Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Pediatric Drugs
Published in: Pediatric Drugs 2/2009

01-04-2009 | Review Article

Etiology, Diagnosis, and Pharmacologic Treatment of Pediatric Pulmonary Hypertension

Author: Dr Robert Tulloh

Published in: Pediatric Drugs | Issue 2/2009

Login to get access

Abstract

Major advances have been made in the understanding and treatment of pulmonary hypertension in the last few years. Without treatment (medication) for idiopathic pulmonary arterial hypertension, which is a rare and potentially fatal condition, the survival time is only about 3 years after diagnosis. However, if pulmonary hypertension is secondary to other causes such as congenital heart disease, it is possible to survive for 30 years or more without treatment.
The condition can affect children at any age, from fetal life to adulthood. Patients with pulmonary hypertension can present to the respiratory pediatrician with unresponsive asthma, to the neurologist with faints, or to the general pediatrician with failure to thrive.
Over the last few years there have been significant developments in the available therapy for managing this complicated disease. There is now a generally recognized ladder of long-term therapy for chronic pulmonary hypertension. Treatment can start with oxygen at home at night or even during the day. Next is the use of oral phosphodiesterase inhibitors, mostly type V, such as sildenafil, which enhance endogenous nitric oxide. More potent are the endothelin receptor antagonists and the most potent are the prostanoids, especially epoprostenol, which is given by constant intravenous infusion. In addition to interventional catheterization with atrial septostomy, these agents have improved the prognostic outlook. This article reviews the current knowledge about the etiology, investigation, and treatment of children with pulmonary hypertension in the clinical setting.
Literature
1.
Wood P. The Eisenmenger syndrome or pulmonary hypertension with reversed central shunt. BMJ 1958; 2: 701–9PubMedCrossRef
2.
Dresdale DT, Schultz M, Michtom RJ. Primary pulmonary hypertension: I. Clinical and hemodynamic study. Am J Med 1951; 11(6): 686–705PubMedCrossRef
3.
Eisenmenger V. Die angeboren defects des kammerscheidewand des herzen. Z Klin Med 1897; 32: 1–28
4.
Heath D, Edwards J. A description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac defects. Circulation 1958; 18: 533–47PubMedCrossRef
5.
Rabinovitch M, Keane J, Norwood W. Vascular structure in lung tissue obtained at biopsy correlated with pulmonary haemodynamic findings after repair of congenital heart defects. Circulation 1984; 69: 655–67PubMedCrossRef
6.
Rabinovitch M. Pathobiology of pulmonary hypertension: impact on clinical management. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2000; 3: 63–81PubMed
7.
8.
Andrews R, Tulloh R. Pulmonary hypertension in paediatrics. Curr Opin Ped 2002; 14: 603–5
9.
Kovesi T, Abdurahman A, Blayney M. Elevated carbon dioxide tension as a predictor of subsequent adverse events in infants with bronchopulmonary dysplasia. Lung 2006; 184(1): 7–13PubMedCrossRef
10.
Gibbs J. Recommendations on the management of pulmonary hypertension in clinical practice. Heart 2001; 86Suppl. 1: 1–13
11.
Proceedings of the 3rd World Symposium on Pulmonary Arterial Hypertension, Venice, Italy, 23–25 Jun 2003. J Am Coll Cardiol 2004; 43(12 Suppl. S): 1S–90S
12.
Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004; 43(12 Suppl. S): 5S–12SPubMedCrossRef
13.
Abman SH. Pathogenesis and treatment of neonatal and postnatal pulmonary hypertension. Curr Opin Pediatr 1994; 6(3): 239–47PubMedCrossRef
14.
