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
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