Abstract

Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome of failed circulatory adaptation at birth, seen in about 2/1000 live born infants. While it is more commonly encountered in term and near term babies, it can be recognized in some premature babies with respiratory distress or bronchopulmonary dysplasia. Most commonly, PPHN is secondary to delayed or impaired relaxation of the pulmonary vasculature associated with diverse neonatal pulmonary pathologies such as meconium aspiration syndrome, congenital diaphragmatic hernia and respiratory distress syndrome.

• 1.   Lakshminrusimha S, Steinhorn RH. Pulmonary vascular biology during neonatal transition. Clinics in perinatology. 1999 Sep 1;26(3):601-19.
• 2.   Delaney C, Gien J, Grover TR, Roe G, Abman SH. Pulmonary vascular effects of serotonin and selective serotonin reuptake inhibitors in the late-gestation ovine fetus. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2011 Dec;301(6):L937-44.
• 3.   Delaney C, Gien J, Roe G, Isenberg N, Kailey J, Abman SH. Serotonin contributes to high pulmonary vascular tone in a sheep model of persistent pulmonary hypertension of the newborn. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2013 Jun 15;304(12):L894-901.
• 4.   Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, Mitchell AA. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. New England Journal of Medicine. 2006 Feb 9;354(6):579-87.
• 5.   Teitel DF, Iwamoto HS, Rudolph AM. Changes in the pulmonary circulation during birth-related events. Pediatric Research. 1990 Apr;27(4):372-8.
• 6.   Haworth SG, Hislop AA. Adaptation of the pulmonary circulation to extra-uterine life in the pig and its relevance to the human infant. Cardiovascular research. 1981 Feb 1;15(2):108-19.
• 7.   Konduri GG, Theodorou AA, Mukhopadhyay A, Deshmukh DR. Adenosine triphosphate and adenosine increase the pulmonary blood flow to postnatal levels in fetal lambs. Pediatric research. 1992 May;31(5):451-7.
• 8.   Steinhorn RH, Morin 3rd FC, Van Wylen DG, Gugino SF, Giese EC, Russell JA. Endotheliumdependent relaxations to adenosine in juvenile rabbit pulmonary arteries and veins. American Journal of Physiology-Heart and Circulatory Physiology. 1994 May 1;266(5):H2001-6.
• 9.   Shaul PW, Farrar MA, Zellers TM. Oxygen modulates endothelium-derived relaxing factor production in fetal pulmonary arteries. American Journal of Physiology-Heart and Circulatory Physiology. 1992 Feb 1;262(2):H355-64.
• 10.   Bloch KD, Filippov G, Sanchez LS, Nakane M, De La Monte SM. Pulmonary soluble guanylate cyclase, a nitric oxide receptor, is increased during the perinatal period. American Journal of Physiology-Lung Cellular and Molecular Physiology. 1997 Mar 1;272(3):L400-6.
• 11.   Hanson KA, Ziegler JW, Rybalkin SD, Miller JW, Abman SH, Clarke WR. Chronic pulmonary hypertension increases fetal lung cGMP phosphodiesterase activity. American Journal of Physiology-Lung Cellular and Molecular Physiology. 1998 Nov 1;275(5):L931-41.
• 12.   Sanchez LS, De La Monte SM, Filippov G, Jones RC, Zapol WM, Bloch KD. Cyclic-GMPbinding, cyclic-GMP-specific phosphodiesterase (PDE5) gene expression is regulated during rat pulmonary development. Pediatric research. 1998 Feb;43(2):163-8.
• 13.   Van Marter LJ, Hernandez-Diaz S, Werler MM, Louik C, Mitchell AA. Nonsteroidal antiinflammatory drugs in late pregnancy and persistent pulmonary hypertension of the
• 14.   Lakshminrusimha S, D'Angelis CA, Russell JA, Nielsen LC, Gugino SF, Nickerson PA, Steinhorn RH. C-type natriuretic peptide system in fetal ovine pulmonary vasculature. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2001 Aug 1;281(2):L361-8.