Humbert M, Nunes H, Sitbon O, et al. Risk factors for pulmonary arterial hypertension. Clin Chest Med 2001; 22(3): 459–75PubMedCrossRef
15.
Luchese S, Manica JL, Zielinsky P. Intrauterine ductus arteriosus constriction: analysis of a historic cohort of 20 cases. Arq Bras Cardiol 2003; 81(4): 405–10, 399–404PubMedCrossRef
16.
Carlo WF, Villamor E, Ambalavanan N, et al. Chronic exposure to cigarette smoke extract impairs endothelium-dependent relaxation of chicken embryo pulmonary arteries. Biol Neonate 2001; 80(3): 247–50PubMedCrossRef
17.
Chambers CD, Hernandez-Diaz S, Li VM, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 2006; 354: 579–87PubMedCrossRef
18.
Rosenzweig EB, Barst RJ. Eisenmenger’s syndrome: current management. Prog Cardiovasc Dis 2002; 45: 129–38CrossRef
19.
Andrews R, Tulloh R, Magee A, et al. Atrial septal defect with failure to thrive in infancy: hidden pulmonary vascular disease? Pediatr Cardiol 2002; 23(5): 528–30PubMed
20.
Haworth SG. Development of the normal and hypertensive pulmonary vasculature. Exp Physiol 1995; 80(5): 843–53PubMed
21.
Bando K, Turrentine MW, Sharp TG, et al. Pulmonary hypertension after operations for congenital heart disease: analysis of risk factors and management. J Thorac Cardiovasc Surg 1996; 112(6): 1600–7; discussion 1607-9PubMedCrossRef
22.
Kumar A, Taylor GP, Sandor GG, et al. Pulmonary vascular disease in neonates with transposition of the great arteries and intact ventricular septum. Br Heart J 1993; 69(5): 442–5PubMedCrossRef
23.
Anderson RH, Baker EJ, McCartney FJ, et al., editors. Paediatric cardiology. 2nd ed. London: Churchill Livingstone, 2002
24.
Holcomb R, Tyson R, Ivy D, et al. Congenital pulmonary venous stenosis presenting as persistent pulmonary hypertension of the newborn. Pediatr Pulmonol 1999; 28: 301–6PubMedCrossRef
25.
Ricci M, Elliott M, Cohen GA, et al. Management of pulmonary venous obstruction after correction of TAPVC: risk factors for adverse outcome. Eur J Cardiothorac Surg 2003; 24(1): 28–36; discussion 36PubMedCrossRef
26.
Rabinovitch M, Haworth S, Castaneda AR, et al. Lung biopsy in congenital heart disease: a morphometric approach to pulmonary vascular disease. Circulation 1978; 58: 1107–22PubMedCrossRef
27.
Meyrick B, Reid L. Ultrastructural findings in lung biopsy material from children with congenital heart defects. Am J Pathol 1980; 101: 527–37PubMed
28.
Rabinovitch M, Bothwell T, Hayakawa B. Pulmonary artery endothelial abnormalities in patients with congenital heart defects and pulmonary hypertension: a correlation of light with scanning electron microscopy and transmission electron microscopy. Lab Invest 1986; 55: 632–53PubMed
29.
Taipale J, Lohi J. Human mast cell chymase and leukocyte elastase release latent transforming growth factor B1 from the extracellular matrix of cultured human epithelial and endothelial cells. J Biol Chem 1995; 270: 4689–96PubMedCrossRef
30.
Jones P, Cowan K, Rabinovitch M. Induction of tenascin and fibronectin are features associated with increased smooth muscle cell proliferation during the development of progressive pulmonary hypertension in children. Am J Pathol 1997; 150: 1349–60PubMed
31.
Thomson J, Machado R, Pauciulo M, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-2, a receptor member of the TGF-beta family. J Med Genet 2000; 37: 741–5PubMedCrossRef
32.
Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-family signalling. Nature 2003; 425: 577–84PubMedCrossRef
33.
Roberts KE, McElroy JJ, Wong WP, et al. BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease. Eur Respir J 2004; 24(3): 371–4PubMedCrossRef
34.
Rosenzweig EB, Barst RJ. Idiopathic pulmonary arterial hypertension in children. Curr Opin Pediatr 2005; 17(3): 372–80PubMedCrossRef
