1. Viagra ® and the Neonate Robert E. Lyle, M.D. Associate Professor of Pediatrics

2. Objectives Review Perinatal Data Sets stage for why new drugs are needed Review Bronchopulmonary Dysplasia Late Complication: Pulmonary Hypertension Cor Pulmonale Phosphodiesterase Inhibitors for Pulmonary Hypertension Viagra (Sildenafil)

6. Neonatal Outcomes UAMS/ACH NICU:2002 nSurvival(%)BPDHome O2 401-500g6 3(50)2(67)2(67) 501-750g5949(83)26(53)18(37) 751-1000g8575(88)29(38)16(21) 1001-1250g8888(100)16(18)12(13) 1251-1500g6965(94)4(6)3(4) VLBW Overall 301277(92)75(27)49(18)

7. Day 55 7 Months BPD

8. “Mild” initial lung disease – often wean to room air quickly A “honeymoon period may follow In subsequent days a progressive deterioration in lung function – often due to infection and/or PDA Clinical Presentation of “New” BPD

9. Evolution of oxygen requirements: Infants with “Classic” vs “New” BPD Bland /Coalson 2000

10. PULMONARY IMMATURITY AIRWAY COMPLIANCE PRESSURE/FLOW INHOMOGENEITY IMMATURE CELLS SURFACTANT DEFICIENCY BAROTRAUMA PROTEIN LEAK RETAINED FLUID HYALINE MEMBRANE DISEASE STARVATION RECOVERY UP-REGULATION OF GENES DIFFUSE ALVEOLAR/ VASCULAR DAMAGE BPD PDA O 2 TOXICITY ABERRANT GENE EXPRESSION BAROTRAUMA INFECTION/ INFLAMMATION BAROTRAUMA STARVATION Adapted from deLemos et al. Clin Perin 1992 ADRENAL INSUFFICIENCY TLR-2 IL-8 VEGF/Flt-1 Elastase MIP-1 ABERRANT GENE EXPRESSION NF k B TGF KGF

11. BPD Can Occur in Older Infants Pulmonary Hypoplasia Congenital Diaphragmatic Hernia Meconium Aspiration

12. Treatment of Lung Disease in Older Infants Volume ventilation vs High Frequency Ventilation (HFOV) Surfactant replacement Inhaled Nitric Oxide Only approved selective pulmonary vasodilator for the treatment of persistent pulmonary hypertension of the newborn (PPHN)

13. ECMO: Extracorporeal Membrane Oxygenation Used to treat severe respiratory failure in infants weighing > 2000g unresponsive to conventional management Meconium Aspiration Syndrome Persistent Pulmonary Hypertension of Newborn (PPHN) Diaphragmatic Hernia Congenital Heart Disease

14. ECMO

15. BPD Complications Cor Pulmonale Right heart failure due to high PVR Maintain high index of suspicion, avoid hypoxemia Diagnostic Issues Difficult to assess severity/risk EKG vs ECHO Nitric oxide (iNO) Limited data on use in chronic BPD Cyclic GMP inhibitors Sildenafil Abman, Arch Dis Child, 2002

16. Pulmonary Vascular Changes in BPD Normal Lung BPD

17. Sildenafil Has no direct relaxant effect but enhances the effect of nitric oxide Inhibits phosphodiesterase type 5 Selective for PDE5 Rapidly absorbed orally Eliminated by hepatic metabolism (mainly cytochrome P450 3A4) with one active metabolite Cyp 3A4 inhibitors (erthyomycin, ketoconazole) may result in increased plasma levels Both sidenafil and metabolite half lives of 4 hours

18. Nitric oxide – cGMP – PDE Pathway Travadi and Patole, Ped Pulm, 2003

19. Cyclic Nucleotide Phosphodiesterases Travadi and Patole, Ped Pulm, 2003

20. Change in Pulmonary Pressures following Sildenafil Infusion Control Nitric Oxide ∆ Sildenafil o Am J Resp Crit Car Med, 2002

21. Limited Clinical Data

22. Ameliorates effect of iNO withdrawal 3 cases – congenital heart disease Atz and Wessel, Anesthesiology 1999 Treatment of rebound pulmonary hypertension in CDH Keller et al, Ped Crit Care Med, 2004 ACH Experience: 2002-2005 “Rescue” use in BPD (n = 3), CDH (1) and Gastroschisis (1), plus post-op CHD patients

23. Potential Problems Effects on infant cardiac function, pulmonary gas exchange and systemic hemodynamics, especially in presence of sepsis, need to be evaluated May not have a role in situations where iNO has failed Given hepatic elimination, use in hepatic dysfunction is unclear Potential interaction with other drugs Potential risk of irreversible retinal damage linked to PDE6 inhibition Potential for severe ROP – Br J Oph, 2004;88:298-315

24. What’s the Future? Randomized-controlled trials are required to determine the safety, efficacy and long-term outcome following treatment with sildenafil BPD with pulmonary hypertension/cor pulmonale CDH with rebound pulmonary hypertension Post-operative congenital heart disease Clinical trials should also assess the efficacy as a synergistic agent with iNO Pharmacokinetic studies are necessary to determine the optimal dose and mode of administration of sildenafil in neonates

25. Should Sildenafil Be Used? “Such unlicensed drug use might be justified as last resort” BMJ 2002;325:1174 Conventional management of PPHN aside from iNO not based on evidence from randomised controlled trials Hyperventilation, bicarbonate infusion and in the past, tolazoline Sildenafil’s use should be viewed as experimental and only after failure of conventional therapy and informed consent