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Drug Treatment of Pulmonary Hypertension in Children

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Abstract

Pulmonary arterial hypertension (PAH) is a rare disease in infants and children that is associated with significant morbidity and mortality. The disease is characterized by progressive pulmonary vascular functional and structural changes resulting in increased pulmonary vascular resistance and eventual right heart failure and death. In many pediatric patients, PAH is idiopathic or associated with congenital heart disease and rarely is associated with other conditions such as connective tissue or thromboembolic disease. PAH associated with developmental lung diseases such as bronchopulmonary dysplasia or congenital diaphragmatic hernia is increasingly more recognized in infants and children. Although treatment of the underlying disease and reversal of advanced structural changes have not yet been achieved with current therapy, quality of life and survival have improved significantly. Targeted pulmonary vasodilator therapies, including endothelin receptor antagonists, prostacyclin analogs, and phosphodiesterase type 5 inhibitors have resulted in hemodynamic and functional improvement in children. The management of pediatric PAH remains challenging as treatment decisions depend largely on results from evidence-based adult studies and the clinical experience of pediatric experts. This article reviews the current drug therapies and their use in the management of PAH in children.

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Fig. 1

From Del Cerro et al. Pulm Circ, with permission [13]

Fig. 2

From van Loon RL, et al. Circulation. 2011, with permission [11]

Fig. 3

From Haworth SG, et al. Heart. 2009, with permission [9]

Fig. 4

Reproduced with permission from Diller GP & Baumgartner H, Int J Clin Pract Suppl. 2010 [25]

Fig. 5

From Haworth SG, Arch Dis Child. 2008 [30], with permission

Fig. 6

Reproduced with permission from Barst RJ, et al. Pediatr Cardiol. 2010 [54]

Fig. 7

From Barst RJ, et al. Circulation. 2012, with permission [66]

Fig. 8

From Barst RJ, et al. Circulation. 2012, with permission [66]

Fig. 9

Reproduced with permission from Mourani PM, et al. J Pediatr. 2009 [77]

Fig. 10

From Takatsuki S, et al. Pediatr Cardiol. 2012, with permission [95]

Fig. 11

Reproduced with permission from Galie N, et al. Circulation. 2006 [120]

Fig. 12

Reproduced with permission from Galie N, et al. Circulation. 2006 [120]

Fig. 13

Reproduced with permission from Beghetti M, et al. Br J Clin Pharmacol. 2009 [122]

Fig. 14

Reproduced with permission from Siehr SL, et al. J Heart Lung Transplant. 2013 [151]

Fig. 15

Reproduced with permission from Siehr SL, et al. J Heart Lung Transplant. 2013 [151]

Fig. 16

From Takatsuki S, et al. Pediatr Cardiol. 2013, with permission [161]

Fig. 17

Reproduced with permission from Rimensberger P, et al. Circulation. 2001 [167]

Fig. 18

Reproduced with permission from Rosenzweig E, et al. Eur Resp J. 2019 [12]

Fig. 19

Reproduced with permission from Rosenzweig E, et al. Eur Resp J. 2019 [12]

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References

  1. Rubin LJ. Primary pulmonary hypertension. N Engl J Med. 1997;336:111–7.

    CAS  PubMed  Google Scholar 

  2. Allen KM, Haworth SG. Cytoskeletal features of immature pulmonary vascular smooth muscle cells: the influence of pulmonary hypertension on normal development. J Pathol. 1989;158:311–7.

    CAS  PubMed  Google Scholar 

  3. Humbert M, Morrell NW, Archer SL, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43:13S–24S.

    CAS  PubMed  Google Scholar 

  4. Mandegar M, Fung YC, Huang W, Remillard CV, Rubin LJ, Yuan JX. Cellular and molecular mechanisms of pulmonary vascular remodeling: role in the development of pulmonary hypertension. Microvasc Res. 2004;68:75–103.

    CAS  PubMed  Google Scholar 

  5. Hassoun PM, Mouthon L, Barbera JA, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol. 2009;54:S10–9.

    CAS  PubMed  Google Scholar 

  6. Rabinovitch M. Pathobiology of pulmonary hypertension. Annu Rev Pathol. 2007;2:369–99.

    CAS  PubMed  Google Scholar 

  7. Barst RJ, McGoon MD, Elliott CG, Foreman AJ, Miller DP, Ivy DD. Survival in childhood pulmonary arterial hypertension: insights from the registry to evaluate early and long-term pulmonary arterial hypertension disease management. Circulation. 2012;125:113–22.

    PubMed  Google Scholar 

  8. Berger RM, Beghetti M, Humpl T, et al. Clinical features of paediatric pulmonary hypertension: a registry study. Lancet. 2012;379:537–46.

    PubMed  PubMed Central  Google Scholar 

  9. Haworth SG, Hislop AA. Treatment and survival in children with pulmonary arterial hypertension: the UK Pulmonary Hypertension Service for Children 2001-2006. Heart. 2009;95:312–7.

    CAS  PubMed  Google Scholar 

  10. Fraisse A, Jais X, Schleich JM, et al. Characteristics and prospective 2-year follow-up of children with pulmonary arterial hypertension in France. Arch Cardiovasc Dis. 2010;103:66–74.

    PubMed  Google Scholar 

  11. van Loon RL, Roofthooft MT, Hillege HL, et al. Pediatric pulmonary hypertension in the Netherlands: epidemiology and characterization during the period 1991 to 2005. Circulation. 2011;124:1755–64.

    PubMed  Google Scholar 

  12. Rosenzweig EB, Abman SH, Adatia I, et al. Paediatric pulmonary arterial hypertension: updates on definition, classification, diagnostics and management. Eur Respir J. 2019. https://doi.org/10.1183/13993003.01916-2018.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Del Cerro MJ, Abman S, Diaz G, et al. A consensus approach to the classification of pediatric pulmonary hypertensive vascular disease: report from the PVRI Pediatric Taskforce, Panama 2011. Pulm Circ. 2011;1:286–98.

    PubMed  PubMed Central  Google Scholar 

  14. van Albada ME, Berger RM. Pulmonary arterial hypertension in congenital cardiac disease—the need for refinement of the Evian–Venice classification. Cardiol Young. 2008;18:10–7.

    PubMed  Google Scholar 

  15. Schulze-Neick I, Beghetti M. Classifying pulmonary hypertension in the setting of the congenitally malformed heart—cleaning up a dog’s dinner. Cardiol Young. 2008;18:22–5.