35.
Manes A, Campana C. Pulmonary hypertension: classification and diagnostic algorithm. Ital Heart J 2005; 6(10): 834–9PubMed
36.
Hattle L. Noninvasive assessment and differentiation of left ventricular outflow obstruction with Doppler ultrasound. Circulation 1981; 64: 381–7CrossRef
37.
Ebeid MR, Ferrer PL, Robinson B, et al. Doppler echocardiographic evaluation of pulmonary vascular resistance in children with congenital heart disease. J Am Soc Echocardiogr 1996; 9(6): 822–31PubMedCrossRef
38.
Bossone E, Bodini BD, Mazza A, et al. Pulmonary arterial hypertension: the key role of echocardiography. Chest 2005; 127: 1836–43PubMedCrossRef
39.
Lopez-Candales A, Dohi K, Rajagopalan N, et al. Right ventricular dyssynchrony in patients with pulmonary hypertension is associated with disease severity and functional class. Cardiovasc Ultrasound 2005; 3: 23–6PubMedCrossRef
40.
Maiya S, Hislop AA, Flynn Y, et al. Response to bosentan in children with pulmonary hypertension. Heart 2006; 92(5): 664–70PubMedCrossRef
41.
42.
Atz AM, Adatia I, Lock JE, et al. Combined effects of nitric oxide during acute pulmonary vasodilator testing. J Am Coll Cardiol 1999; 33: 813–9PubMedCrossRef
43.
Mikhail G, Gibbs J, Richardson M, et al. An evaluation of nebulized prostacycin in patients with primary and secondary pulmonary hypertension. Eur Heart J 1997; 18:1499–504PubMedCrossRef
44.
Holcomb SS. Understanding pulmonary arterial hypertension. Nursing 2004; 34(9): 50–4PubMed
45.
Sigurdsson G, Troughton RW, Xu XF, et al. Detection of pulmonary vein stenosis by transesophageal echocardiography: comparison with multidetector computed tomography. Am Heart J 2007; 153(5): 800–6PubMedCrossRef
46.
Monagle P, Adams M, Mahoney M, et al. Outcome of pediatric thromboembolic disease: a report from the Canadian Childhood Thrombophilia Registry. Pediatr Res 2000; 47: 763–6PubMedCrossRef
47.
Muthurangu V, Taylor A, Tulloh R, et al. Novel method of quantifying pulmonary vascular resistance by use of simultaneous invasive pressure monitoring and phase-contrast magnetic resonance flow. Circulation 2004; 110(7): 826–34PubMedCrossRef
48.
Muthurangu V, Atkinson D, Sermesant M, et al. Measurement of total pulmonary arterial compliance using invasive pressure monitoring and MR flow quantification during MR-guided cardiac catheterization. Am J Physiol Heart Circ Physiol 2005; 289(3): H1301–6PubMedCrossRef
49.
Tulloh R, Hislop A, Boels P, et al. Chronic hypoxia inhibits postnatal maturation of porcine intrapulmonary artery relaxation. Am J Physiol 1997; 272: H2436–45PubMed
50.
Black SM, Bekker JM, McMullan DM, et al. Alterations in nitric oxide production in 8-week-old lambs with increased pulmonary blood flow. Pediatr Res 2002; 52(2): 233–44PubMedCrossRef
51.
Adatia I, Haworth S. Circulating endothelin levels in children with congenital heart disease. Br Heart J 1993; 69: 233–6PubMedCrossRef
52.
Blyth KG, Groenning BA, Mark PB, et al. NT-proBNP can be used to detect RV systolic dysfunction in pulmonary hypertension. Eur Respir J 2007; 29(4): 737–44PubMedCrossRef
53.
Yuan JX, Rubin LJ. Pathogenesis of pulmonary arterial hypertension: the need for multiple hits. Circulation 2005; 111(5): 534–8PubMedCrossRef
54.
Lindberg L, Olsson AK, Jogi P, et al. How common is severe pulmonary hypertension after pediatric cardiac surgery? J Thorac Cardiovasc Surg 2002; 123(6): 1155–63PubMedCrossRef
55.
Ohsumi H, Sakamoto M, Yamazaki T, et al. Effects of fentanyl on carotid sinus baroreflex control of circulation in rabbits. Am J Physiol 1989; 256: R625–31PubMed
56.