• 15.   Singh SA, Ibrahim T, Clark DJ, Taylor RS, George DH. Persistent pulmonary hypertension of newborn due to congenital capillary alveolar dysplasia. Pediatric pulmonology. 2005 Oct;40(4):349-53.
• 16.   Hamvas A, Cole FS, Nogee LM. Genetic disorders of surfactant proteins. Neonatology. 2007;91(4):311-7.
• 17.   Shulenin S, Nogee LM, Annilo T, Wert SE, Whitsett JA, Dean M. ABCA3 gene mutations in newborns with fatal surfactant deficiency. New England Journal of Medicine. 2004 Mar 25;350(13):1296-303.
• 18.   Byers HM, Dagle JM, Klein JM, Ryckman KK, McDonald EL, Murray JC, Borowski KS. Variations in CRHR1 are associated with persistent pulmonary hypertension of the newborn. Pediatric research. 2012 Feb;71(2):162-7.
• 19.   Dargaville PA, South M, McDougall PN. Surfactant and surfactant inhibitors in meconium aspiration syndrome. The Journal of pediatrics. 2001 Jan 1;138(1):113-5.
• 20.   Lapointe A, Barrington KJ. Pulmonary hypertension and the asphyxiated newborn. The Journal of pediatrics. 2011 Feb 1;158(2):e19-24.
• 21.   Shah PS, Ohlsson A, Perlman M. Hypothermia to treat neonatal hypoxic ischemic encephalopathy: systematic review. Archives of pediatrics & adolescent medicine. 2007 Oct 1;161(10):951-8.
• 22.   Van Meurs KP, Wright LL, Ehrenkranz RA, Lemons JA, Ball MB, Poole WK, Perritt R, Higgins RD, Oh W, Hudak ML, Laptook AR. Inhaled nitric oxide for premature infants with severe respiratory failure. New England Journal of Medicine. 2005 Jul 7;353(1):13-22.
• 23.   Kumar VH, Hutchison AA, Lakshminrusimha S, Morin FC, Wynn RJ, Ryan RM. Characteristics of pulmonary hypertension in preterm neonates. Journal of Perinatology. 2007 Apr;27(4):214-9.
• 24.   Check J, Gotteiner N, Liu X, Su E, Porta N, Steinhorn R, Mestan KK. Fetal growth restriction and pulmonary hypertension in premature infants with bronchopulmonary dysplasia. Journal of Perinatology. 2013 Jul;33(7):553-7.
• 25.   Mourani PM, Abman SH. Pulmonary vascular disease in bronchopulmonary dysplasia: pulmonary hypertension and beyond. Current opinion in pediatrics. 2013 Jun 1;25(3):329-37.
• 26.   Alano MA, Ngougmna E, Ostrea EM, Konduri GG. Analysis of nonsteroidal antiinflammatory drugs in meconium and its relation to persistent pulmonary hypertension of the newborn. Pediatrics. 2001 Mar 1;107(3):519-23.
• 27.   Wild LM, Nickerson PA, Morin FC. Ligating the ductus arteriosus before birth remodels the pulmonary vasculature of the lamb. Pediatric research. 1989 Mar;25(3):251-7.
• 28.   Dukarm RC, Morin FC, Russell JA, Steinhorn RH. Pulmonary and systemic effects of the phosphodiesterase inhibitor dipyridamole in newborn lambs with persistent pulmonary hypertension. Pediatric research. 1998 Dec;44(6):831-7.
• 29.   Shaul PW, Yuhanna IS, German Z, Chen Z, Steinhorn RH, Morin 3rd FC. Pulmonary endothelial NO synthase gene expression is decreased in fetal lambs with pulmonary
• 30.   Steinhorn RH, Russell JA, Morin 3rd FC. Disruption of cGMP production in pulmonary arteries isolated from fetal lambs with pulmonary hypertension. American Journal of PhysiologyHeart and Circulatory Physiology. 1995 Apr 1;268(4):H1483-9.
• 31.   Villanueva ME, Zaher FM, Svinarich DM, Konduri GG. Decreased gene expression of endothelial nitric oxide synthase in newborns with persistent pulmonary hypertension. Pediatric research. 1998 Sep;44(3):338-43.