    PubMed  Google Scholar 

  16. Badesch DB, Champion HC, Sanchez MA, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S55–66.

    PubMed  Google Scholar 

  17. Douwes JM, van Loon RL, Hoendermis ES, et al. Acute pulmonary vasodilator response in paediatric and adult pulmonary arterial hypertension: occurrence and prognostic value when comparing three response criteria. Eur Heart J. 2011;32:3137–46.

    PubMed  Google Scholar 

  18. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019. https://doi.org/10.1183/13993003.01913-2018.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hosein RB, Clarke AJ, McGuirk SP, et al. Factors influencing early and late outcome following the Fontan procedure in the current era. The ‘Two Commandments’? Eur J Cardiothorac Surg. 2007;31:344–52 (discussion 353).

    PubMed  Google Scholar 

  20. Mayer JE Jr, Bridges ND, Lock JE, Hanley FL, Jonas RA, Castaneda AR. Factors associated with marked reduction in mortality for Fontan operations in patients with single ventricle. J Thorac Cardiovasc Surg. 1992;103:444–51 (discussion 451–2).

    PubMed  Google Scholar 

  21. D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115:343–9.

    PubMed  Google Scholar 

  22. Sandoval J, Bauerle O, Gomez A, Palomar A, Martinez Guerra ML, Furuya ME. Primary pulmonary hypertension in children: clinical characterization and survival. J Am Coll Cardiol. 1995;25:466–74.

    CAS  PubMed  Google Scholar 

  23. Moledina S, Hislop AA, Foster H, Schulze-Neick I, Haworth SG. Childhood idiopathic pulmonary arterial hypertension: a national cohort study. Heart. 2010;96:1401–6.

    CAS  PubMed  Google Scholar 

  24. Dimopoulos K, Inuzuka R, Goletto S, et al. Improved survival among patients with Eisenmenger syndrome receiving advanced therapy for pulmonary arterial hypertension. Circulation. 2010;121:20–5.

    PubMed  Google Scholar 

  25. Diller GP, Baumgartner H. Pulmonary arterial hypertension in adults with congenital heart disease. Int J Clin Pract Suppl. 2010;64(165):13–24. https://doi.org/10.1111/j.1742-1241.2009.02244.x.

    Article  Google Scholar 

  26. Rich S. Primary pulmonary hypertension. Executive summary from world symposium; 1998.

  27. Ploegstra MJ, Douwes JM, Roofthooft MT, Zijlstra WM, Hillege HL, Berger RM. Identification of treatment goals in paediatric pulmonary arterial hypertension. Eur Respir J. 2014;44:1616–26.

    PubMed  Google Scholar 

  28. Lammers AE, Adatia I, Cerro MJ, et al. Functional classification of pulmonary hypertension in children: report from the PVRI pediatric taskforce, Panama 2011. Pulm Circ. 2011;1:280–5.

    PubMed  PubMed Central  Google Scholar 

  29. Rosenzweig EB, Feinstein JA, Humpl T, Ivy DD. Pulmonary arterial hypertension in children: diagnostic work up and challenges. Prog Pediatr Cardiol. 2009;27:7–11.

    Google Scholar 

  30. Haworth SG. The management of pulmonary hypertension in children. Arch Dis Child. 2008;93(7):620–625. https://doi.org/10.1136/adc.2007.120493.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rich S, Seidlitz M, Dodin E, et al. The short-term effects of digoxin in patients with right ventricular dysfunction from pulmonary hypertension. Chest. 1998;114:787–92.

    CAS  PubMed  Google Scholar 

  32. Sandoval J, Santos LE, Cordova J, et al. Does anticoagulation in Eisenmenger syndrome impact long-term survival? Congenit Heart Dis. 2012;7:268–76.

    PubMed  Google Scholar 

  33. Barst RJ. Pharmacologically induced pulmonary vasodilatation in children and young adults with primary pulmonary hypertension. Chest. 1986;89:497–503.

    CAS  PubMed  Google Scholar 

  34. Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension [see comments]. N Engl J Med. 1992;327:76–81.

    CAS  PubMed  Google Scholar 

  35. Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111:3105–11.

    CAS  PubMed  Google Scholar 

  36. Barst RJ, Maislin G, Fishman AP. Vasodilator therapy for primary pulmonary hypertension in children. Circulation. 1999;99:1197–208.

    CAS  PubMed  Google Scholar 

  37. Douwes JM, Humpl T, Bonnet D, et al. Acute vasodilator response in pediatric pulmonary arterial hypertension: current clinical practice from the TOPP Registry. J Am Coll Cardiol. 2016;67:1312–23.

    PubMed  Google Scholar 

  38. Yung D, Widlitz AC, Rosenzweig EB, Kerstein D, Maislin G, Barst RJ. Outcomes in children with idiopathic pulmonary arterial hypertension. Circulation. 2004;110:660–5.

    PubMed  Google Scholar 

  39. Klinger JR. The nitric oxide/cGMP signaling pathway in pulmonary hypertension. Clin Chest Med. 2007;28:143–67, ix.

    PubMed  Google Scholar 

  40. Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from l-arginine. Nature. 1988;333:664–6.

    CAS  PubMed  Google Scholar 

  41. Day RW, Lynch JM, White KS, Ward RM. Acute response to inhaled nitric oxide in newborns with respiratory failure and pulmonary hypertension. Pediatrics. 1996;98:698–705.

    CAS  PubMed  Google Scholar 

  42. Barefield ES, Karle VA, Phillips JB 3rd, Carlo WA. Inhaled nitric oxide in term infants with hypoxemic respiratory failure. J Pediatr. 1996;129:279–86.

    CAS  PubMed  Google Scholar 

  43. Roberts JD Jr, Fineman JR, Morin FC 3rd, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group. N Engl J Med. 1997;336:605–10.

    CAS  PubMed  Google Scholar 

  44. 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;131:55–62.

    CAS  PubMed  Google Scholar 

  45. Wessel DL, Adatia I, Van Marter LJ, et al. Improved oxygenation in a randomized trial of inhaled nitric oxide for persistent pulmonary hypertension of the newborn. Pediatrics. 1997;100:E7.

    CAS  PubMed  Google Scholar 

  46. Davidson D, Barefield ES, Kattwinkel J, et al. 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. The I-NO/PPHN Study Group. Pediatrics. 1998;101:325–34.

    CAS  PubMed  Google Scholar 

  47. Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. The Neonatal Inhaled Nitric Oxide Study Group. N Engl J Med. 1997;336:597–604.

    Google Scholar 

  48. Clark RH, Kueser TJ, Walker MW, et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group. N Engl J Med. 2000;342:469–74.

