Viagra® and the Neonate

Robert E. Lyle, M.D.Associate Professor of

Pediatrics

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)

Neonatal Outcomes

UAMS/ACH NICU:2002n Survival(%) BPD Home

O2

401-500g 6 3(50) 2(67) 2(67) 501-750g 59 49(83) 26(53) 18(37) 751-1000g 85 75(88) 29(38) 16(21) 1001-1250g 88 88(100) 16(18) 12(13) 1251-1500g 69 65(94) 4(6) 3(4) VLBW Overall 301 277(92) 75(27) 49(18)

Day 55

7 Months

BPD

“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

Evolution of oxygen requirements: Infants with “Classic” vs “New” BPD

Bland /Coalson 2000

PULMONARY IMMATURITY

AIRWAYCOMPLIANCE

PRESSURE/FLOWINHOMOGENEITY

IMMATURECELLS

SURFACTANTDEFICIENCY

BAROTRAUMA

PROTEIN LEAKRETAINEDFLUID

HYALINE MEMBRANE DISEASE

STARVATION RECOVERY

UP-REGULATIONOF GENES

DIFFUSE ALVEOLAR/ VASCULAR DAMAGE

BPD

PDA

O2 TOXICITY

ABERRANT GENEEXPRESSION

BAROTRAUMA

INFECTION/INFLAMMATIONBAROTRAUMA

STARVATION

Adapted from deLemos et al. Clin Perin 1992

ADRENALINSUFFICIENCY

TLR-2IL-8VEGF/Flt-1ElastaseMIP-1

ABERRANT GENEEXPRESSION

NFkBTGF

KGF

BPD Can Occur in Older Infants

Pulmonary Hypoplasia

Congenital Diaphragmatic Hernia Meconium Aspiration

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)

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

ECMO

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

Pulmonary Vascular Changes in BPD

Normal Lung BPD

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

Nitric oxide –cGMP – PDE

Pathway

Travadi and Patole, Ped Pulm, 2003

Cyclic Nucleotide Phosphodiesterases

Travadi and Patole, Ped Pulm, 2003

Change in Pulmonary Pressures followingSildenafil Infusion

Control • Nitric Oxide ∆Sildenafil o

Am J Resp Crit Car Med, 2002

Limited Clinical Data

Limited Clinical Data

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

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

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

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