMed  Google Scholar 

  • 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 1328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 2002

    Article  PubMed  Google Scholar 

  • 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 62:313–318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 47:57–62

    Article  PubMed  Google Scholar 

  • Lees MH (1970) Cyanosis of the newborn. J Pediatr 77:484–498

    Article  CAS  PubMed  Google Scholar 

  • Levin DL, Heymann MA, Kitterman JA, Gregory GA, Phibbs RH, Rudolph AM (1976) Persistent pulmonary hypertension of the newborn infant. J Pediatr 89:626–630

    Article  CAS  PubMed  Google Scholar 

  • 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 92:265–269

    Article  CAS  PubMed  Google Scholar 

  • 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 32:1634–1636

    Article  CAS  PubMed  Google Scholar 

  • 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 9:1049–1053

    Article  Google Scholar 

  • 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 166:251–256

    Article  PubMed  Google Scholar 

  • Martin RJ, Walsh MC (2005) Inhaled nitric oxide for preterm infants – who benefits? N Engl J Med 353:82–84

    Article  CAS  PubMed  Google Scholar 

  • 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):217–222

    Article  CAS  PubMed  Google Scholar 

  • 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 264:865–871

    Google Scholar 

  • 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–H294

    CAS  Google Scholar 

  • 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):346–354

    Article  CAS  PubMed  Google Scholar 

  • Mestan KK, Marks JD, Hecox K et al (2005) Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N Engl J Med 353:23–32

    Article  CAS  PubMed  Google Scholar 

  • 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 24:319–323

    Article  PubMed  Google Scholar 

  • 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):608–613

    Article  CAS  PubMed  Google Scholar 

  • Morin FC III, Eagan EA (1989) The effect of closing the ductus arteriosus on the pulmonary circulation of the fetal sheep. J Dev Physiol 11:245–250

    Google Scholar 

  • Murphy J, Aronovitz M, Reid L (1986) Effects of chronic in utero hypoxia on the pulmonary vasculature of the newborn guinea pig. Pediatr Res 20:292–295

    Article  CAS  PubMed  Google Scholar 

  • 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 336:597–604

    Article  Google Scholar 

  • 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 167:762–764

    Article  PubMed  PubMed Central  Google Scholar 

  • Palmer RMJ, Ferrige AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327:524–526

    Article  CAS  PubMed  Google Scholar 

  • 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 155:743–746

    Article  CAS  PubMed  Google Scholar 

  • 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 139–154

    Google Scholar 

  • 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):1832–1838

    Article  CAS  PubMed  Google Scholar 

  • 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 126:450–453

    Article  CAS  PubMed  Google Scholar 

  • 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 338:1173–1174

    Article  CAS  PubMed  Google Scholar 

  • Pierro M, Thebaud B (2014) Understanding and treating pulmonary hypertension in congenital diaphragmatic hernia. Semin Fetal Neonatal Med 19:357–363

    Article  CAS  PubMed  Google Scholar 

  • Radicioni M, Troiani S, Camerini PG (2012) Effects of terlipressin on pulmonary artery pressure in a septic cooled infant: an echocardiographic assessment. J Perinatol 32:893–895

    Article  CAS  PubMed  Google Scholar 

  • Roberton NRC, Hallidie-Smith DA, Davis JA (1967) Severe respiratory distress syndrome mimicking cyanotic heart disease in term babies. Lancet 2:1108–1110

    Article  CAS  PubMed  Google Scholar 

  • Roberts JD, Polaner DM, Lang P et al (1992) Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 340:818–819

    Article  CAS  PubMed  Google Scholar 

  • Roberts JD, Chen TY, Kawai N et al (1993) Inhaled nitric oxide reverses pulmonary vasoconstriction in the hypoxic and acidotic newborn lamb. Circ Res 72:246–254

    Article  CAS  PubMed  Google Scholar 

  • Roberts JD, Fineman JR, Morin FC et al (1997) Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. N Engl J Med 336:605–610

    Article  CAS  PubMed  Google Scholar 

  • 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 123:109–114

    Article  CAS  PubMed  Google Scholar 

  • Rossaint R, Falke KJ, Lopez F et al (1993) Inhaled nitric oxide for the adult respiratory distress syndrome. NEJM 328:399–405

    Article  CAS  PubMed  Google Scholar 

  • 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 39:20–27

    Article  CAS  PubMed  Google Scholar 

  • Rudolph AM (1980) High pulmonary vascular resistance after birth: pathophysiologic considerations and etiologic classification. Clin Pediatr 19:585–590

    Article  CAS  Google Scholar 

  • 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 27:551–556

    CAS  PubMed  Google Scholar 

  • Russ RD, Walker BR (1992) Role of nitric oxide in vasopressinergic pulmonary vasodilatation. Am J Phys 262:H743–H747