    CAS  PubMed  Google Scholar 

  49. Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. The Neonatal Inhaled Nitric Oxide Study Group (NINOS). Pediatrics. 1997;99:838–45.

    Google Scholar 

  50. Campbell BT, Herbst KW, Briden KE, Neff S, Ruscher KA, Hagadorn JI. Inhaled nitric oxide use in neonates with congenital diaphragmatic hernia. Pediatrics. 2014;134:e420–6.

    PubMed  Google Scholar 

  51. Putnam LR, Tsao K, Morini F, et al. Evaluation of variability in inhaled nitric oxide use and pulmonary hypertension in patients with congenital diaphragmatic hernia. JAMA Pediatr. 2016;170:1188–94.

    PubMed  Google Scholar 

  52. Abman SH, Hansmann G, Archer SL, et al. Pediatric pulmonary hypertension: guidelines from the American Heart Association and American Thoracic Society. Circulation. 2015;132:2037–99.

    PubMed  Google Scholar 

  53. Puligandla PS, Skarsgard ED, Offringa M, et al. Diagnosis and management of congenital diaphragmatic hernia: a clinical practice guideline. Can Med Assoc J. 2018;190:E103–12.

    Google Scholar 

  54. Barst RJ, Agnoletti G, Fraisse A, Baldassarre J, Wessel DL. Vasodilator testing with nitric oxide and/or oxygen in pediatric pulmonary hypertension. Pediatr Cardiol. 2010;31:598–606.

    PubMed  Google Scholar 

  55. Ricciardi MJ, Knight BP, Martinez FJ, Rubenfire M. Inhaled nitric oxide in primary pulmonary hypertension: a safe and effective agent for predicting response to nifedipine. J Am Coll Cardiol. 1998;32:1068–73.

    CAS  PubMed  Google Scholar 

  56. Mourani PM, Ivy DD, Gao D, Abman SH. Pulmonary vascular effects of inhaled nitric oxide and oxygen tension in bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2004;170:1006–13.

    PubMed  Google Scholar 

  57. Beghetti M, Habre W, Friedli B, Berner M. Continuous low dose inhaled nitric oxide for treatment of severe pulmonary hypertension after cardiac surgery in paediatric patients. Br Heart J. 1995;73:65–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Checchia PA, Bronicki RA, Muenzer JT, et al. Nitric oxide delivery during cardiopulmonary bypass reduces postoperative morbidity in children-a randomized trial. J Thorac Cardiovasc Surg. 2013;146:530–6.

    CAS  PubMed  Google Scholar 

  59. Miller OI, Tang SF, Keech A, Pigott NB, Beller E, Celermajer DS. Inhaled nitric oxide and prevention of pulmonary hypertension after congenital heart surgery: a randomised double-blind study. Lancet. 2000;356:1464–9.

    CAS  PubMed  Google Scholar 

  60. Checchia PA, Bronicki RA, Goldstein B. Review of inhaled nitric oxide in the pediatric cardiac surgery setting. Pediatr Cardiol. 2012;33:493–505.

    PubMed  Google Scholar 

  61. Barst RJ, Channick R, Ivy D, Goldstein B. Clinical perspectives with long-term pulsed inhaled nitric oxide for the treatment of pulmonary arterial hypertension. Pulm Circ. 2012;2:139–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Archer SL, Michelakis ED. Phosphodiesterase type 5 inhibitors for pulmonary arterial hypertension. N Engl J Med. 2009;361:1864–71.

    CAS  PubMed  Google Scholar 

  63. Michelakis E, Tymchak W, Archer S. Sildenafil: from the bench to the bedside. Can Med Assoc J. 2000;163:1171–5.

    CAS  Google Scholar 

  64. Cunningham AV, Smith KH. Anterior ischemic optic neuropathy associated with viagra. J Neuro-ophthalmol. 2001;21:22–5.

    CAS  Google Scholar 

  65. Pomeranz HD, Smith KH, Hart WM Jr, Egan RA. Sildenafil-associated nonarteritic anterior ischemic optic neuropathy. Ophthalmology. 2002;109:584–7.

    PubMed  Google Scholar 

  66. Barst RJ, Ivy DD, Gaitan G, et al. A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension. Circulation. 2012;125:324–34.

    CAS  PubMed  Google Scholar 

  67. Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353:2148–57.

    CAS  PubMed  Google Scholar 

  68. Maxey DM, Ivy DD, Ogawa MT, Feinstein JA. Food and Drug Administration (FDA) postmarket reported side effects and adverse events associated with pulmonary hypertension therapy in pediatric patients. Pediatr Cardiol. 2013;34:1628–36.

    PubMed  PubMed Central  Google Scholar 

  69. Khan AS, Sheikh Z, Khan S, Dwivedi R, Benjamin E. Viagra deafness—sensorineural hearing loss and phosphodiesterase-5 inhibitors. Laryngoscope. 2011;121:1049–54.

    CAS  PubMed  Google Scholar 

  70. Humpl T, Reyes JT, Holtby H, Stephens D, Adatia I. Beneficial effect of oral sildenafil therapy on childhood pulmonary arterial hypertension: twelve-month clinical trial of a single-drug, open-label, pilot study. Circulation. 2005;111:3274–80.

    CAS  PubMed  Google Scholar 

  71. Karatza AA, Bush A, Magee AG. Safety and efficacy of sildenafil therapy in children with pulmonary hypertension. Int J Cardiol. 2005;100:267–73.

    PubMed  Google Scholar 

  72. Barst RJ, Beghetti M, Pulido T, et al. STARTS-2: long-term survival with oral sildenafil monotherapy in treatment-naive pediatric pulmonary arterial hypertension. Circulation. 2014;129:1914–23.

    CAS  PubMed  Google Scholar 

  73. European Medicines Agency. Assessment report for Revatio. International non-proprietary name: sildenafil. Procedure No. EMEA/H/C/000638/II/0028. London, UK: European Medicines Agency; 2011. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000638/WC500107804.pdf. Accessed 6 May 2019.

  74. U.S. Food and Drug Administration. Revatio (sildenafil): drug safety communication - recommendation against use in children. Silver Spring: U.S. Food and Drug Administration; 2012. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm317743.htm. Accessed 6 May 2019.

  75. Abman SH, Kinsella JP, Rosenzweig EB, et al. Implications of the U.S. Food and Drug Administration warning against the use of sildenafil for the treatment of pediatric pulmonary hypertension. Am J Respir Crit Care Med. 2013;187:572–5.

