Am J Perinatol 2018; 35(14): 1366-1375
DOI: 10.1055/s-0038-1660462
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The Practical Challenges of Diagnosis and Treatment Options in Persistent Pulmonary Hypertension of the Newborn: A Developing Country's Perspective

Narongsak Nakwan
1   Department of Pediatrics, Hat Yai Medical Education Center, Hat Yai Hospital, Hat Yai, Songkhla, Thailand
› Author Affiliations
Funding None.
Further Information

Publication History

02 February 2018

02 May 2018

Publication Date:
19 June 2018 (online)

Abstract

Persistent pulmonary hypertension of the newborn (PPHN) is a complication of several respiratory diseases characterized by an elevation in pulmonary vascular resistance with resultant right-to-left shunting of blood and severe hypoxemia in the neonatal period. PPHN carries a high rate of morbidity and mortality, particularly in limited-resource settings (low-income and/or developing country). Echocardiography remains the gold standard for diagnosis of PPHN. Modern therapies such as inhaled nitric oxide, high-frequency oscillatory ventilation, extracorporeal membrane oxygenation, and/or other pulmonary vasodilators agents can reduce the mortality rate of PPHN. Unfortunately, echocardiography and the use of these modern therapies are often difficult for a medical institution to provide for patients in developing countries, even when a timely diagnosis of PPHN has been made. In this review, the practical challenges of timely diagnosis of PPHN and efficient use of available treatment options faced by pediatricians or neonatologists in limited-resource settings are discussed.

