Hostname: page-component-78c5997874-8bhkd Total loading time: 0 Render date: 2024-11-10T05:59:33.297Z Has data issue: false hasContentIssue false
  • English
  • Français

Sildenafil therapy for neonatal and childhood pulmonary hypertensive vascular disease

Published online by Cambridge University Press:  08 December 2010

Tilman Humpl ,
Janette T. Reyes ,
Simon Erickson ,
Ruth Armano ,
Helen Holtby  and
Ian Adatia
Tilman Humpl
Affiliation:
Hospital for Sick Children, University of Toronto, Toronto, Canada
Janette T. Reyes
Affiliation:
Hospital for Sick Children, University of Toronto, Toronto, Canada
Simon Erickson
Affiliation:
Princess Margaret Hospital, University of Western Australia, Perth, Australia
Ruth Armano
Affiliation:
Cliniques Universitaires de St Luc, Brussels, Belgium
Helen Holtby
Affiliation:
Hospital for Sick Children, University of Toronto, Toronto, Canada
Ian Adatia*
Affiliation:
Stollery Children's Hospital, University of Alberta, Edmonton, Alberta, Canada
*
Correspondence to: Dr I. Adatia, Room 3A1.44, Walter C Mackenzie Health Sciences Center, 8440 112 Street, Edmonton, Alberta T6G 3T7, Canada. Tel: 780 407 3642; Fax: 780 407 3954 E-mails: iadatia@ualberta.ca, ianadatia@me.com
Get access Rights & Permissions [Opens in a new window]

Abstract

Objectives

We hypothesised that sildenafil would improve hemodynamics in children with pulmonary hypertension and attenuate rebound pulmonary hypertension after inhaled nitric oxide withdrawal.

Patients and methods

We undertook an open-label, single-drug study of sildenafil in patients under 5 years of age with either symptomatic or rebound pulmonary hypertension following inhaled nitric oxide withdrawal.

Results

We recruited 25 patients (median age 180 days, 10–1790) to receive sildenafil. The median right ventricular to systemic systolic blood pressure ratio before sildenafil therapy was 1.0 (0.5–1.4) and decreased to 0.5 (with a range from 0.3 to 1.3; p = 0.0002). In five patients the baseline pulmonary vascular resistance index was 10 (7.1–13.6) Wood units metre square and decreased to 5.8 (2.7–15.6) Wood units metre square (p = 0.04) at 6 months. Ten patients were treated with sildenafil for a median of 34 days (9–499) until resolution of pulmonary artery hypertension and continue to do well. Six patients continued sildenafil therapy for a median of 1002 days (384–1574) with improvement but without resolution of pulmonary hypertension. There was no change in serum creatinine, urea, liver function tests, or platelet count. In 15 patients sildenafil abolished rebound pulmonary artery hypertension following withdrawal of inhaled nitric oxide. Median right ventricular pressure to systemic systolic pressure ratio decreased from 1.0 (0.8–1.4) during nitric oxide withdrawal to 0.4 (0.3–0.8) p = 0.006 after pre-treatment with sildenafil.

Conclusion

In children under 5 years of age with severe pulmonary hypertension, sildenafil therapy resulted in prolonged hemodynamic improvements without adverse effects. Sildenafil attenuated rebound pulmonary hypertension after withdrawal of inhaled nitric oxide.

Keywords

Sildenafilneonatalpulmonary hypertensioncongenital cardiac diseasecongenital diaphragmatic hernia
Type
Original Articles
Information
Cardiology in the Young , Volume 21 , Issue 2 , April 2011 , pp. 187 - 193
Copyright
Copyright © Cambridge University Press 2010

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. Adatia, I. Recent advances in pulmonary vascular disease. Curr Opin Pediatr 2002; 14: 292–297.CrossRefGoogle ScholarPubMed
2. Khemani, E, McElhinney, DB, Rhein, L, et al. Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era. Pediatrics 2007; 120: 1260–1269.CrossRefGoogle ScholarPubMed
3. Ghofrani, HA, Pepke-Zaba, J, Barbera, JA, et al. Nitric oxide pathway and phosphodiesterase inhibitors in pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43: 68S–72S.CrossRefGoogle ScholarPubMed
4. 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: 3274–3280.CrossRefGoogle Scholar
5. Sastry, BK, Narasimhan, C, Reddy, NK, Raju, BS. Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol 2004; 43: 1149–1153.CrossRefGoogle ScholarPubMed
6. Michelakis, ED, Tymchak, W, Noga, M, et al. Long-term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension. Circulation 2003; 108: 2066–2069.CrossRefGoogle ScholarPubMed
7. 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: 379–384.CrossRefGoogle ScholarPubMed
8. 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; e841.Google Scholar
9. 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–II173.CrossRefGoogle ScholarPubMed
10. 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.CrossRefGoogle ScholarPubMed
11. Noori, S, Friedlich, P, Wong, P, Garingo, A, Seri, I. Cardiovascular effects of sildenafil in neonates and infants with congenital diaphragmatic hernia and pulmonary hypertension. Neonatology 2007; 91: 92–100.CrossRefGoogle ScholarPubMed
12. Galie, N, Torbicki, A, Barst, R, et al. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur Heart J 2004; 25: 2243–2278.Google ScholarPubMed
13. Grunig, E, Weissmann, S, Ehlken, N, et al. Stress Doppler echocardiography in relatives of patients with idiopathic and familial pulmonary arterial hypertension: results of a multicenter European analysis of pulmonary artery pressure response to exercise and hypoxia. Circulation 2009; 119: 1747–1757.CrossRefGoogle ScholarPubMed
14. Adatia, I. Improving the outcome of childhood pulmonary arterial hypertension: the effect of bosentan in the setting of a dedicated pulmonary hypertension clinic. J Am Coll Cardiol 2005; 46: 705–706.CrossRefGoogle ScholarPubMed
15. Adatia, I. Pulmonary veno-occlusive disease. In: Freedom RM, Yoo S-J, Mikailian H and Williams WG (eds). The Natural and Modified History of Congenital Heart Disease. Futura, New York, 2004; 513.Google Scholar
16. Atz, AM, Adatia, I, Wessel, DL. Rebound pulmonary hypertension after inhalation of nitric oxide. Ann Thorac Surg 1996; 62: 1759–1764.Google Scholar
17. Miller, OI, Tang, SF, Keech, A, Celermajer, DS. Rebound pulmonary hypertension on withdrawal from inhaled nitric oxide. Lancet 1995; 346: 51–52.CrossRefGoogle ScholarPubMed
18. 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: 1042–1047.CrossRefGoogle ScholarPubMed
19. Cordell, WH, Maturi, RK, Costigan, TM, et al. Retinal effects of 6 months of daily use of tadalafil or sildenafil. Arch Ophthalmol 2009; 127: 367–373.CrossRefGoogle ScholarPubMed
20. Keller, RL, Moore, P, Teitel, D, Hawgood, S, McQuitty, J, Fineman, JR. Abnormal vascular tone in infants and children with lung hypoplasia: findings from cardiac catheterization and the response to chronic therapy. Pediatr Crit Care Med 2006; 7: 589–594.CrossRefGoogle ScholarPubMed