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 the majority of 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. Although treatment of the underlying disease and reversal of advanced structural changes has not yet been achieved with current therapy, quality of life and survival have been improved significantly. Targeted pulmonary vasodilator therapies, including endothelin receptor antagonists, prostacyclin analogs, and phosphodiesterase type 5 inhibitors, have demonstrated hemodynamic and functional improvement in children. The management of pediatric PAH remains challenging, as treatment decisions continue to 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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References
Rubin LJ. Primary pulmonary hypertension. N Engl J Med. 1997;336(2):111–7.
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(4):311–7.
Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(12 Suppl S):13S–24S.
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(2):75–103.
Hassoun PM, Mouthon L, Barbera JA, Eddahibi S, Flores SC, Grimminger F, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol. 2009;54(1 Suppl):S10–9.
Rabinovitch M. Pathobiology of pulmonary hypertension. Annu Rev Pathol. 2007;2:369–99.
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(1):113–22.
Berger RM, Beghetti M, Humpl T, Raskob GE, Ivy DD, Jing ZC, et al. Clinical features of paediatric pulmonary hypertension: a registry study. Lancet. 2012;379(9815):537–46.
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(4):312–7.
Fraisse A, Jais X, Schleich JM, di Filippo S, Maragnes P, Beghetti M, et al. Characteristics and prospective 2-year follow-up of children with pulmonary arterial hypertension in France. Arch Cardiovasc Dis. 2010;103(2):66–74.
van Loon RL, Roofthooft MT, Hillege HL, ten Harkel AD, van Osch-Gevers M, Delhaas T, et al. Pediatric pulmonary hypertension in the Netherlands: epidemiology and characterization during the period 1991 to 2005. Circulation. 2011;124(16):1755–64.
Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S43–54.
McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, 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(17):1573–619.
Cerro MJ, Abman S, Diaz G, Freudenthal AH, Freudenthal F, Harikrishnan S, 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(2):286–98.
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(1):10–7.
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(1):22–5.
Badesch DB, Champion HC, Sanchez MA, Hoeper MM, Loyd JE, Manes A, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S55–66.
Douwes JM, van Loon RL, Hoendermis ES, Vonk-Noordegraaf A, Roofthooft MT, Talsma MD, 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(24):3137–46.
Hosein RB, Clarke AJ, McGuirk SP, Griselli M, Stumper O, De Giovanni JV, 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(3):344–52 discussion 53.
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(3):444–51 discussion 51-2.
D’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115(5):343–9.
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(2):466–74.
Moledina S, Hislop AA, Foster H, Schulze-Neick I, Haworth SG. Childhood idiopathic pulmonary arterial hypertension: a national cohort study. Heart. 2010;96(17):1401–6.
Dimopoulos K, Inuzuka R, Goletto S, Giannakoulas G, Swan L, Wort SJ, et al. Improved survival among patients with Eisenmenger syndrome receiving advanced therapy for pulmonary arterial hypertension. Circulation. 2010;121(1):20–5.
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.
Haworth SG. The management of pulmonary hypertension in children. Arch Dis Child. 2008;93(7):620–5.
Rich S, Seidlitz M, Dodin E, Osimani D, Judd D, Genthner D, et al. The short-term effects of digoxin in patients with right ventricular dysfunction from pulmonary hypertension. Chest. 1998;114(3):787–92.
Sandoval J, Santos LE, Cordova J, Pulido T, Gutierrez G, Bautista E, et al. Does anticoagulation in Eisenmenger syndrome impact long-term survival? Congenit Heart Dis. 2012;7(3):268–76.
Barst RJ, Maislin G, Fishman AP. Vasodilator therapy for primary pulmonary hypertension in children. Circulation. 1999;99(9):1197–208.
Barst RJ. Pharmacologically induced pulmonary vasodilatation in children and young adults with primary pulmonary hypertension. Chest. 1986;89(4):497–503.
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(2):76–81.
Sitbon O, Humbert M, Jais X, Ioos V, Hamid AM, Provencher S, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111(23):3105–11.
Yung D, Widlitz AC, Rosenzweig EB, Kerstein D, Maislin G, Barst RJ. Outcomes in children with idiopathic pulmonary arterial hypertension. Circulation. 2004;110(6):660–5.