 
  • References

  • 1 Khorana M, Yookaseam T, Layangool T, Kanjanapattanakul W, Paradeevisut H. Outcome of oral sildenafil therapy on persistent pulmonary hypertension of the newborn at Queen Sirikit National Institute of Child Health. J Med Assoc Thai 2011; 94 (Suppl. 03) S64-S73
  • 2 Nakwan N, Pithaklimnuwong S. Acute kidney injury and pneumothorax are risk factors for mortality in persistent pulmonary hypertension of the newborn in Thai neonates. J Matern Fetal Neonatal Med 2016; 29 (11) 1741-1746
  • 3 Walsh-Sukys MC, Tyson JE, Wright LL. , et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics 2000; 105 (1 Pt 1): 14-20
  • 4 Steurer MA, Jelliffe-Pawlowski LL, Baer RJ, Partridge JC, Rogers EE, Keller RL. Persistent pulmonary hypertension of the newborn in late preterm and term infants in California. Pediatrics 2017; 139 (01) e20161165
  • 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 Sadiq HF, Mantych G, Benawra RS, Devaskar UP, Hocker JR. Inhaled nitric oxide in the treatment of moderate persistent pulmonary hypertension of the newborn: a randomized controlled, multicenter trial. J Perinatol 2003; 23 (02) 98-103
  • 7 Schaible T, Hermle D, Loersch F, Demirakca S, Reinshagen K, Varnholt V. A 20-year experience on neonatal extracorporeal membrane oxygenation in a referral center. Intensive Care Med 2010; 36 (07) 1229-1234
  • 8 Kelly LE, Ohlsson A, Shah PS. Sildenafil for pulmonary hypertension in neonates. Cochrane Database Syst Rev 2017; 8: CD005494
  • 9 Maneenil G, Thatrimontrichai A, Janjindamai W, Dissaneevate S. Effect of bosentan therapy in persistent pulmonary hypertension of the newborn. Pediatr Neonatol 2018; 59 (01) 58-64
  • 10 Nakwan N, Choksuchat D, Saksawad R, Thammachote P, Nakwan N. Successful treatment of persistent pulmonary hypertension of the newborn with bosentan. Acta Paediatr 2009; 98 (10) 1683-1685
  • 11 Boo NY, Rohana J, Yong SC, Bilkis AZ, Yong-Junina F. Inhaled nitric oxide and intravenous magnesium sulphate for the treatment of persistent pulmonary hypertension of the newborn. Singapore Med J 2010; 51 (02) 144-150
  • 12 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 (02) 217-222
  • 13 Nair J, Lakshminrusimha S. Update on PPHN: mechanisms and treatment. Semin Perinatol 2014; 38 (02) 78-91
  • 14 Simonneau G, Gatzoulis MA, Adatia I. , et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013; 62 (25, Suppl): D34-D41
  • 15 Bearer C, Emerson RK, O'Riordan MA, Roitman E, Shackleton C. Maternal tobacco smoke exposure and persistent pulmonary hypertension of the newborn. Environ Health Perspect 1997; 105 (02) 202-206
  • 16 Alano MA, Ngougmna E, Ostrea Jr EM, Konduri GG. Analysis of nonsteroidal antiinflammatory drugs in meconium and its relation to persistent pulmonary hypertension of the newborn. Pediatrics 2001; 107 (03) 519-523
  • 17 Grigoriadis S, Vonderporten EH, Mamisashvili L. , et al. Prenatal exposure to antidepressants and persistent pulmonary hypertension of the newborn: systematic review and meta-analysis. BMJ 2014; 348: f6932
  • 18 Hernández-Díaz S, Van Marter LJ, Werler MM, Louik C, Mitchell AA. Risk factors for persistent pulmonary hypertension of the newborn. Pediatrics 2007; 120 (02) e272-e282
  • 19 Lakshminrusimha S, Konduri GG, Steinhorn RH. Considerations in the management of hypoxemic respiratory failure and persistent pulmonary hypertension in term and late preterm neonates. J Perinatol 2016; 36 (Suppl. 02) S12-S19
  • 20 Bendapudi P, Rao GG, Greenough A. Diagnosis and management of persistent pulmonary hypertension of the newborn. Paediatr Respir Rev 2015; 16 (03) 157-161
  • 21 Fraisse A, Geva T, Gaudart J, Wessel DL. Doppler echocardiographic predictors of outcome in newborns with persistent pulmonary hypertension. Cardiol Young 2004; 14 (03) 277-283