Levy M, Tulloh RMH, Komai H, et al. Maturation of the contractile response and its endothelial modulation in newborn porcine intrapulmonary arteries. Pediatr Res 1995; 38: 25–9PubMedCrossRef
57.
Adatia I, Wessel DL. Therapeutic use of inhaled nitric oxide. Curr Opin Pediatr 1994; 6(5): 583–90PubMedCrossRef
58.
Abman SH. Neonatal pulmonary hypertension: a physiologic approach to treatment. Pediatr Pulmonol 2004; 26 Suppl.: 127–8CrossRef
59.
Hermon M, Golej J, Burda G, et al. Intravenous prostacyclin mitigates inhaled nitric oxide rebound effect: a case control study. Artif Organs 1999; 23: 975–8PubMedCrossRef
60.
Kinsella JP, Abman SH. Inhaled nitric oxide therapy in children. Paediatr Respir Rev 2005; 6(3): 190–8PubMedCrossRef
61.
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(2): 174–8PubMedCrossRef
62.
Badesch DB, McLaughlin VV, Delcroix M, et al. Prostanoid therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43(12 Suppl. S): 56S–61SPubMedCrossRef
63.
Clark RH, Huckaby JL, Kueser TJ, et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension: 1-year follow-up. J Perinatol 2003; 23(4): 300–3PubMedCrossRef
64.
Adatia I, Perry S, Landzberg M, et al. Inhaled nitric oxide and hemodynamic evaluation of patients with pulmonary hypertension before transplantation. J Am Coll Cardiol 1995; 25(7): 1656–64PubMedCrossRef
65.
Wimmer M, Schlemmer M. Long-term hemodynamic effects of nifedipine on congenital heart disease with Eisenmenger’s mechanism in children. Cardiovasc Drugs Ther 1992; 6(2): 183–6PubMedCrossRef
66.
McMahon CJ, Kadkin J, Nihill MR. Rapid regression of primary pulmonary hypertension. Heart 2001; 86(1): E1PubMedCrossRef
67.
Humpl T, Reyes JT, Holtby H, et al. 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): 3274–80PubMedCrossRef
68.
Weimann J, Ullrich R, Hromi J, et al. Sildenafil is a pulmonary vasodilator in awake lambs with acute pulmonary hypertension. Anesthesiology 2000; 92: 1702–12PubMedCrossRef
69.
Atz AM, Lefler AK, Fairbrother DL, et al. Sildenafil augments the effect of inhaled nitric oxide for postoperative pulmonary hypertensive crises. J Thorac Cardiovasc Surg 2002; 124(3): 628–9PubMedCrossRef
70.
Bharani A, Mathew V, Sahu A, et al. The efficacy and tolerability of sildenafil in patients with moderate-to-severe pulmonary hypertension. Indian Heart J 2003; 55(1): 55–9PubMed
71.
Brun H, Holmstrom H, Thaulow E. Sudden death during a change in treatment for pulmonary hypertension. Cardiol Young 2005; 15(2): 223–5PubMedCrossRef
72.
Della Torre F, Della Torre E, Di Berardino F. Sildenafil in pulmonary hypertension. Sarcoidosis Vasc Diffuse Lung Dis 2005; 22(1): 78–9PubMed
73.
Matot I, Gozal Y. Pulmonary responses to selective phosphodiesterase-5 and phosphodiesterase-3 inhibitors. Chest 2004; 125(2): 644–51PubMedCrossRef
74.
Cacoub P, Dorent R, Nataf P, et al. Endothelin-1 in pulmonary hypertension. N Engl J Med 1993; 329(26): 1967–8PubMedCrossRef
75.
Rosenzweig EB, Ivy DD, Dingemanse J, et al. Effects of long-term bosentan in children with pulmonary arterial hypertension. J Am Coll Cardiol 2005; 46(4): 697–704PubMedCrossRef
76.
Barst RJ, Ivy D, Dingemanse J, et al. Pharmacokinetics, safety efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. Clin Pharmacol Ther 2003; 73(4): 372–82PubMedCrossRef
77.
Gatzoulis MA, Rogers P, Li W, et al. Safety and tolerability of bosentan in adults with Eisenmenger physiology. Int J Cardiol 2005; 98(1): 147–51PubMedCrossRef
78.
Apostolopoulou SC, Rammos S. Sitaxsentan in pulmonary arterial hypertension. Chest 2003; 123(5): 1772; author reply 1772–3PubMedCrossRef
79.
Barst RJ, Langleben D, Frost A, et al. Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med 2004; 169(4): 441–7PubMedCrossRef
80.