• 32.   Pearson DL, Dawling S, Walsh WF, Haines JL, Christman BW, Bazyk A, Scott N, Summar ML. Neonatal pulmonary hypertension: ureacycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function. New England Journal of Medicine. 2001 Jun 14;344(24):1832-8.
• 33.   Storme L, Aubry E, Rakza T, Houeijeh A, Debarge V, Tourneux P, Deruelle P, Pennaforte T, French Congenital Diaphragmatic Hernia Study Group. Pathophysiology of persistent pulmonary hypertension of the newborn: impact of the perinatal environment. Archives of cardiovascular diseases. 2013 Mar 1;106(3):169-77.
• 34.   Reynolds EW, Ellington JG, Vranicar M, Bada HS. Brain-type natriuretic peptide in the diagnosis and management of persistent pulmonary hypertension of the newborn. Pediatrics. 2004 Nov 1;114(5):1297-304.
• 35.   Vijlbrief DC, Benders MJ, Kemperman H, van Bel F, de Vries WB. B-type natriuretic peptide and rebound during treatment for persistent pulmonary hypertension. The Journal of pediatrics. 2012 Jan 1;160(1):111-5.
• 36.   Lakshminrusimha S, Russell JA, Steinhorn RH, Ryan RM, Gugino SF, Morin FC, Swartz DD, Kumar VH. Pulmonary arterial contractility in neonatal lambs increases with 100% oxygen resuscitation. Pediatric research. 2006 Jan;59(1):137-41.
• 37.   Lakshminrusimha S, Russell JA, Steinhorn RH, Swartz DD, Ryan RM, Gugino SF, Wynn KA, Kumar VH, Mathew B, Kirmani K, Morin FC. Pulmonary hemodynamics in neonatal lambs resuscitated with 21%, 50%, and 100% oxygen. Pediatric research. 2007 Sep;62(3):313-8.
• 38.   Lakshminrusimha S, Swartz DD, Gugino SF, Ma CX, Wynn KA, Ryan RM, Russell JA, Steinhorn RH. Oxygen concentration and pulmonary hemodynamics in newborn lambs with pulmonary hypertension. Pediatric research. 2009 Nov;66(5):539-44.
• 39.   Pabalan MJ, Nayak SP, Ryan RM, Kumar VH, Lakshminrusimha S. Methemoglobin to cumulative nitric oxide ratio and response to inhaled nitric oxide in PPHN. Journal of
• 40.   Carlo WA, Beoglos A, Chatburn RL, Walsh MC, Martin RJ. High-frequency jet ventilation in neonatal pulmonary hypertension. Am J Dis Child. 1989;143:233–8.
• 41.   Engle WA, Yoder MC, Andreoli SP, Darragh RK, Langefeld CD, Hui SL. Controlled prospective randomized comparison of high-frequency jet ventilation and conventional ventilation in neonates with respiratory failure and persistent pulmonary hypertension. Journal of Perinatology. 1997;17:3–9.
• 42.   Kinsella JP, Abman SH. Clinical approaches to the use of high-frequency oscillatory ventilation in neonatal respiratory failure. Journal of Perinatology. 1996;16:S52–5.
• 43.   Kinsella JP, Abman SH. High-frequency oscillatory ventilation augments the response to inhaled nitric oxide in persistent pulmonary hypertension of the newborn: Nitric Oxide Study Group. Chest. 1998;114:100S.
• 44.   Kinsella JP, Truog WE, Walsh WF, Goldberg RN, Bancalari E, Mayock DE, et al. Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn. J Pediatr. 1997;131:55–62.
• 45.   Lotze A, Mitchell BR, Bulas DI, Zola EM, Shalwitz RA, Gunkel JH. Multicenter study of surfactant (beractant) use in the treatment of term infants with severe respiratory failure. Survanta in Term Infants Study Group. J Pediatr. 1998;132:40–7.
• 46.   Aly H, Sahni R, Wung JT. Weaning strategy with inhaled nitric oxide treatment in persistent pulmonary hypertension of the newborn. Arch Dis Child Fetal Neonatal Ed. 1997;76:F118–22.