    CAS  PubMed  Google Scholar 

  76. U.S. Food and Drug Administration. Revatio (sildenafil): drug safety communication—FDA clarifies warning about pediatric use of sildenafil for pulmonary arterial hypertension. Silver Spring: U.S. Food and Drug Administration; 2014. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-clarifies-warning-about-pediatric-use-revatio-sildenafil-pulmonary. Accessed 6 May 2019.

  77. Mourani PM, Sontag MK, Ivy DD, Abman SH. Effects of long-term sildenafil treatment for pulmonary hypertension in infants with chronic lung disease. J Pediatr. 2009;154:379–84, 384 e1–2.

    Google Scholar 

  78. Cohen JL, Nees SN, Valencia GA, Rosenzweig EB, Krishnan US. Sildenafil use in children with pulmonary hypertension. J Pediatr. 2019;205(29–34):e1.

    Google Scholar 

  79. Ivy DD, Kinsella JP, Ziegler JW, Abman SH. Dipyridamole attenuates rebound pulmonary hypertension after inhaled nitric oxide withdrawal in postoperative congenital heart disease. J Thorac Cardiovasc Surg. 1998;115:875–82.

    CAS  PubMed  Google Scholar 

  80. Atz AM, Wessel DL. Sildenafil ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology. 1999;91:307–10.

    CAS  PubMed  Google Scholar 

  81. Namachivayam P, Theilen U, Butt WW, Cooper SM, Penny DJ, Shekerdemian LS. Sildenafil prevents rebound pulmonary hypertension after withdrawal of nitric oxide in children. Am J Respir Crit Care Med. 2006;174:1042–7.

    CAS  PubMed  Google Scholar 

  82. Atz Am LA, Fairbrother DL, Uber WE, Bradley SM. Sildenafil augments the effect of inhaled nitric oxide for postoperative pulmonary hypertensive crisis. J Thorac Cardiovasc Surg. 2002;124:628–9.

    PubMed  Google Scholar 

  83. Do P, Randhawa I, Chin T, Parsapour K, Nussbaum E. Successful management of plastic bronchitis in a child post Fontan: case report and literature review. Lung. 2012;190:463–8.

    PubMed  Google Scholar 

  84. Giardini A, Balducci A, Specchia S, Gargiulo G, Bonvicini M, Picchio FM. Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients. Eur Heart J. 2008;29:1681–7.

    CAS  PubMed  Google Scholar 

  85. Ciliberti P, Giardini A. Impact of oral chronic administration of sildenafil in children and young adults after the Fontan operation. Future Cardiol. 2011;7:609–12.

    CAS  PubMed  Google Scholar 

  86. Avitabile CM, Goldberg DJ, Dodds K, Dori Y, Ravishankar C, Rychik J. A multifaceted approach to the management of plastic bronchitis after cavopulmonary palliation. Ann Thorac Surg. 2014;98:634–40.

    PubMed  PubMed Central  Google Scholar 

  87. Mourani PM, Sontag MK, Ivy DD, Abman SH. Effects of long-term sildenafil treatment for pulmonary hypertension in infants with chronic lung disease. J Pediatr. 2009;154:379–84.

    CAS  PubMed  Google Scholar 

  88. Nahata MC, Morosco RS, Brady MT. Extemporaneous sildenafil citrate oral suspensions for the treatment of pulmonary hypertension in children. Am J Health Syst Pharm. 2006;63:254–7.

    CAS  PubMed  Google Scholar 

  89. Burgess G, Hoogkamer H, Collings L, Dingemanse J. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur J Clin Pharmacol. 2008;64:43–50.

    CAS  PubMed  Google Scholar 

  90. Steinhorn RH, Kinsella JP, Pierce C, et al. Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension. J Pediatr. 2009;155(841–847):e1.

    Google Scholar 

  91. Fraisse A, Butrous G, Taylor MB, Oakes M, Dilleen M, Wessel DL. Intravenous sildenafil for postoperative pulmonary hypertension in children with congenital heart disease. Intensive Care Med. 2011;37:502–9.

    CAS  PubMed  Google Scholar 

  92. Schulze-Neick I, Hartenstein P, Li J, et al. Intravenous sildenafil is a potent pulmonary vasodilator in children with congenital heart disease. Circulation. 2003;108(Suppl 1):II167–73.

    PubMed  Google Scholar 

  93. Stocker C, Penny DJ, Brizard CP, Cochrane AD, Soto R, Shekerdemian LS. Intravenous sildenafil and inhaled nitric oxide: a randomised trial in infants after cardiac surgery. Intensive Care Med. 2003;29:1996–2003.

    PubMed  Google Scholar 

  94. Galie N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119:2894–903.

    CAS  PubMed  Google Scholar 

  95. Takatsuki S, Calderbank M, Ivy DD. Initial experience with tadalafil in pediatric pulmonary arterial hypertension. Pediatr Cardiol. 2012;33:683–8.

    PubMed  PubMed Central  Google Scholar 

  96. Rosenzweig EB. Tadalafil for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother. 2010;11:127–32.

    CAS  PubMed  Google Scholar 

  97. Shiva A, Shiran M, Rafati M, et al. Oral tadalafil in children with pulmonary arterial hypertension. Drug Res. 2016;66:7–10.

    CAS  Google Scholar 

  98. Pettit RS, Johnson CE, Caruthers RL. Stability of an extemporaneously prepared tadalafil suspension. Am J Health Syst. 2012;69:592–4.

    CAS  Google Scholar 

  99. Wrishko RE, Dingemanse J, Yu A, Darstein C, Phillips DL, Mitchell MI. Pharmacokinetic interaction between tadalafil and bosentan in healthy male subjects. J Clin Pharmacol. 2008;48:610–8.

    CAS  PubMed  Google Scholar 

  100. Channick RN, Sitbon O, Barst RJ, Manes A, Rubin LJ. Endothelin receptor antagonists in pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43:62S–7S.

    CAS  PubMed  Google Scholar 

  101. Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. 1995;333:214–21.

    CAS  PubMed  Google Scholar 

  102. Abman SH. Role of endothelin receptor antagonists in the treatment of pulmonary arterial hypertension. Annu Rev Med. 2009;60:13–23.

    CAS  PubMed  Google Scholar 

  103. Actelion receives FDA approval of tracleer (bosentan) for use in pediatric patients with pulmonary arterial hypertension; 2017. https://www.jnj.com/media-center/press-releases/actelion-receives-fda-approval-of-tracleer-bosentan-for-use-in-pediatric-patients-with-pulmonary-arterial-hypertension#_ftnref1. Accessed 6 May 2019.

  104. Barst RJ, Ivy D, Dingemanse J, et al. Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. Clin Pharmacol Ther. 2003;73:372–82.