Askie LM, Ballard RA, Cutter GR, Dani C, Elbourne D, Field D, et al. Inhaled nitric oxide in preterm infants: an individual-patient data meta-analysis of randomized trials. Pediatrics. 2011;128(4):729–39.
Davidson D, Barefield ES, Kattwinkel J, Dudell G, Damask M, Straube R, 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(3 Pt 1):325–34.
Roberts JD Jr, Fineman JR, Morin FC 3rd, Shaul PW, Rimar S, Schreiber MD, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group. N Engl J Med. 1997;336(9):605–10.
Klinger JR. The nitric oxide/cGMP signaling pathway in pulmonary hypertension. Clin Chest Med. 2007;28(1):143–67, ix.
Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988;333(6174):664–6.
Banks BA, Seri I, Ischiropoulos H, Merrill J, Rychik J, Ballard RA. Changes in oxygenation with inhaled nitric oxide in severe bronchopulmonary dysplasia. Pediatrics. 1999;103(3):610–8.
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(1):65–8.
Checchia PA, Bronicki RA, Muenzer JT, Dixon D, Raithel S, Gandhi SK, et al. Nitric oxide delivery during cardiopulmonary bypass reduces postoperative morbidity in children: a randomized trial. J Thorac Cardiovasc Surg. 2013;146(3):530–6.
Karamanoukian HL, Glick PL, Zayek M, Steinhorn RH, Zwass MS, Fineman JR, et al. Inhaled nitric oxide in congenital hypoplasia of the lungs due to diaphragmatic hernia or oligohydramnios. Pediatrics. 1994;94(5):715–8.
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(9240):1464–9.
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(9):1006–13.
Roberts JD Jr, Lang P, Bigatello LM, Vlahakes GJ, Zapol WM. Inhaled nitric oxide in congenital heart disease. Circulation. 1993;87(2):447–53.
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(9):597–604.
Clark RH, Kueser TJ, Walker MW, Southgate WM, Huckaby JL, Perez JA, 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(7):469–74.
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(5):598–606.
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(4):1068–73.
Checchia PA, Bronicki RA, Goldstein B. Review of inhaled nitric oxide in the pediatric cardiac surgery setting. Pediatr Cardiol. 2012;33(4):493–505.
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(2):139–47.
Diller GP, Baumgartner H. Pulmonary arterial hypertension in adults with congenital heart disease. Int J Clin Pract Suppl. 2010;165:13–24.
Archer SL, Michelakis ED. Phosphodiesterase type 5 inhibitors for pulmonary arterial hypertension. N Engl J Med. 2009;361(19):1864–71.
Michelakis E, Tymchak W, Archer S. Sildenafil: from the bench to the bedside. Canad Med Assoc J. 2000;163(9):1171–5.
Cunningham AV, Smith KH. Anterior ischemic optic neuropathy associated with viagra. J Neuro-Ophthalmol. 2001;21(1):22–5.
Pomeranz HD, Smith KH, Hart WM Jr, Egan RA. Sildenafil-associated nonarteritic anterior ischemic optic neuropathy. Ophthalmology. 2002;109(3):584–7.
Barst RJ, Ivy DD, Gaitan G, Szatmari A, Rudzinski A, Garcia AE, 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(2):324–34.
Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353(20):2148–57.
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(7):1628–36
Khan AS, Sheikh Z, Khan S, Dwivedi R, Benjamin E. Viagra deafness—sensorineural hearing loss and phosphodiesterase-5 inhibitors. Laryngoscope. 2011;121(5):1049–54.
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(24):3274–80.
Karatza AA, Bush A, Magee AG. Safety and efficacy of sildenafil therapy in children with pulmonary hypertension. Int J Cardiol. 2005;100(2):267–73.
Barst R, Layton G, Konourina I, Richardson H, Beghetti M, Ivy D. STARTS-2: Long-term survival with oral sildenafil monotherapy in treatment-naive patients with pediatric pulmonary arterial hypertension. Eur Heart J. 2012;33(suppl 1):979.
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 30 May 2013.