    CAS  Google Scholar 

  • 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 129:464–466

    Article  PubMed  Google Scholar 

  • 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 349:2099–2107

    Article  CAS  PubMed  Google Scholar 

  • Share L (1988) Role of vasopressin in cardiovascular regulation. Physiol Rev 68:1248–1284

    CAS  PubMed  Google Scholar 

  • 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–L1012

    CAS  Google Scholar 

  • 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 165:1098–2002

    Article  PubMed  Google Scholar 

  • 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 2007

    Article  CAS  PubMed  Google Scholar 

  • SIassi B, Goldberg SJ, Emmanouilides GC, Higashimo SM, Lewis E (1971) Persistent pulmonary vascular obstruction in newborn infants. J Pediatr 78:610–615

    Article  CAS  PubMed  Google Scholar 

  • Stahlman M (1964) Treatment of cardiovascular diseases of the newborn. Pediatr Clin N Am 11:363–400

    Article  CAS  Google Scholar 

  • 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–H1489

    CAS  Google Scholar 

  • 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–614

    Google Scholar 

  • Stevenson DK, Kasting DS, Darnall RA et al (1979) Refractory hypoxemia associated with neonatal pulmonary disease: the use and limitations of tolazoline. J Pediatr 95:595–599

    Article  CAS  PubMed  Google Scholar 

  • 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 45:575–581

    Article  CAS  PubMed  Google Scholar 

  • 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–F190

    Article  CAS  Google Scholar 

  • 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 14:30–35

    Article  CAS  PubMed  Google Scholar 

  • 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 354:1066–1071

    Article  Google Scholar 

  • The Neonatal Inhaled Nitric Oxide Study Group (NINOS) (1997) Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics 99:838–845

    Article  Google Scholar 

  • Tiktinsky MH, Morin FC (1993) Increasing oxygen tension dilates fetal pulmonary circulation via endothelium-derived relaxing factor. Am J Phys 265:H376–H380

    CAS  Google Scholar 

  • 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 31:97–105

    Article  CAS  PubMed  Google Scholar 

  • 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–e435

    Article  PubMed  Google Scholar 

  • Van Marter LJ, Leviton A, Allred EN (1996) PPHN and smoking and aspirin and nonsteroidal antiinflammatory drug consumption during pregnancy. Pediatrics 97:658–663

    PubMed  Google Scholar 

  • Van Meurs KP, Wright LL, Ehrenkranz RA et al (2005) Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med 353:13–22

    Article  PubMed  Google Scholar 

  • 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–L1020

    CAS  Google Scholar 

  • 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 6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 105:14–20

    Article  CAS  PubMed  Google Scholar 

  • Wedgwood S, Black SM (2003) Role of reactive oxygen species in vascular remodeling associated with pulmonary hypertension. Antioxid Redox Signal 5(6):759–769

    Article  CAS  PubMed  Google Scholar 

  • 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 2003

    CAS  Google Scholar 

  • Weimann J, Ullrich R, Hromi J, Fu**o Y, Clark MWH, Bloch KD, Zapol WM (2000) Sildenafil is a pulmonary vasodilator in awake lambs with acute pulmonary hypertension. Anesthesiology 92:1702–1712

    Article  CAS  PubMed  Google Scholar 

  • 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:e7

    Article  CAS  PubMed  Google Scholar 

  • 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 163:114–119

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 30:907–914

    Article  PubMed  Google Scholar 

  • 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 158:1388–1395

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of Colorado Denver, Denver, CO, USA

    Jason Gien

  2. University of Denver, Denver, CO, USA

    John P. Kinsella

  3. University of Colorado Denver – Anschutz Medical Campus, Denver, CO, USA

    Steven H. Abman

Authors
  1. Jason Gien
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John P. Kinsella
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Steven H. Abman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jason Gien .

Editor information

Editors and Affiliations

  1. Siena, Italy

    Giuseppe Buonocore

  2. Medicina della Riproduzione, Università di Siena Dipto. Pediatria, Ostetricia e, Siena, Italy

    Rodolfo Bracci

  3. Liverpool Women's Hospital Neonatal Unit, Liverpool, United Kingdom

    Michael Weindling

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this entry

Cite this entry

Gien, J., Kinsella, J.P., Abman, S.H. (2017). Persistent Pulmonary Hypertension of the Newborn. In: Buonocore, G., Bracci, R., Weindling, M. (eds) Neonatology. Springer, Cham. https://doi.org/10.1007/978-3-319-18159-2_208-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-18159-2_208-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-18159-2

  • Online ISBN: 978-3-319-18159-2

  • eBook Packages: Springer Reference MedicineReference Module Medicine

Publish with us

Policies and ethics

Search

Navigation