    CAS  PubMed  Google Scholar 

  105. Galie N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation. 2008;117:3010–9.

    CAS  PubMed  Google Scholar 

  106. Oudiz RJ, Galie N, Olschewski H, et al. Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:1971–81.

    PubMed  Google Scholar 

  107. Apostolopoulou SC, Papagiannis J, Rammos S. Bosentan induces clinical, exercise and hemodynamic improvement in a pre-transplant patient with plastic bronchitis after Fontan operation. J Heart Lung Transpl. 2005;24:1174–6.

    Google Scholar 

  108. Beghetti M. Bosentan in pediatric patients with pulmonary arterial hypertension. Curr Vasc Pharmacol. 2009;7:225–33.

    CAS  PubMed  Google Scholar 

  109. Beghetti M, Hoeper MM, Kiely DG, et al. Safety experience with bosentan in 146 children 2–11 years old with pulmonary arterial hypertension: results from the European Postmarketing Surveillance program. Pediatr Res. 2008;64:200–4.

    CAS  PubMed  Google Scholar 

  110. D’Alto M, Romeo E, Argiento P, et al. Therapy for pulmonary arterial hypertension due to congenital heart disease and Down’s syndrome. Int J Cardiol. 2011. https://doi.org/10.1016/j.ijcard.2011.07.009.

    Article  PubMed  Google Scholar 

  111. Duffels MG, Vis JC, van Loon RL, et al. Down patients with Eisenmenger syndrome: is bosentan treatment an option? Int J Cardiol. 2009;134:378–83.

    PubMed  Google Scholar 

  112. Hislop AA, Moledina S, Foster H, Schulze-Neick I, Haworth SG. Long-term efficacy of bosentan in treatment of pulmonary arterial hypertension in children. Eur Respir J. 2011;38:70–7.

    CAS  PubMed  Google Scholar 

  113. Ivy DD, Doran A, Claussen L, Bingaman D, Yetman A. Weaning and discontinuation of epoprostenol in children with idiopathic pulmonary arterial hypertension receiving concomitant bosentan. Am J Cardiol. 2004;93:943–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Ivy DD, Rosenzweig EB, Lemarie JC, Brand M, Rosenberg D, Barst RJ. Long-term outcomes in children with pulmonary arterial hypertension treated with bosentan in real-world clinical settings. Am J Cardiol. 2010;106:1332–8.

    PubMed  PubMed Central  Google Scholar 

  115. Maiya S, Hislop AA, Flynn Y, Haworth SG. Response to bosentan in children with pulmonary hypertension. Heart. 2006;92:664–70.

    CAS  PubMed  Google Scholar 

  116. Rosenzweig EB, Ivy DD, Widlitz A, et al. Effects of long-term bosentan in children with pulmonary arterial hypertension. J Am Coll Cardiol. 2005;46:697–704.

    CAS  PubMed  Google Scholar 

  117. Taguchi M, Ichida F, Hirono K, et al. Pharmacokinetics of bosentan in routinely treated Japanese pediatric patients with pulmonary arterial hypertension. Drug Metab Pharmacokinet. 2011;26:280–7.

    CAS  PubMed  Google Scholar 

  118. van Loon RL, Hoendermis ES, Duffels MG, et al. Long-term effect of bosentan in adults versus children with pulmonary arterial hypertension associated with systemic-to-pulmonary shunt: does the beneficial effect persist? Am Heart J. 2007;154:776–82.

    PubMed  Google Scholar 

  119. Votava-Smith JK, Perens GS, Alejos JC. Bosentan for increased pulmonary vascular resistance in a patient with single ventricle physiology and a bidirectional Glenn shunt. Pediatr Cardiol. 2007;28:314–6.

    CAS  PubMed  Google Scholar 

  120. Galie N, Beghetti M, Gatzoulis MA, et al. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation. 2006;114:48–54.

    CAS  PubMed  Google Scholar 

  121. Bowater SE, Weaver RA, Thorne SA, Clift PF. The safety and effects of bosentan in patients with a Fontan circulation. Congenit Heart Dis. 2012;7:243–9.

    PubMed  Google Scholar 

  122. Beghetti M, Haworth SG, Bonnet D, et al. Pharmacokinetic and clinical profile of a novel formulation of bosentan in children with pulmonary arterial hypertension: the FUTURE-1 study. Br J Clin Pharmacol. 2009;68:948–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Klinger JR, Oudiz RJ, Spence R, Despain D, Dufton C. Long-term pulmonary hemodynamic effects of ambrisentan in pulmonary arterial hypertension. Am J Cardiol. 2011;108:302–7.

    CAS  PubMed  Google Scholar 

  124. Galie N, Badesch D, Oudiz R, et al. Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2005;46:529–35.

    CAS  PubMed  Google Scholar 

  125. Takatsuki S, Rosenzweig EB, Zuckerman W, Brady D, Calderbank M, Ivy DD. Clinical safety, pharmacokinetics, and efficacy of ambrisentan therapy in children with pulmonary arterial hypertension. Pediatr Pulmonol. 2013;48:27–34.

    PubMed  Google Scholar 

  126. Zuckerman WA, Leaderer D, Rowan CA, Mituniewicz JD, Rosenzweig EB. Ambrisentan for pulmonary arterial hypertension due to congenital heart disease. Am J Cardiol. 2011;107:1381–5.

    CAS  PubMed  Google Scholar 

  127. Spence R, Mandagere A, Dufton C, Venitz J. Pharmacokinetics and safety of ambrisentan in combination with sildenafil in healthy volunteers. J Clin Pharmacol. 2008;48:1451–9.

    CAS  PubMed  Google Scholar 

  128. Galie N, Barbera JA, Frost AE, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015;373:834–44.

    CAS  PubMed  Google Scholar 

  129. Iglarz M, Binkert C, Morrison K, et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther. 2008;327:736–45.

    CAS  PubMed  Google Scholar 

  130. Weiss J, Theile D, Ruppell MA, Speck T, Spalwisz A, Haefeli WE. Interaction profile of macitentan, a new non-selective endothelin-1 receptor antagonist, in vitro. Eur J Pharmacol. 2013;701:168–75.

    CAS  PubMed  Google Scholar 

  131. Rubin LJ, Pulido T, Channick R, et al. Effect of macitentan on morbidity and mortality in pulmonary arterial hypertension (PAH): results from the SERAPHIN trial. Chest. 2012;142:1026A.

    Google Scholar 

  132. Aypar E, Alehan D, Karagoz T, Aykan HH, Ertugrul I. Clinical efficacy and safety of switch from bosentan to macitentan in children and young adults with pulmonary arterial hypertension. Cardiol Young. 2018;28:542–7.