• 47.   Sokol GM, Fineberg NS, Wright LL, Ehrenkranz RA. Changes in arterial oxygen tension when weaning neonates from inhaled nitric oxide. Pediatr Pulmonol. 2001;32:14–9.
• 48.   Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics. 2006;117:1077–83.
• 49.   Vargas-Origel A, Gomez-Rodriguez G, AldanaValenzuela C, Vela-Huerta MM, Alarcon-Santos SB, Amador-Licona N. The Use of Sildenafil in Persistent Pulmonary Hypertension of the Newborn. Am J Perinatol. 2009...
• 50.   Steinhorn RH, Kinsella JP, Butrous G, Dilleen M, Oakes M, Wessel DL. Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension of the newborn. J Pediatr. 2009 In press.
• 51.   Lakshminrusimha S, Porta NF, Farrow KN, Chen B, Gugino SF, Kumar VH, et al. Milrinone enhances relaxation to prostacyclin and iloprost in pulmonary arteries isolated from lambs with persistent pulmonary hypertension of the newborn. Pediatric critical care medicine: a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2009;10:106–12.
• 52.   McNamara PJ, Shivananda SP, Sahni M, Freeman D, Taddio A. Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxide. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive
• 53.   Bassler D, Choong K, McNamara P, Kirpalani H. Neonatal persistent pulmonary hypertension treated with milrinone: four case reports. Biol Neonate. 2006;89:1–5.
• 54.   McNamara PJ, Laique F, Muang-In S, Whyte HE. Milrinone improves oxygenation in neonates with severe persistent pulmonary hypertension of the newborn. J Crit Care. 2006;21:217–22.
• 55.   Lakshminrusimha S, Steinhorn RH. Inodilators in nitric oxide resistant persistent pulmonary hypertension of the newborn. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2013;14:107–9.
• 56.   Ivy DD, Parker TA, Ziegler JW, Galan HL, Kinsella JP, Tuder RM, et al. Prolonged endothelin A receptor blockade attenuates chronic pulmonary hypertension in the ovine fetus. J Clin Invest. 1997;99:1179–86.
• 57.   Tripathi S, Saili A. The effect of steroids on the clinical course and outcome of neonates with meconium aspiration syndrome. J Trop Pediatr. 2007;53:8–12.
• 58.   Perez M, akshminrusimha S, Wedgwood S, Czech L, Gugino SF, Russell JA, et al. Hydrocortisone Normalizes Oxygenation and cGMP Regulation in Lambs with Persistent Pulmonary Hypertension of the Newborn. Am J Physiol Lung Cell Mol Physiol. 2011.
• 59.   Lakshminrusimha S, Russell JA, Wedgwood S, Gugino SF, Kazzaz JA, Davis JM, et al. Superoxide dismutase improves oxygenation and reduces oxidation in neonatal pulmonary hypertension. Am J Respir Crit Care Med. 2006;174:1370–7.
• 60.   Steinhorn RH, Albert G, Swartz DD, Russell JA, Levine CR, Davis JM. Recombinant human superoxide dismutase enhances the effect of inhaled nitric oxide in persistent pulmonary hypertension. American Journal of Respiratory & Critical Care Medicine. 2001;164:834–9.
• 61.   Wedgwood S, Lakshminrusimha S, Farrow KN, Czech L, Gugino SF, Soares F, et al. Apocynin improves oxygenation and increases eNOS in persistent pulmonary hypertension of the newborn. Am J Physiol Lung Cell Mol Physiol. 2012;302:L616–26.
• 62.   Konduri GG, Vohr B, Robertson C, Sokol GM, Solimano A, Singer J, et al. 2007;150:235–40. 40 e1.
• 63.   Robertson CM, Tyebkhan JM, Hagler ME, Cheung PY, Peliowski A, Etches PC. Late-onset, progressive sensorineural hearing loss after severe neonatal respiratory failure. Otol Neurotol. 2002;23:353–6.
• 64.   Lipkin PH, Davidson D, Spivak L, Straube R, Rhines J, Chang CT. Neurodevelopmental and medical outcomes of persistent pulmonary hypertension in term newborns treated with nitric oxide. Journal of Pediatrics. 2002;140:306–10.

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