  • 22 Puthiyachirakkal M, Mhanna MJ. Pathophysiology, management, and outcome of persistent pulmonary hypertension of the newborn: a clinical review. Front Pediatr 2013; 1: 23
  • 23 Narang A, Bhakoo ON, Nair PM, Bhandari V. Persistent pulmonary arterial hypertension of the newborn. Indian J Pediatr 1992; 59 (06) 735-739
  • 24 Farrow KN, Groh BS, Schumacker PT. , et al. Hyperoxia increases phosphodiesterase 5 expression and activity in ovine fetal pulmonary artery smooth muscle cells. Circ Res 2008; 102 (02) 226-233
  • 25 Farrow KN, Lakshminrusimha S, Reda WJ. , et al. Superoxide dismutase restores eNOS expression and function in resistance pulmonary arteries from neonatal lambs with persistent pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2008; 295 (06) L979-L987
  • 26 Lakshminrusimha S, Swartz DD, Gugino SF. , et al. Oxygen concentration and pulmonary hemodynamics in newborn lambs with pulmonary hypertension. Pediatr Res 2009; 66 (05) 539-544
  • 27 Nagaya N, Nishikimi T, Okano Y. , et al. Plasma brain natriuretic peptide levels increase in proportion to the extent of right ventricular dysfunction in pulmonary hypertension. J Am Coll Cardiol 1998; 31 (01) 202-208
  • 28 Shah N, Natarajan G, Aggarwal S. B-type natriuretic peptide: biomarker of persistent pulmonary hypertension of the newborn?. Am J Perinatol 2015; 32 (11) 1045-1049
  • 29 Lakshminrusimha S, Steinhorn RH. Pulmonary vascular biology during neonatal transition. Clin Perinatol 1999; 26 (03) 601-619
  • 30 Morin III FC, Egan EA, Ferguson W, Lundgren CE. Development of pulmonary vascular response to oxygen. Am J Physiol 1988; 254 (3 Pt 2): H542-H546
  • 31 Nakwan N, Chaiwiriyawong P. An international survey on persistent pulmonary hypertension of the newborn: a need for an evidence-based management. J Neonatal Perinatal Med 2016; 9 (03) 243-250
  • 32 Kinsella JP, Abman SH. Recent developments in the pathophysiology and treatment of persistent pulmonary hypertension of the newborn. J Pediatr 1995; 126 (06) 853-864
  • 33 Oca MJ, Nelson M, Donn SM. Randomized trial of normal saline versus 5% albumin for the treatment of neonatal hypotension. J Perinatol 2003; 23 (06) 473-476
  • 34 Lynch SK, Mullett MD, Graeber JE, Polak MJ. A comparison of albumin-bolus therapy versus normal saline-bolus therapy for hypotension in neonates. J Perinatol 2008; 28 (01) 29-33
  • 35 Jaillard S, Houfflin-Debarge V, Riou Y. , et al. Effects of catecholamines on the pulmonary circulation in the ovine fetus. Am J Physiol Regul Integr Comp Physiol 2001; 281 (02) R607-R614
  • 36 Liet JM, Boscher C, Gras-Leguen C, Gournay V, Debillon T, Rozé JC. Dopamine effects on pulmonary artery pressure in hypotensive preterm infants with patent ductus arteriosus. J Pediatr 2002; 140 (03) 373-375
  • 37 Rozé JC, Tohier C, Maingueneau C, Lefèvre M, Mouzard A. Response to dobutamine and dopamine in the hypotensive very preterm infant. Arch Dis Child 1993; 69 (1 Spec No): 59-63
  • 38 Subhedar NV, Shaw NJ. Dopamine versus dobutamine for hypotensive preterm infants. Cochrane Database Syst Rev 2003; 3 (03) CD001242
  • 39 Magnenant E, Jaillard S, Deruelle P. , et al. Role of the alpha2-adrenoceptors on the pulmonary circulation in the ovine fetus. Pediatr Res 2003; 54 (01) 44-51
  • 40 Tulloh RM, Dyamenahalli U, Stuart-Smith K, Haworth SG. Adrenoceptor-stimulated endothelium-dependent relaxation in porcine intrapulmonary arteries. Pulm Pharmacol 1994; 7 (05) 299-303
  • 41 Wilson LE, Levy M, Stuart-Smith K, Haworth SG. Postnatal adrenoreceptor maturation in porcine intrapulmonary arteries. Pediatr Res 1993; 34 (05) 591-595
  • 42 Tourneux P, Rakza T, Bouissou A, Krim G, Storme L. Pulmonary circulatory effects of norepinephrine in newborn infants with persistent pulmonary hypertension. J Pediatr 2008; 153 (03) 345-349