    PubMed  Google Scholar 

  133. Cheng Y, Austin SC, Rocca B, et al. Role of prostacyclin in the cardiovascular response to thromboxane A2. Science. 2002;296:539–41.

    CAS  PubMed  Google Scholar 

  134. Ruan KH. Advance in understanding the biosynthesis of prostacyclin and thromboxane A2 in the endoplasmic reticulum membrane via the cyclooxygenase pathway. Mini Rev Med Chem. 2004;4:639–47.

    CAS  PubMed  Google Scholar 

  135. Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med. 1999;159:1925–32.

    CAS  PubMed  Google Scholar 

  136. Chow KB, Jones RL, Wise H. Protein kinase A-dependent coupling of mouse prostacyclin receptors to Gi is cell-type dependent. Eur J Pharmacol. 2003;474:7–13.

    CAS  PubMed  Google Scholar 

  137. Barst R. How has epoprostenol changed the outcome for patients with pulmonary arterial hypertension? Int J Clin Pract Suppl. 2010;64(168):23–32.

    CAS  Google Scholar 

  138. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med. 1996;334:296–302.

    CAS  PubMed  Google Scholar 

  139. Barst RJ, Rubin LJ, McGoon MD, Caldwell EJ, Long WA, Levy PS. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med. 1994;121:409–15.

    CAS  PubMed  Google Scholar 

  140. Ivy DD, Claussen L, Doran A. Transition of stable pediatric patients with pulmonary arterial hypertension from intravenous epoprostenol to intravenous treprostinil. Am J Cardiol. 2007;99:696–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Lammers AE, Hislop AA, Flynn Y, Haworth SG. Epoprostenol treatment in children with severe pulmonary hypertension. Heart. 2007;93:739–43.

    CAS  PubMed  Google Scholar 

  142. Rosenzweig EB, Kerstein D, Barst RJ. Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects. Circulation. 1999;99:1858–65.

    CAS  PubMed  Google Scholar 

  143. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;53:1573–619.

    PubMed  Google Scholar 

  144. Tissot C, Ivy DD, Beghetti M. Medical therapy for pediatric pulmonary arterial hypertension. J Pediatr. 2010;157:528–32.

    PubMed  PubMed Central  Google Scholar 

  145. Ivy DD. Prostacyclin in the intensive care setting. Pediatr Crit Care Med. 2010;11:S41–5.

    PubMed  PubMed Central  Google Scholar 

  146. Melnick L, Barst RJ, Rowan CA, Kerstein D, Rosenzweig EB. Effectiveness of transition from intravenous epoprostenol to oral/inhaled targeted pulmonary arterial hypertension therapy in pediatric idiopathic and familial pulmonary arterial hypertension. Am J Cardiol. 2010;105:1485–9.

    CAS  PubMed  Google Scholar 

  147. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 2002;106:1477–82.

    CAS  PubMed  Google Scholar 

  148. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;40:780–8.

    CAS  PubMed  Google Scholar 

  149. Doran A, Harris S, Goetz B. Advances in prostanoid infusion therapy for pulmonary arterial hypertension. J Infus Nurs. 2008;31:336–45.

    PubMed  Google Scholar 

  150. Doran AK, Ivy DD, Barst RJ, Hill N, Murali S, Benza RL. Guidelines for the prevention of central venous catheter-related blood stream infections with prostanoid therapy for pulmonary arterial hypertension. Int J Clin Pract Suppl. 2008;160:5–9.

    Google Scholar 

  151. Siehr SL, Ivy DD, Miller-Reed K, Ogawa M, Rosenthal DN, Feinstein JA. Children with pulmonary arterial hypertension and prostanoid therapy: long-term hemodynamics. J Heart Lung Transpl. 2013;32:546–52.

    Google Scholar 

  152. Levy M, Celermajer DS, Bourges-Petit E, Del Cerro MJ, Bajolle F, Bonnet D. Add-on therapy with subcutaneous treprostinil for refractory pediatric pulmonary hypertension. J Pediatr. 2011;158:584–8.

    PubMed  Google Scholar 

  153. McIntyre CM, Hanna BD, Rintoul N, Ramsey EZ. Safety of epoprostenol and treprostinil in children less than 12 months of age. Pulm Circ. 2013;3:862–9.

    PubMed  PubMed Central  Google Scholar 

  154. Ferdman DJ, Rosenzweig EB, Zuckerman WA, Krishnan U. Subcutaneous treprostinil for pulmonary hypertension in chronic lung disease of infancy. Pediatrics. 2014;134:e274–8.

    PubMed  Google Scholar 

  155. Lawrence KM, Hedrick HL, Monk HM, et al. Treprostinil improves persistent pulmonary hypertension associated with congenital diaphragmatic hernia. J Pediatr. 2018;200:44–9.

    CAS  PubMed  Google Scholar 

  156. Hopper RK, Wang Y, DeMatteo V, et al. Right ventricular function mirrors clinical improvement with use of prostacyclin analogues in pediatric pulmonary hypertension. Pulm Circ. 2018;8:2045894018759247.

    PubMed  PubMed Central  Google Scholar 

  157. Handler SS, Ogawa MT, Hopper RK, Sakarovitch C, Feinstein JA. Subcutaneous treprostinil in pediatric patients with failing single-ventricle physiology. J Heart Lung Transpl. 2017. https://doi.org/10.1016/j.healun.2017.09.008.

    Article  Google Scholar 

  158. Channick RN, Olschewski H, Seeger W, Staub T, Voswinckel R, Rubin LJ. Safety and efficacy of inhaled treprostinil as add-on therapy to bosentan in pulmonary arterial hypertension. J Am Coll Cardiol. 2006;48:1433–7.

    CAS  PubMed  Google Scholar 

  159. Krishnan U, Ivy DD, Takatsuki S, Kerstein J, Calderbank M, Rosenzweig EB. Effectiveness and safety of inhaled treprostinil for the treatment of pulmonary arterial hypertension in children. Am J Cardiol. 2012. https://doi.org/10.1016/j.amjcard.2012.07.037.

    Article  PubMed  PubMed Central  Google Scholar 

  160. McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010;55:1915–22.

    CAS  PubMed  Google Scholar 

  161. Takatsuki S, Parker DK, Doran AK, Friesen RH, Ivy DD. Acute pulmonary vasodilator testing with inhaled treprostinil in children with pulmonary arterial hypertension. Pediatr Cardiol. 2013;34:1006–12.