Abman SH, Kinsella JP, Rosenzweig EB, Krishnan U, Kulik T, Mullen M, 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(6):572–5.
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(4):875–82.
Atz AM, Wessel DL. Sildenafil ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology. 1999;91(1):307–10.
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(9):1042–7.
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.
Ghofrani HA, Wiedemann R, Rose F, Schermuly RT, Olschewski H, Weissmann N, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet. 2002;360(9337):895–900.
Wimmer M, Salzer U, Schlemmer M, Marx M, Proll E. Experience with long-term nifedipine therapy in paediatric cardiological patients. Padiatrie und Padologie. 1990;25(3):181–93.
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(4):463–8.
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(13):1681–7.
Goldberg DJ, French B, McBride MG, Marino BS, Mirarchi N, Hanna BD, et al. Impact of oral sildenafil on exercise performance in children and young adults after the Fontan operation: a randomized, double-blind, placebo-controlled, crossover trial. Circulation. 2011;123(11):1185–93.
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;23(154):379–84.
Satoh T, Saji T, Watanabe H, Ogawa S, Takehara K, Tanabe N, et al. A phase III, multicenter, collaborative, open-label clinical trial of sildenafil in Japanese patients with pulmonary arterial hypertension. Circ J. 2011;75(3):677–82.
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(3):254–7.
Burgess G, Hoogkamer H, Collings L, Dingemanse J. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur J Clin Pharmacol. 2008;64(1):43–50.
Steinhorn RH, Kinsella JP, Pierce C, Butrous G, Dilleen M, Oakes M, et al. Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension. J Pediatr. 2009;155(6):841–7 e1.
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(3):502–9.
Schulze-Neick I, Hartenstein P, Li J, Stiller B, Nagdyman N, Hubler M, et al. Intravenous sildenafil is a potent pulmonary vasodilator in children with congenital heart disease. Circulation. 2003;108(Suppl 1):II167–73.
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(11):1996–2003.
Galie N, Brundage BH, Ghofrani HA, Oudiz RJ, Simonneau G, Safdar Z, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119(22):2894–903.
Takatsuki S, Calderbank M, Ivy DD. Initial experience with tadalafil in pediatric pulmonary arterial hypertension. Pediatr Cardiol. 2012;33(5):683–8.
Rosenzweig EB. Tadalafil for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother. 2010;11(1):127–32.
Pettit RS, Johnson CE, Caruthers RL. Stability of an extemporaneously prepared tadalafil suspension. Am J Health Syst Pharm. 2012;69(7):592–4.
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(5):610–8.
Channick RN, Sitbon O, Barst RJ, Manes A, Rubin LJ. Endothelin receptor antagonists in pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(12 Suppl S):62S–7S.
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(4):214–21.
Abman SH. Role of endothelin receptor antagonists in the treatment of pulmonary arterial hypertension. Annu Rev Med. 2009;60:13–23.
Barst RJ, Ivy D, Dingemanse J, Widlitz A, Schmitt K, Doran A, et al. Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. Clin Pharmacol Ther. 2003;73(4):372–82.
Galie N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA, 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(23):3010–9.
Oudiz RJ, Galie N, Olschewski H, Torres F, Frost A, Ghofrani HA, et al. Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(21):1971–81.
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(8):1174–6.
Beghetti M. Bosentan in pediatric patients with pulmonary arterial hypertension. Curr Vasc Pharmacol. 2009;7(2):225–33.
Beghetti M, Hoeper MM, Kiely DG, Carlsen J, Schwierin B, Segal ES, 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(2):200–4.
D’Alto M, Romeo E, Argiento P, D’Andrea A, Sarubbi B, Correra A, et al. Therapy for pulmonary arterial hypertension due to congenital heart disease and Down’s syndrome. Int J Cardiol. 2013;164(3):323-6.
Duffels MG, Vis JC, van Loon RL, Berger RM, Hoendermis ES, van Dijk AP, et al. Down patients with Eisenmenger syndrome: is bosentan treatment an option? Int J Cardiol. 2009;134(3):378–83.
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(1):70–7.
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(7):943–6.
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(9):1332–8.
Maiya S, Hislop AA, Flynn Y, Haworth SG. Response to bosentan in children with pulmonary hypertension. Heart. 2006;92(5):664–70.