Barst RJ, Rich S, Widlitz A, et al. Clinical efficacy of sitaxsentan, an endothelin-A receptor antagonist, in patients with pulmonary arterial hypertension: open-label pilot study. Chest 2002; 121(6): 1860–8PubMedCrossRef
81.
Prostacyclin: basic principles and clinical application in congestive heart failure and primary pulmonary hypertension. Proceedings of a symposium in Bologna, Italy, November 20, 1993. Am J Cardiol 1995; 75(3): 1A–73A
82.
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(5): 296–302PubMedCrossRef
83.
Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002; 165(6): 800–4PubMed
84.
Vizza CD, Sciomer S, Morelli S, et al. Long term treatment of pulmonary arterial hypertension with beraprost, an oral prostacyclin analogue. Heart 2001; 86(6): 661–5PubMedCrossRef
85.
Barst RJ, McGoon M, McLaughlin V, et al. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2003; 41(12): 2119–25PubMedCrossRef
86.
Baker SE, Hockman RH. Inhaled iloprost in pulmonary arterial hypertension. Ann Pharmacother 2005; 39(7–8): 1265–74PubMedCrossRef
87.
Hoeper MM, Faulenbach C, Golpon H, et al. Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur Respir J 2004; 24: 1007–10PubMedCrossRef
88.
Mogollon MV, Lage E, Cabezon S, et al. Combination therapy with sildenafil and bosentan reverts severe pulmonary hypertension and allows heart transplantation [case report]. Transplant Proc 2006; 38(8): 2522–3PubMedCrossRef
89.
Driscoll JA, Chakinala MM. Medical therapy for pulmonary arterial hypertension. Expert Opin Pharmacother 2008; 9(1): 65–81PubMedCrossRef
90.
Arima M, Kanoh T, Takagi A, et al. Clinical features of acute pulmonary thromboembolism in younger patients. Circ J 2003; 67(4): 330–3PubMedCrossRef
91.
Tanaka E, Harigai M, Tanaka M, et al. Pulmonary hypertension in systemic lupus erythematosus: evaluation of clinical characteristics and response to immunosuppressive treatment. J Rheumatol 2002; 29(2): 282–7PubMed
92.
Cheever KH. An overview of pulmonary arterial hypertension: risks, pathogenesis, clinical manifestations management. J Cardiovasc Nurs 2005; 20(2): 108–16; quiz 117–8PubMed
93.
National pulmonary hypertension centres of the UK and Ireland: consensus statement on the management of pulmonary hypertension in the UK and Ireland. Heart 2008; 94: 1–41CrossRef
94.
Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992; 327(2): 76–81PubMedCrossRef
95.
Higenbottam T. Intravenous epoprostenol for primary pulmonary hypertension [letter]. N Engl J Med 1996; 334(22): 1477; author reply 1477–8PubMedCrossRef
96.
Sandoval J, Aguirre JS, Pulido T, et al. Nocturnal oxygen therapy in patients with the Eisenmenger syndrome. Am J Respir Crit Care Med 2001; 164(9): 1682–7PubMed
97.
Kerstein D, Levy PS, Hsu DT, et al. Blade balloon atrial septostomy in patients with severe primary pulmonary hypertension. Circulation 1995; 91(7): 2028–35PubMedCrossRef
Metadata
Title
Etiology, Diagnosis, and Pharmacologic Treatment of Pediatric Pulmonary Hypertension
Author
Dr Robert Tulloh
Publication date
01-04-2009
Publisher
Springer International Publishing
Published in
Pediatric Drugs / Issue 2/2009
Print ISSN: 1174-5878
Electronic ISSN: 1179-2019
DOI
https://doi.org/10.2165/00148581-200911020-00003

Other articles of this Issue 2/2009

Pediatric Drugs 2/2009 Go to the issue

Review Article

Anti-Diarrheal Effects of Diosmectite in the Treatment of Acute Diarrhea in Children

Review Article

The Role of Inhaled Corticosteroids in the Management of Cystic Fibrosis

Review Article

Pediatric Palliative Care

Original Research Article

Incidence, Preventability, and Impact of Adverse Drug Events (ADEs) and Potential ADEs in Hospitalized Children in New Zealand