  • 43 Mokra D, Tonhajzerova I, Petraskova M, Calkovska A. Effects of dexamethasone on cardiovascular functions in acute phase in meconium-injured rabbits. Pediatr Int 2009; 51 (01) 132-137
  • 44 Vaage J. Effects of high-dose corticosteroids on the pulmonary circulation. Acta Chir Scand Suppl 1985; 526: 73-82
  • 45 Ullian ME. The role of corticosteriods in the regulation of vascular tone. Cardiovasc Res 1999; 41 (01) 55-64
  • 46 Perez M, Wedgwood S, Lakshminrusimha S, Farrow KN, Steinhorn RH. Hydrocortisone normalizes phosphodiesterase-5 activity in pulmonary artery smooth muscle cells from lambs with persistent pulmonary hypertension of the newborn. Pulm Circ 2014; 4 (01) 71-81
  • 47 Perez M, Lakshminrusimha S, Wedgwood S. , et al. Hydrocortisone normalizes oxygenation and cGMP regulation in lambs with persistent pulmonary hypertension of the newborn. Am J Physiol Lung Cell Mol Physiol 2012; 302 (06) L595-L603
  • 48 Peeples ES. An evaluation of hydrocortisone dosing for neonatal refractory hypotension. J Perinatol 2017; 37 (08) 943-946
  • 49 Rudolph AM, Yuan S. Response of the pulmonary vasculature to hypoxia and H+ ion concentration changes. J Clin Invest 1966; 45 (03) 399-411
  • 50 Pokela ML. Pain relief can reduce hypoxemia in distressed neonates during routine treatment procedures. Pediatrics 1994; 93 (03) 379-383
  • 51 Tobias JD. Sedation and analgesia in the pediatric intensive care unit. Pediatr Ann 2005; 34 (08) 636-645
  • 52 Collins C, Koren G, Crean P, Klein J, Roy WL, MacLeod SM. Fentanyl pharmacokinetics and hemodynamic effects in preterm infants during ligation of patent ductus arteriosus. Anesth Analg 1985; 64 (11) 1078-1080
  • 53 Santeiro ML, Christie J, Stromquist C, Torres BA, Markowsky SJ. Pharmacokinetics of continuous infusion fentanyl in newborns. J Perinatol 1997; 17 (02) 135-139
  • 54 Saarenmaa E, Neuvonen PJ, Fellman V. Gestational age and birth weight effects on plasma clearance of fentanyl in newborn infants. J Pediatr 2000; 136 (06) 767-770
  • 55 Arnold JH, Truog RD, Scavone JM, Fenton T. Changes in the pharmacodynamic response to fentanyl in neonates during continuous infusion. J Pediatr 1991; 119 (04) 639-643
  • 56 Orsini AJ, Leef KH, Costarino A, Dettorre MD, Stefano JL. Routine use of fentanyl infusions for pain and stress reduction in infants with respiratory distress syndrome. J Pediatr 1996; 129 (01) 140-145
  • 57 Fahnenstich H, Steffan J, Kau N, Bartmann P. Fentanyl-induced chest wall rigidity and laryngospasm in preterm and term infants. Crit Care Med 2000; 28 (03) 836-839
  • 58 Johnson PN, Miller J, Gormley AK. Continuous-infusion neuromuscular blocking agents in critically ill neonates and children. Pharmacotherapy 2011; 31 (06) 609-620
  • 59 Levene MI, Quinn MW. Use of sedatives and muscle relaxants in newborn babies receiving mechanical ventilation. Arch Dis Child 1992; 67 (7 Spec No): 870-873
  • 60 Dargaville PA. Respiratory support in meconium aspiration syndrome: a practical guide. Int J Pediatr 2012; 2012: 965159
  • 61 Kinsella JP, Truog WE, Walsh WF. , 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 (1 Pt 1): 55-62
  • 62 Tworetzky W, Bristow J, Moore P. , et al. Inhaled nitric oxide in neonates with persistent pulmonary hypertension. Lancet 2001; 357 (9250): 118-120
  • 63 U. S. Food and Drug Administration 2001. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/20845_INOmax_Approv.pdf . Accessed May 1, 2018
  • 64 Moon JK, Evey LW, Moon YS, Gest AL, Gomez MR, Wearden ME. Nitric oxide supplied from a 10% source provides inhaled therapy without lowering inspired oxygen fraction. Biomed Instrum Technol 1997; 31 (02) 164-168
  • 65 Zapol WM, Rimar S, Gillis N, Marletta M, Bosken CH. Nitric oxide and the lung. Am J Respir Crit Care Med 1994; 149 (05) 1375-1380