Rosenzweig EB, Ivy DD, Widlitz A, Doran A, Claussen LR, Yung D, et al. Effects of long-term bosentan in children with pulmonary arterial hypertension. J Am Coll Cardiol. 2005;46(4):697–704.
Taguchi M, Ichida F, Hirono K, Miyawaki T, Yoshimura N, Nakamura T, et al. Pharmacokinetics of bosentan in routinely treated Japanese pediatric patients with pulmonary arterial hypertension. Drug Metab Pharmacokinet. 2011;26(3):280-7.
van Loon RL, Hoendermis ES, Duffels MG, Vonk-Noordegraaf A, Mulder BJ, Hillege HL, 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(4):776–82.
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(4):314–6.
Galie N, Beghetti M, Gatzoulis MA, Granton J, Berger RM, Lauer A, et al. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation. 2006;114(1):48–54.
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(3):243–9.
Beghetti M, Haworth SG, Bonnet D, Barst RJ, Acar P, Fraisse A, 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(6):948–55.
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(2):302–7.
Galie N, Badesch D, Oudiz R, Simonneau G, McGoon MD, Keogh AM, et al. Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2005;46(3):529–35.
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(1):27-34.
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(9):1381–5.
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(12):1451–9.
Cheng Y, Austin SC, Rocca B, Koller BH, Coffman TM, Grosser T, et al. Role of prostacyclin in the cardiovascular response to thromboxane A2. Science. 2002;296(5567):539–41.
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(6):639–47.
Tuder RM, Cool CD, Geraci MW, Wang J, Abman SH, Wright L, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med. 1999;159(6):1925–32.
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(1):7–13.
Barst R. How has epoprostenol changed the outcome for patients with pulmonary arterial hypertension? Int J Clin Pract Suppl. 2010;64(168):23–32.
Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, 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(5):296–302.
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(6):409–15.
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(5):696–8.
Lammers AE, Hislop AA, Flynn Y, Haworth SG. Epoprostenol treatment in children with severe pulmonary hypertension. Heart. 2007;93(6):739–43.
Rosenzweig EB, Kerstein D, Barst RJ. Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects. Circulation. 1999;99(14):1858–65.
Tissot C, Ivy DD, Beghetti M. Medical therapy for pediatric pulmonary arterial hypertension. J Pediatr. 2010;157(4):528–32.
Ivy DD. Prostacyclin in the intensive care setting. Pediatr Crit Care Med. 2010;11(2 Suppl):S41–5.
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(10):1485–9.
McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 2002;106(12):1477–82.
Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Herve P, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;40(4):780–8.
Doran A, Harris S, Goetz B. Advances in prostanoid infusion therapy for pulmonary arterial hypertension. J Infus Nurs. 2008;31(6):336–45.
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.
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(4):584–8.
Siehr SL, Ivy DD, Miller-Reed K. Children with pulmonary arterial hypertension and prostanoid therapy: long-term hemodynamics. J Heart Lung Transplant. 2013;32(5):546–52.
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(7):1433–7.
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;110(11):1704-9.
McLaughlin VV, Benza RL, Rubin LJ, Channick RN, Voswinckel R, Tapson VF, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010;55(18):1915–22.
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(4):1006–12.
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(8):170–2.
Ivy DD, Calderbank M, Wagner BD, Dolan S, Nyquist AC, Wade M, 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(9):823–9.
Rich JD, Glassner C, Wade M, Coslet S, Arneson C, Doran A, et al. The effect of diluent pH on bloodstream infection rates in patients receiving IV treprostinil for pulmonary arterial hypertension. Chest. 2012;141(1):36–42.
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(3):E10.
Hoeper MM, Schwarze M, Ehlerding S, Adler-Schuermeyer A, Spiekerkoetter E, Niedermeyer J, et al. Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue. N Engl J Med. 2000;342(25):1866–70.
Ivy DD, Doran AK, Smith KJ, Mallory GB Jr, Beghetti M, Barst RJ, et al. Short- and long-term effects of inhaled iloprost therapy in children with pulmonary arterial hypertension. J Am Coll Cardiol. 2008;51(2):161–9.
