Biology Reference
In-Depth Information
vascular resistance, but also produced systemic hypotension and decreased oxyge-
nation (Shekerdemian et al.
2004
). Similarly, in neonates after repair of ventricular
or atrioventricular septal defects, systemic hypotension and decreased oxygenation
were noted when sildenafil and iNO were given concurrently (Stocker et al.
2003
).
It is possible that sildenafil in combination with iNO may increase pulmonary
perfusion to underventilated lung segments, thereby leading to worsening VQ
mismatch and decreasing oxygenation. Furthermore, when given intravenously,
sildenafil may not be selective to the pulmonary vascular bed. It is possible that a
drop in systemic blood pressure may be poorly tolerated if combined with dimin-
ished oxygenation due to worsened VQ mismatch. We have shown that idiopathic
PPHN is associated with increased PDE5 expression and activity in the pulmonary
vascular bed (Farrow et al.
2008a
,
2010a
,
b
). Thus, those infants may be better able
to tolerate the combined therapy of iNO and intravenous sildenafil.
The clinical use of sildenafil has recently been reported in infants with PPHN,
including one small, randomized controlled trial with oral sildenafil, and one pilot
pharmacokinetic, pharmacodynamic trial with intravenous sildenafil (Baquero et al.
2006
; Steinhorn et al.
2009
). As mentioned previously, the only FDA-approved
pulmonary vasodilator for infants is iNO. However, iNO therapy is currently
expensive and unavailable in many parts of the world, leading to much higher
mortality from PPHN in those regions. For this reason, the use of oral sildenafil as
the primary treatment for severe PPHN was studied in term and near-term infants in
Colombia. This study randomized 13 infants (
35 5/7 weeks gestation and age
>
3 days) with an oxygenation index greater than 25, indicating severe PPHN.
In the sildenafil treatment group, a significant improvement in oxygenation was
observed by 24 h and six of the seven infants survived. In contrast, the infants in the
placebo group did not improve their oxygenation and only one of the six infants
survived (Baquero et al.
2006
). Despite these encouraging results, significant
concerns exist regarding giving sildenafil enterally to infants who may have
compromised intestinal perfusion with unknown and inconsistent rates of gastro-
intestinal absorption.
Two recently published papers described the results of a multicenter pilot trial
examining the safety and pharmacokinetics of intravenous sildenafil in term
and near-term neonates with PPHN (Mukherjee et al.
2009
; Steinhorn et al.
2009
). Thirty-six neonates (
<
>
34 weeks gestation) were enrolled at a mean age of
34
17 h when they had moderate to severe pulmonary hypertension with an
oxygenation index
>
15 (Mukherjee et al.
2009
; Steinhorn et al.
2009
). Infants with
congenital anomalies including CDH were excluded. Infants received IV sildenafil
administered within eight progressive, “step-up” dosing groups, and the study also
determined the optimal loading dose and duration. Infants received sildenafil for a
minimum of 48 h. After that time, sildenafil was discontinued once infants had been
successfully weaned from iNO for at least 1 h, or after 7 days (168 h). Based on data
from adults, clearance via the hepatic CYP3A4 and CYP2C9 enzymes was
expected. In the study, sildenafil clearance in neonates increased threefold between
day of life one and the end of the first week of life, likely reflecting postnatal
maturation of this CYP system. Hence, postnatal age at the time of sildenafil