  • 66 Pfeifer A, Ruth P, Dostmann W, Sausbier M, Klatt P, Hofmann F. Structure and function of cGMP-dependent protein kinases. Rev Physiol Biochem Pharmacol 1999; 135: 105-149
  • 67 Lucas KA, Pitari GM, Kazerounian S. , et al. Guanylyl cyclases and signaling by cyclic GMP. Pharmacol Rev 2000; 52 (03) 375-414
  • 68 Vachiéry JL. Prostacyclins in pulmonary arterial hypertension: the need for earlier therapy. Adv Ther 2011; 28 (04) 251-269
  • 69 Eronen M, Pohjavuori M, Andersson S, Pesonen E, Raivio KO. Prostacyclin treatment for persistent pulmonary hypertension of the newborn. Pediatr Cardiol 1997; 18 (01) 3-7
  • 70 Kinugasa H, Horigome H, Sugiura M, Saito T, Iijima T, Matsui A. Intravenous prostacyclin combined with inhaled nitric oxide therapy for an infant with alveolar capillary dysplasia. Pediatr Int 2002; 44 (05) 525-527
  • 71 Kelly LK, Porta NFM, Goodman DM, Carroll CL, Steinhorn RH. Inhaled prostacyclin for term infants with persistent pulmonary hypertension refractory to inhaled nitric oxide. J Pediatr 2002; 141 (06) 830-832
  • 72 Chotigeat U, Jaratwashirakul S. Inhaled iloprost for severe persistent pulmonary hypertension of the newborn. J Med Assoc Thai 2007; 90 (01) 167-170
  • 73 Nakwan N, Wannaro J, Nakwan N. Intravenous iloprost may be an effective first-line treatment for persistent pulmonary hypertension of the newborn in limited-resource situations. Asian Biomed 2013; 7: 873-880
  • 74 Janjindamai W, Thatrimontrichai A, Maneenil G, Chanvitan P, Dissaneevate S. Effectiveness and safety of intravenous iloprost for severe persistent pulmonary hypertension of the newborn. Indian Pediatr 2013; 50 (10) 934-938
  • 75 Nakwan N, Nakwan N, Wannaro J. Persistent pulmonary hypertension of the newborn successfully treated with beraprost sodium: a retrospective chart review. Neonatology 2011; 99 (01) 32-37
  • 76 Ivy DD, Le Cras TD, Horan MP, Abman SH. Increased lung preproET-1 and decreased ETB-receptor gene expression in fetal pulmonary hypertension. Am J Physiol 1998; 274 (4 Pt 1): L535-L541
  • 77 Mohamed WA, Ismail M. A randomized, double-blind, placebo-controlled, prospective study of bosentan for the treatment of persistent pulmonary hypertension of the newborn. J Perinatol 2012; 32 (08) 608-613
  • 78 Steinhorn RH, Fineman J, Kusic-Pajic A. , et al; FUTURE-4 study investigators. Bosentan as adjunctive therapy for persistent pulmonary hypertension of the newborn: results of the randomized multicenter placebo-controlled exploratory trial. J Pediatr 2016; 177: 90-96.e3
  • 79 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. Pediatr Crit Care Med 2013; 14 (01) 74-84
  • 80 Lakshminrusimha S, Keszler M. Persistent pulmonary hypertension of the newborn. Neoreviews 2015; 16 (12) e680-e692
  • 81 Chandran S, Haqueb ME, Wickramasinghe HT, Wint Z. Use of magnesium sulphate in severe persistent pulmonary hypertension of the newborn. J Trop Pediatr 2004; 50 (04) 219-223
  • 82 Tolsa JF, Cotting J, Sekarski N, Payot M, Micheli JL, Calame A. Magnesium sulphate as an alternative and safe hypertension of the newborn treatment for severe persistent pulmonary hypertension of the newborn. Arch Dis Child Fetal Neonatal Ed 1995; 72 (03) F184-F187
  • 83 Ho JJ, Rasa G. Magnesium sulfate for persistent pulmonary hypertension of the newborn. Cochrane Database Syst Rev 2007; 3 (03) CD005588
  • 84 Kamolvisit W, Jaroensri S, Ratchatapantanakorn B, Nakwan N. Factors and outcomes of persistent pulmonary hypertension of the newborn associated with acute kidney injury in Thai neonates. Am J Perinatol 2018; 35 (03) 298-304
  • 85 Sheehy AM, Burson MA, Black SM. Nitric oxide exposure inhibits endothelial NOS activity but not gene expression: a role for superoxide. Am J Physiol 1998; 274 (5 Pt 1): L833-L841