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(1):98–104.
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(3):333-8.
Tissot C, Beghetti M. Review of inhaled iloprost for the control of pulmonary artery hypertension in children. Vasc Health Risk Manag. 2009;5(1):325–31.
Rimensberger PC, Spahr-Schopfer I, Berner M, Jaeggi E, Kalangos A, Friedli B, 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(4):544–8.
Loukanov T, Bucsenez D, Springer W, Sebening C, Rauch H, Roesch E, 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(7):595–602.
Galie N, Humbert M, Vachiery JL, Vizza CD, Kneussl M, Manes A, 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(9):1496–502.
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(5):375–8.
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(2):244–7.
Barst RJ, McGoon M, McLaughlin V, Tapson V, Rich S, Rubin L, et al. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2003;41(12):2119–25.
Hoeper MM, Barst RJ, Bourge RC, Feldman J, Frost AE, Galie N, et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation. 2013;127(10):1128–38.
Iglarz M, Binkert C, Morrison K, Fischli W, Gatfield J, Treiber A, et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther. 2008;327(3):736–45.
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(1–3):168–75.
Pulido T, Adzerikho I, Channick RN, Delcroix M, Galie N, Ghofrani HA, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809–18.
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(4):567–76.
Stasch JP, Becker EM, Alonso-Alija C, Apeler H, Dembowsky K, Feurer A, et al. NO-independent regulatory site on soluble guanylate cyclase. Nature. 2001;410(6825):212–5.
Ghofrani HA, Galie N, Grimminger F, Grunig E, Humbert M, Jing ZC, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330–40.
Ghofrani HA, D’Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369(4):319–29.
Kuwano K, Hashino A, Asaki T, Hamamoto T, Yamada T, Okubo K, 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(3):1181–8.
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(1):249–55.
Simonneau G, Torbicki A, Hoeper MM, Delcroix M, Karlocai K, Galie N, et al. Selexipag, an oral, selective IP receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J. 2012;40(4):874-80.
Kawut SM, Bagiella E, Lederer DJ, Shimbo D, Horn EM, Roberts KE, et al. Randomized clinical trial of aspirin and simvastatin for pulmonary arterial hypertension: ASA-STAT. Circulation. 2011;123(25):2985–93.
Fukumoto Y, Matoba T, Ito A, Tanaka H, Kishi T, Hayashidani S, et al. Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension. Heart. 2005;91(3):391–2.
Ishikura K, Yamada N, Ito M, Ota S, Nakamura M, Isaka N, et al. Beneficial acute effects of rho-kinase inhibitor in patients with pulmonary arterial hypertension. Circ J. 2006;70(2):174–8.
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(3):363–6.
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(2):195–200.
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(4):442–50.
Wang XX, Zhang FR, Shang YP, Zhu JH, Xie XD, Tao QM, 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(14):1566–71.
Zhu JH, Wang XX, Zhang FR, Shang YP, Tao QM, Zhu JH, 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(6):650–5.
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(5):858–63.
Humbert M, Barst RJ, Robbins IM, Channick RN, Galie N, Boonstra A, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J. 2004;24(3):353–9.
McLaughlin VV, Oudiz RJ, Frost A, Tapson VF, Murali S, Channick RN, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006;174(11):1257–63.
Simonneau G, Rubin LJ, Galie N, Barst RJ, Fleming TR, Frost AE, 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(8):521–30.
Lunze K, Gilbert N, Mebus S, Miera O, Fehske W, Uhlemann F, 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.
Acknowledgments
The Frederick and Margaret L Weyerhaeuser Foundation The Jayden de Luca Foundation NIH/NHLBI R01 HL114753; HL084923 UL1 TR000154 from NCATS/NIH.
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None.
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The University of Colorado receives fees for Dr Ivy to be a consultant for Actelion, Bayer, Gilead, Lilly, Pfizer, and United Therapeutics.
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Vorhies, E.E., Ivy, D.D. Drug Treatment of Pulmonary Hypertension in Children. Pediatr Drugs 16, 43–65 (2014). https://doi.org/10.1007/s40272-013-0052-2
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DOI: https://doi.org/10.1007/s40272-013-0052-2