The Use of Sildenafil in Persistent Pulmonary Hypertension of the Newborn

ABSTRACT

We evaluated the effectiveness of sildenafil in the treatment of neonatal pulmonary hypertension. We performed a double-blind randomized clinical trial in 51 full-term infants with persistent pulmonary hypertension confirmed by Doppler echocardiography. Patients were divided in two groups: 20 infants in group A received placebo when the oxygenation index was >20, and 31 infants in group B received 3 mg/kg of oral sildenafil every 6 hours. Arterial blood gases were taken at 1, 4, 7, 13, 19, and 25 hours after treatment was started. Main outcome measures were oxygenation changes, time on mechanical ventilation, and mortality. Both groups were comparable in general variables as well as in illness severity. We observed better oxygenation parameters after 7 hours of sildenafil treatment, but no significant changes were found in the placebo group. Mortality was higher in the placebo group (40%) than in those infants who received sildenafil (6%; p = 0.004), although no difference was found in time on mechanical ventilation between groups. Our results confirm that sildenafil may be a useful adjuvant therapy for term infants with pulmonary hypertension in centers lacking inhaled nitric oxide and extracorporeal membrane oxygenation.

KEYWORDS

Neonatal pulmonary hypertension - sildenafil - oxygenation index

REFERENCES

• 1 Boden G, Bennett C. The management of persistent pulmonary hypertension of the newborn.  Curr Paediatr. 2004;  14 290-297
• 2 D'Alonzo G E, Barst R J, Ayres S M et al.. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry.  Ann Intern Med. 1991;  115 343-349
• 3 Travadi J N, Patole S K. Phosphodiesterase inhibitors for persistent pulmonary hypertension of the newborn: a review.  Pediatr Pulmonol. 2003;  36 529-535
• 4 Channick R N, Newhart J W, Johnson F W et al.. Pulsed delivery of inhaled nitric oxide to patients with primary pulmonary hypertension: an ambulatory delivery system and initial clinical tests.  Chest. 1996;  109 1545-1549
• 5 Kelly L K, Porta N F, Goodman D M, Carroll C L, Steinhorn R H. Inhaled prostacyclin for term infants with persistent pulmonary hypertension refractory to inhaled nitric oxide.  J Pediatr. 2002;  141 830-832
• 6 Sola A, Baquero H. Sildenafilo oral en medicina neonatal “Investigado para adultos, usado también por neonatos”.  An Pediatr (Barc). 2007;  66 167-176
• 7 Beavo J A. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms.  Physiol Rev. 1995;  75 725-748
• 8 Buck M L. Sildenafil for the treatment of pulmonary hypertension in children.  Pediatr Pharm. 2004;  10 1-4
• 9 Weimann J, Ullrich R, Hromi J et al.. Sildenafil is a pulmonary vasodilator in awake lambs with acute pulmonary hypertension.  Anesthesiology. 2000;  92 1702-1712
• 10 Shekerdemian L S, Ravn H B, Penny D J. Intravenous sildenafil lowers pulmonary vascular resistance in a model of neonatal pulmonary hypertension.  Am J Respir Crit Care Med. 2002;  165 1098-1102
• 11 Sastry B KS, Narasimhan C, Reddy N K et al.. A study of clinical efficacy of sildenafil in patients with primary pulmonary hypertension.  Indian Heart J. 2002;  54 410-414
• 12 Singh T P, Rohit M, Grover A, Malhotra S, Vijayvergiya R. A randomized, placebo-controlled, double-blind, crossover study to evaluate the efficacy of oral sildenafil therapy in severe pulmonary artery hypertension.  Am Heart J. 2006;  151 851 e1-e5
• 13 Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto K, Archer S. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide.  Circulation. 2002;  105 2398-2403
• 14 Prasad S, Wilkinson J, Gatzoulis M A. Sildenafil in primary pulmonary hypertension.  N Engl J Med. 2000;  343 1342-1343
• 15 Erickson S, Reyes J, Bohn D et al.. Sildenafil (Viagra) in childhood and neonatal pulmonary hypertension.  J Am Coll Cardiol. 2002;  39 402A
• 16 Fernández González N, Rodríguez Fernández A, Jerez Rojas J et al.. Sildenafilo oral como tratamiento de un neonato con hipertensión pulmonar persistente.  An Pediatr (Barc). 2004;  61 567-568
• 17 Bonino A, Moraes M, Mortinotti M et al.. Sildenafil: ¿una alternativa para el tratamiento de la hipertensión pulmonar persistente?.  Arch Pediatr Urug. 2005;  76 130-134
• 18 Namachivayam P, Theilen U, Butt W W, Cooper S M, Penny D J, Shekerdemian L S. Sildenafil prevents rebound pulmonary hypertension after withdrawal of nitric oxide in children.  Am J Respir Crit Care Med. 2006;  174 1042-1047
• 19 Herrera Torres R, Concha Gonzalez E P, Holberto Castillo J et al.. Sildenafil oral como alternativa en el tratamiento de recién nacidos con hipertensión pulmonar persistente.  Rev Mex Pediatr. 2006;  73 159-163
• 20 Baquero H, Soliz A, Neira F, Venegas M E, Sola A. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study.  Pediatrics. 2006;  117 1077-1083
• 21 Wood B R. Principios fisiológicos. In: Goldsmith JP, Karotkin EH Ventilación asistida neonatal. Bogotá; Editorial Distribuna 2005: 25-61
• 22 Su B H, Watanabe T, Shimizu M et al.. Doppler assessment of pulmonary artery pressure in neonates at risk of chronic lung disease.  Arch Dis Child Fetal Neonatal Ed. 1997;  77 F23-F27
• 23 Berger M, Haimowitz A, Van Tosh A et al.. Quantitative assessment of pulmonary hypertension in patients with tricuspid regurgitation using continuous wave Doppler ultrasound.  J Am Coll Cardiol. 1985;  6 359-365
• 24 Halley S B, Cummings S R. Diseño de la investigación clínica. Barcelona; Ediciones Doyma 1993: 232-233
• 25 Dawson-Saunders B, Trapo R G. Bioestadística médica. 2nd ed. Mexico, DF; El Manual Moderno 1997 124-126 149-160 175-177
• 26 Lemus-Varela M L, Sola A, Gómez-Meda B C et al.. Oral sildenafil citrate lacks genotoxicity and cytotoxicity in a primate model: Callithrix jacchus.  J Perinatol. 2006;  26 423-427
• 27 Marsh C S, Marden B, Newsom R. Severe retinopathy of prematurity (ROP) in a premature baby treated with sildenafil acetate (Viagra) for pulmonary hypertension.  Br J Ophthalmol. 2004;  88 306-307