Download Bronchopulmonary Dysplasia

Viagra and the Neonate
®
Robert E. Lyle, M.D.
Associate Professor of Pediatrics
Objectives
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Review Perinatal Data
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Sets stage for why new drugs are needed
Review Bronchopulmonary Dysplasia
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Late Complication:
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Pulmonary Hypertension
Cor Pulmonale
Phosphodiesterase Inhibitors for Pulmonary
Hypertension

Viagra (Sildenafil)
Neonatal Outcomes
UAMS/ACH NICU:2002
n
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401-500g
501-750g
751-1000g
1001-1250g
1251-1500g
VLBW Overall
6
59
85
88
69
301
Survival(%)
BPD
Home O2
3(50)
49(83)
75(88)
88(100)
65(94)
277(92)
2(67)
26(53)
29(38)
16(18)
4(6)
75(27)
2(67)
18(37)
16(21)
12(13)
3(4)
49(18)
BPD
Day 55
7 Months
Clinical Presentation of
“New” BPD
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“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
Evolution of oxygen requirements: Infants with “Classic” vs “New” BPD
Bland /Coalson 2000
PULMONARY IMMATURITY
AIRWAY
COMPLIANCE
PRESSURE/FLOW
INHOMOGENEITY
BAROTRAUMA
IMMATURE
CELLS
SURFACTANT
DEFICIENCY
RETAINED
FLUID
PROTEIN LEAK
ABERRANT GENE
EXPRESSION
BAROTRAUMA
ABERRANT GENE
EXPRESSION
ADRENAL
INSUFFICIENCY
NFkB
TGF
STARVATION
TLR-2
IL-8
VEGF/Flt-1
Elastase
MIP-1
HYALINE MEMBRANE DISEASE
O2 TOXICITY
PDA
UP-REGULATION
OF GENES
KGF
DIFFUSE ALVEOLAR/ VASCULAR DAMAGE
BAROTRAUMA
INFECTION/
INFLAMMATION
STARVATION
BPD
RECOVERY
Adapted from deLemos et al. Clin Perin 1992
BPD Can Occur in Older Infants
Pulmonary Hypoplasia
Congenital Diaphragmatic Hernia
Meconium Aspiration
Treatment of Lung Disease in
Older Infants
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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
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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
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Cor Pulmonale
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Right heart failure due to high PVR
Maintain high index of suspicion, avoid hypoxemia
Diagnostic Issues
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Nitric oxide (iNO)
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Difficult to assess severity/risk
EKG vs ECHO
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
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Has no direct relaxant effect but enhances the effect
of nitric oxide
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Selective for PDE5
Rapidly absorbed orally
Eliminated by hepatic metabolism (mainly
cytochrome P450 3A4) with one active metabolite
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Inhibits phosphodiesterase type 5
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 following
Sildenafil Infusion
Control •
Nitric Oxide ∆
Sildenafil o
Am J Resp Crit Car Med, 2002
Limited Clinical Data
Limited Clinical Data

Ameliorates effect of iNO withdrawal
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3 cases – congenital heart disease
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Treatment of rebound pulmonary
hypertension in CDH
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Atz and Wessel, Anesthesiology 1999
Keller et al, Ped Crit Care Med, 2004
ACH Experience: 2002-2005
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“Rescue” use in BPD (n = 3), CDH (1) and
Gastroschisis (1), plus post-op CHD patients
Potential Problems
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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
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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?
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Randomized-controlled trials are required to
determine the safety, efficacy and long-term
outcome following treatment with sildenafil
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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”
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Conventional management of PPHN aside from iNO
not based on evidence from randomised controlled
trials
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BMJ 2002;325:1174
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