The Journal of Pediatrics
Volume 155, Issue 6 , Pages 841-847.e1 , December 2009

Intravenous Sildenafil in the Treatment of Neonates with Persistent Pulmonary Hypertension

  • Robin H. Steinhorn, MD

      Affiliations

    • Department of Pediatrics, Northwestern University Feinberg School of Medicine and Children's Memorial Hospital, Chicago, IL
    • Corresponding Author InformationReprint requests: Robin H. Steinhorn, MD, Children's Memorial Hospital, 2300 Children's Plaza, Box 45, Chicago, IL 60614.
    • ,
  • John P. Kinsella, MD

      Affiliations

    • Department of Pediatrics, University of Colorado and The Children's Hospital, Denver, CO
    • ,
  • Christine Pierce, MD

      Affiliations

    • Paediatric and Neonatal Intensive Care Unit, Great Ormond Street Hospital for Children, London, UK
    • ,
  • Ghazwan Butrous, MB, PhD

      Affiliations

    • Division of Cardiopulmonary Sciences, University of Kent, Canterbury, UK
    • ,
  • Maria Dilleen, MSc

      Affiliations

    • Pfizer Global Research and Development, Sandwich, UK
    • ,
  • Michael Oakes, MSc, PhD

      Affiliations

    • Pfizer Global Research and Development, Sandwich, UK
    • ,
  • David L. Wessel, MD

      Affiliations

    • Department of Pediatrics, Children's National Medical Center, Washington, DC

Received 3 February 2009 ,Revised 8 May 2009 ,Accepted 8 June 2009.

References 

  1. Walsh-Sukys MC, Tyson JE, Wright LL, Bauer CR, Korones SB, Stevenson DK, et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics. 2000;105:14–20
  2. 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. N Engl J Med. 2000;342:469–474
  3. Neonatal Inhaled Nitric Oxide Study Group . Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. New Engl J Med. 1997;336:597–604
  4. Farrow KN, Fliman P, Steinhorn RH. The diseases treated with ECMO: focus on PPHN. Semin Perinatol. 2005;29:8–14
  5. Konduri GG, Solimani A, Sokol GM, Singer J, Ehrenkranz RA, Singhal N, et al. A randomized trial of early versus standard inhaled nitric oxide therapy in term and near-term newborn infants with hypoxic respiratory failure. Pediatrics. 2004;113:559–564
  6. Konduri GG, Vohr B, Robertson C, Sokol GM, Solimano A, Singer J, et al. Early inhaled nitric oxide therapy for term and near-term newborn infants with hypoxic respiratory failure: neurodevelopmental follow-up. J Pediatr. 2007;150:235–240
  7. Steinhorn RH, Russell JA, Morin FC. Disruption of cyclic GMP production in pulmonary arteries isolated from fetal lambs with pulmonary hypertension. Am J Physiol Heart Circ Physiol. 1995;268:H1483–H1489
  8. Ichinose F, Erana-Garcia J, Hromi J, Raveh Y, Jones R, Krim L, et al. Nebulized sildenafil is a selective pulmonary vasodilator in lambs with acute pulmonary hypertension. Crit Care Med. 2001;29:1000–1005
  9. Weimann J, Ullrich R, Hromi J, Fujino Y, Clark MWH, Bloch KD, et al. Sildenafil is a pulmonary vasodilator in awake lambs with acute pulmonary hypertension. Anesthesiology. 2000;92:1702–1712
  10. Shekerdemian L, Ravn H, Penny D. Intravenous sildenafil lowers pulmonary vascular resistance in a model of neonatal pulmonary hypertension. Am J Resp Crit Care Med. 2002;165:1098–2002
  11. Shekerdemian LS, Ravn HB, Penny DJ. Interaction between inhaled nitric oxide and intravenous sildenafil in a porcine model of meconium aspiration syndrome. Pediatr Res. 2004;55:413–418
  12. 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;353:2148–2157
  13. Atz AM, Wessel DL. Sildenafil ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology. 1999;91:307–310
  14. Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics. 2006;117:1077–1083
  15. Mukherjee A, Dombi T, Wittke B, Lalonde R. Population pharmacokinetics of sildenafil in term neonates: evidence of rapid maturation of metabolic clearance in the early postnatal period. Clin Pharmacol Ther. 2008;85:56–63
  16. Lacroix D, Sonnier M, Moncion A, Cheron G, Cresteil T. Expression of CYP3A in the human liver: evidence that the shift between CYP3A7 and CYP3A4 occurs immediately after birth. Eur J Biochem. 1997;247:625–634
  17. Anderson BJ, Meakin GH. Scaling for size: some implications for paediatric anaesthesia dosing. Paediatr Anaesth. 2002;12:205–219
  18. Tzao C, Nickerson PA, Russell JA, Gugino SF, Steinhorn RH. Pulmonary hypertension alters soluble guanylate cyclase activity and expression in pulmonary arteries isolated from fetal lambs. Pediatr Pulmonol. 2001;31:97–105
  19. Tzao C, Nickerson PA, Russell JA, Noble BK, Steinhorn RH. Paracrine role of soluble guanylate cyclase and type III nitric oxide synthase in ovine fetal pulmonary circulation: a double-labeling immunohistochemical study. Histochem Cell Biol. 2003;119:125–130
  20. Hanson KA, Burns F, Rybalkin SD, Miller JW, Beavo J, Clarke WR. Developmental changes in lung cGMP phosphodiesterase-5 activity, protein. message. Am J Respir Crit Care Med. 1998;158:279–288
  21. Hanson KA, Ziegler JW, Tybalkin SD, Miller JW, Abman SH, Clarke WR. Chronic pulmonary hypertension increases fetal lung cGMP phosphodiesterase activity. Am J Physiol Lung Cell Mol Physiol. 1998;275:L931–L941
  22. Farrow KN, Groh BS, Schumacker PT, Lakshminrusimha S, Czech L, Gugino SF, et al. Hyperoxia increases phosphodiesterase 5 expression and activity in ovine fetal pulmonary artery smooth muscle cells. Circ Res. 2008;102:226–233
  23. 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
  24. Nichols D, Muirhead G, Harness J. Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality. Br J Clin Pharmacol. 2002;53(Suppl 1):5S–12S

 The study sponsor (Pfizer) provided the intravenous sildenafil, financial support for the clinical research nurse and other costs of conducting the study at each site, as well as ongoing site monitoring. The data analysis was performed by the academic authors and reviewed by statisticians who are employees of Pfizer (M.D. and M.O.). The manuscript was prepared by R.H.S., G.B., and J.P.K. No honorarium or other payment was provided to produce the manuscript.

PII: S0022-3476(09)00560-5

doi: 10.1016/j.jpeds.2009.06.012

The Journal of Pediatrics
Volume 155, Issue 6 , Pages 841-847.e1 , December 2009

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