    PubMed  Google Scholar 

  162. Ivy DD, Feinstein JA, Yung D, et al. Oral treprostinil in transition or as add-on therapy in pediatric pulmonary arterial hypertension. Pulm Circ. 2019;9:2045894019856471.

    PubMed  PubMed Central  Google Scholar 

  163. Kanaan U, Varghese NP, Coleman RD, et al. Oral treprostinil use in children: a multicenter, observational experience. Pulm Circ. 2019;9:2045894019862138.

    PubMed  PubMed Central  Google Scholar 

  164. Centers for Disease Control and Prevention (CDC). Bloodstream infections among patients treated with intravenous epoprostenol or intravenous treprostinil for pulmonary arterial hypertension—seven sites, United States, 2003–2006. MMWR Morb Mortal Wkly Rep. 2007;56:170–2.

    Google Scholar 

  165. Ivy DD, Calderbank M, Wagner BD, et al. Closed-hub systems with protected connections and the reduction of risk of catheter-related bloodstream infection in pediatric patients receiving intravenous prostanoid therapy for pulmonary hypertension. Infect Control Hosp Epidemiol. 2009;30:823–9.

    PubMed  PubMed Central  Google Scholar 

  166. Rich JD, Glassner C, Wade M, et al. The effect of diluent pH on bloodstream infection rates in patients receiving IV treprostinil for pulmonary arterial hypertension. Chest. 2012;141:36–42.

    CAS  PubMed  Google Scholar 

  167. Rimensberger PC, Spahr-Schopfer I, Berner M, et al. Inhaled nitric oxide versus aerosolized iloprost in secondary pulmonary hypertension in children with congenital heart disease: vasodilator capacity and cellular mechanisms. Circulation. 2001;103:544–8.

    CAS  PubMed  Google Scholar 

  168. Beghetti M, Berner M, Rimensberger PC. Long term inhalation of iloprost in a child with primary pulmonary hypertension: an alternative to continuous infusion. Heart. 2001;86:E10.

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Hoeper MM, Schwarze M, Ehlerding S, et al. Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue. N Engl J Med. 2000;342:1866–70.

    CAS  PubMed  Google Scholar 

  170. Ivy DD, Doran AK, Smith KJ, et al. Short- and long-term effects of inhaled iloprost therapy in children with pulmonary arterial hypertension. J Am Coll Cardiol. 2008;51:161–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Limsuwan A, Khosithseth A, Wanichkul S, Khowsathit P. Aerosolized iloprost for pulmonary vasoreactivity testing in children with long-standing pulmonary hypertension related to congenital heart disease. Catheter Cardiovasc Interv. 2009;73:98–104.

    PubMed  Google Scholar 

  172. Limsuwan A, Wanitkul S, Khosithset A, Attanavanich S, Samankatiwat P. Aerosolized iloprost for postoperative pulmonary hypertensive crisis in children with congenital heart disease. Int J Cardiol. 2008;129:333–8.

    PubMed  Google Scholar 

  173. Tissot C, Beghetti M. Review of inhaled iloprost for the control of pulmonary artery hypertension in children. Vasc Health Risk Manag. 2009;5:325–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Loukanov T, Bucsenez D, Springer W, et al. Comparison of inhaled nitric oxide with aerosolized iloprost for treatment of pulmonary hypertension in children after cardiopulmonary bypass surgery. Clin Res Cardiol. 2011;100:595–602.

    PubMed  Google Scholar 

  175. Galie N, Humbert M, Vachiery JL, et al. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2002;39:1496–502.

    CAS  PubMed  Google Scholar 

  176. Ono F, Nagaya N, Kyotani S, Oya H, Nakanishi N, Miyatake K. Hemodynamic and hormonal effects of beraprost sodium, an orally active prostacyclin analogue, in patients with secondary precapillary pulmonary hypertension. Circ J. 2003;67:375–8.

    CAS  PubMed  Google Scholar 

  177. Saji T, Ozawa Y, Ishikita T, Matsuura H, Matsuo N. Short-term hemodynamic effect of a new oral PGI2 analogue, beraprost, in primary and secondary pulmonary hypertension. Am J Cardiol. 1996;78:244–7.

    CAS  PubMed  Google Scholar 

  178. Barst RJ, McGoon M, McLaughlin V, et al. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2003;41:2119–25.

    CAS  PubMed  Google Scholar 

  179. Hoeper MM, Barst RJ, Bourge RC, et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation. 2013;127:1128–38.

    CAS  PubMed  Google Scholar 

  180. Schermuly RT, Janssen W, Weissmann N, Stasch JP, Grimminger F, Ghofrani HA. Riociguat for the treatment of pulmonary hypertension. Expert Opin Investig Drugs. 2011;20:567–76.

    CAS  PubMed  Google Scholar 

  181. Stasch JP, Becker EM, Alonso-Alija C, et al. NO-independent regulatory site on soluble guanylate cyclase. Nature. 2001;410:212–5.

    CAS  PubMed  Google Scholar 

  182. Ghofrani H, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study (PATENT-1). Chest. 2012;142:1027A.

    Google Scholar 

  183. Ghofrani H, Grimminger F, Hoeper M, et al. Riociguat for the treatment of inoperable chronic thromboembolic pulmonary hypertension: a randomized, double-blind, placebo-controlled study (CHEST-1). Chest. 2012;142:1023A.

    Google Scholar 

  184. Spreemann T, Bertram H, Happel CM, Kozlik-Feldmann R, Hansmann G. First-in-child use of the oral soluble guanylate cyclase stimulator riociguat in pulmonary arterial hypertension. Pulm Circ. 2018;8:2045893217743123.

    PubMed  Google Scholar 

  185. Kuwano K, Hashino A, Asaki T, et al. 2-[4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy]-N-(methylsulfonyl)acetamide (NS-304), an orally available and long-acting prostacyclin receptor agonist prodrug. J Pharmacol Exp Ther. 2007;322:1181–8.

    CAS  PubMed  Google Scholar 

  186. Morrison K, Ernst R, Hess P, Studer R, Clozel M. Selexipag: a selective prostacyclin receptor agonist that does not affect rat gastric function. J Pharmacol Exp Ther. 2010;335:249–55.

    CAS  PubMed  Google Scholar 

  187. Simonneau G, Torbicki A, Hoeper MM, et al. Selexipag, an oral, selective IP receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J. 2012;40:874–80.

    CAS  PubMed  Google Scholar 

  188. Sitbon O, Channick R, Chin KM, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med. 2015;373:2522–33.

    CAS  PubMed  Google Scholar 

  189. Geerdink LM, Bertram H, Hansmann G. First-in-child use of the oral selective prostacyclin IP receptor agonist selexipag in pulmonary arterial hypertension. Pulm Circ. 2017;7:551–4.

