Biology Reference
In-Depth Information
oxygenation. We speculate that it is because there is increased PDE5 expression
and activity in the pulmonary vessels of infants with PPHN (Farrow et al.
2008a
,
2010a
,
b
). Future studies are planned to further evaluate efficacy of IV sildenafil
in neonates with PPHN. Of note, the intravenous form of sildenafil was FDA-
approved in December of 2009 for adults with pulmonary arterial hypertension.
Smaller case reports and case series have examined the efficacy of oral sildenafil
in infants with CDH and BPD. In one case report, oral sildenafil facilitated weaning
from iNO in a 7-week-old infant with CDH, although the infant ultimately died
(Keller et al.
2004
). In another series of seven infants with CDH, oral sildenafil
improved right cardiac output and decreased pulmonary vascular resistance as
measured by echocardiography, and five of the seven infants survived (Noori et al.
2007
). A larger, double-blind, randomized controlled trial of oral sildenafil in infants
with CDH and severe pulmonary hypertension is ongoing (NCT00133679). Infants
are recruited between 10 and 42 days of age if they continue to have a significant FiO
2
requirement, if they need ECMO beyond 10 days of age, or if they have a pulmonary
artery pressure
2/3 systemic pressure beyond 14 days of age. Target enrollment is
32 infants, who will receive placebo or sildenafil for 5 weeks. The primary outcome is
pulmonary artery pressure on echocardiogram at the end of the treatment period.
Sildenafil is an attractive therapeutic option for infants with chronic pulmonary
hypertension because of its relative ease of administration and apparent low
toxicity. A recent case series examined the effect of oral sildenafil in 25 infants
and children with pulmonary hypertension due to chronic lung disease, who
initiated sildenafil treatment at
>
2 years of age (14-673 days). Most patients
(88%) achieved hemodynamic improvement after a median treatment interval of
40 days, and the majority of infants receiving iNO could be weaned off. Five
patients died after initiation of sildenafil treatment, but none died from refractory
pulmonary hypertension or right heart failure. This important pilot study suggests
that sildenafil is safe for infants with pulmonary hypertension due to chronic lung
disease and indicates that further studies are warranted (Mourani et al.
2009
).
Because sildenafil improved lung alveolarization in neonatal rats, a small double-
blind randomized controlled trial of oral sildenafil in the prevention of BPD is
ongoing (NCT00431418). The target population is extremely preterm infants
<
<
28 weeks gestation who still require ventilatory support at 7 days of age. This
study should also provide important initial data about the safety of sildenafil in
young preterm infants.
2.2 PDE3 Inhibitors
The PDE3 inhibitor milrinone is most commonly used in pediatric patients for its
inotropic effects(Chang et al.
1995
; Hoffman et al.
2003
; Zaccolo and Movsesian
2007
). However, by raising cAMP in the pulmonary vasculature, milrinone can
potentially act as a pulmonary vasodilator and improve oxygenation in patients with
poor response to iNO. In neonatal lambs with PPHN, one of the unexpected results