    PubMed  PubMed Central  Google Scholar 

  190. Gallotti R, Drogalis-Kim DE, Satou G, Alejos J. Single-center experience using selexipag in a pediatric population. Pediatr Cardiol. 2017;38:1405–9.

    PubMed  Google Scholar 

  191. Koestenberger M, Hansmann G. Should we use the oral selective IP receptor agonist selexipag off-label in children with pulmonary arterial hypertension? Pulm Circ. 2018;8:2045894018793580.

    PubMed  PubMed Central  Google Scholar 

  192. Deng Z, Morse JH, Slager SL, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet. 2000;67:737–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Machado RD, Aldred MA, James V, et al. Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat. 2006;27:121–32.

    CAS  PubMed  Google Scholar 

  194. Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet. 2000;37:741–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Stacher E, Graham BB, Hunt JM, et al. Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186:261–72.

    PubMed  PubMed Central  Google Scholar 

  196. Atkinson C, Stewart S, Upton PD, et al. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation. 2002;105:1672–8.

    CAS  PubMed  Google Scholar 

  197. Spiekerkoetter E, Tian X, Cai J, et al. FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. J Clin Investig. 2013;123:3600–13.

    CAS  PubMed  Google Scholar 

  198. Long L, Ormiston ML, Yang X, et al. Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nat Med. 2015;21:777–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Reynolds AM, Holmes MD, Danilov SM, Reynolds PN. Targeted gene delivery of BMPR2 attenuates pulmonary hypertension. Eur Respir J. 2012;39:329–43.

    CAS  PubMed  Google Scholar 

  200. Reynolds AM, Xia W, Holmes MD, et al. Bone morphogenetic protein type 2 receptor gene therapy attenuates hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2007;292:L1182–92.

    CAS  PubMed  Google Scholar 

  201. Spiekerkoetter E, Sung YK, Sudheendra D, et al. Low-dose FK506 (tacrolimus) in end-stage pulmonary arterial hypertension. Am J Respir Crit Care Med. 2015;192:254–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Spiekerkoetter E, Sung YK, Sudheendra D, et al. Randomised placebo-controlled safety and tolerability trial of FK506 (tacrolimus) for pulmonary arterial hypertension. Eur Respir J. 2017. https://doi.org/10.1183/13993003.02449-2016.

    Article  PubMed  Google Scholar 

  203. Kawut SM, Bagiella E, Lederer DJ, et al. Randomized clinical trial of aspirin and simvastatin for pulmonary arterial hypertension: ASA-STAT. Circulation. 2011;123:2985–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Fukumoto Y, Matoba T, Ito A, et al. Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension. Heart. 2005;91:391–2.

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Ishikura K, Yamada N, Ito M, et al. Beneficial acute effects of rho-kinase inhibitor in patients with pulmonary arterial hypertension. Circ J. 2006;70:174–8.

    CAS  PubMed  Google Scholar 

  206. Li F, Xia W, Yuan S, Sun R. Acute inhibition of Rho-kinase attenuates pulmonary hypertension in patients with congenital heart disease. Pediatr Cardiol. 2009;30:363–6.

    PubMed  Google Scholar 

  207. Tawara S, Fukumoto Y, Shimokawa H. Effects of combined therapy with a Rho-kinase inhibitor and prostacyclin on monocrotaline-induced pulmonary hypertension in rats. J Cardiovasc Pharmacol. 2007;50:195–200.

    CAS  PubMed  Google Scholar 

  208. Zhao YD, Courtman DW, Deng Y, Kugathasan L, Zhang Q, Stewart DJ. Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease. Circ Res. 2005;96:442–50.

    CAS  PubMed  Google Scholar 

  209. Wang XX, Zhang FR, Shang YP, et al. Transplantation of autologous endothelial progenitor cells may be beneficial in patients with idiopathic pulmonary arterial hypertension: a pilot randomized controlled trial. J Am Coll Cardiol. 2007;49:1566–71.

    CAS  PubMed  Google Scholar 

  210. Zhu JH, Wang XX, Zhang FR, et al. Safety and efficacy of autologous endothelial progenitor cells transplantation in children with idiopathic pulmonary arterial hypertension: open-label pilot study. Pediatr Transpl. 2008;12:650–5.

    Google Scholar 

  211. Hoeper MM, Markevych I, Spiekerkoetter E, Welte T, Niedermeyer J. Goal-oriented treatment and combination therapy for pulmonary arterial hypertension. Eur Respir J. 2005;26:858–63.

    CAS  PubMed  Google Scholar 

  212. Humbert M, Barst RJ, Robbins IM, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J. 2004;24:353–9.

    CAS  PubMed  Google Scholar 

  213. McLaughlin VV, Oudiz RJ, Frost A, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006;174:1257–63.

    CAS  PubMed  Google Scholar 

  214. Simonneau G, Rubin LJ, Galie N, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med. 2008;149:521–30.

    PubMed  Google Scholar 

  215. Lunze K, Gilbert N, Mebus S, et al. First experience with an oral combination therapy using bosentan and sildenafil for pulmonary arterial hypertension. Eur J Clin Investig. 2006;36(Suppl 3):32–8.

    CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Cardiology, Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Catherine M. Avitabile

  2. Division of Pediatric Cardiology, Department of Pediatrics, University of Calgary Cumming School of Medicine, Alberta Children’s Hospital, Calgary, Canada

    Erika E. Vorhies

  3. B100, Division of Pediatric Cardiology, Department of Pediatrics, University of Colorado School of Medicine, Children’s Hospital Colorado, 13123 East 16th Avenue, Aurora, CO, 80045, USA

    David Dunbar Ivy

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  1. Catherine M. Avitabile
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Dr. Catherine M. Avitabile and Dr. Erika E. Vorhies have no potential conflicts of interest that might be relevant to the contents of this manuscript. The University of Colorado School of Medicine contracts with Actelion, Bayer, and United Therapeutics for Dr. David Dunbar Ivy to be a Consultant. Dr. Ivy currently performs clinical trials with Actelion, Bayer, and United Therapeutics. Dr. Ivy has previously performed clinical trials with Gilead Sciences, GSK, Eli Lilly, and Pfizer.

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Avitabile, C.M., Vorhies, E.E. & Ivy, D.D. Drug Treatment of Pulmonary Hypertension in Children. Pediatr Drugs 22, 123–147 (2020). https://doi.org/10.1007/s40272-019-00374-2

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