Biology Reference
In-Depth Information
Dukarm et al.
1998
; Ivy et al.
1998
). In neonatal lambs with PPHN, dipyridamole
significantly decreased pulmonary vascular resistance and pulmonary blood pres-
sure, and increased pulmonary blood flow. Unfortunately, it was not selective for the
pulmonary vasculature, and it decreased systemic blood pressure to a similar degree
(Dukarm et al.
1998
). In human neonates, there are a handful of case reports reporting
the use of dipyridamole to facilitate iNO weaning in infants with PPHN, congenital
heart disease, and CDH. In two case reports, treatment with dipyridamole facilitated
iNO weaning in infants with PPHN, and in both cases, the infants survived
(al-Alaiyan et al.
1996
; Worwag et al.
2000
). In infants with CDH, successful
treatment with dipyridamole has been reported, but improvement was transient in
at least two cases (Buysse et al.
2001
; Thebaud et al.
1999
). The largest report
of dipyridamole use was in infants who required postoperative iNO therapy for
pulmonary hypertension after repair of congenital heart disease. In a series of 23
consecutive children receiving iNO postoperatively, seven developed rebound pul-
monary hypertension when iNO was acutely stopped. In those seven, dipyridamole
attenuated the rise in pulmonary pressure after acute withdrawal of iNO (Ivy et al.
1998
). None of these case reports described a significant decrease in systemic blood
pressure similar to that observed in the PPHN lamb model (Dukarm et al.
2005
).
2.1.2 Sildenafil
Sildenafil has been demonstrated to acutely decrease pulmonary vascular resis-
tance and improve pulmonary blood flow in a neonatal porcine model of MAS
(Shekerdemian et al.
2002
,
2004
). Chronic use of sildenafil decreased medial wall
thickness and RVH in a rat model of BPD (Ladha et al.
2005
). Like dipyridamole,
one of the earliest clinical uses of sildenafil was to facilitate weaning from iNO in
infants with congenital heart disease following corrective surgery. In an initial case
series, enteral sildenafil increased circulating cGMP and allowed two of three
infants to wean from iNO without rebound pulmonary hypertension (Atz and
Wessel
1999
). Two subsequent studies have expanded these initial observations.
Oral sildenafil facilitated iNO discontinuation in seven infants (ages 3 days to
21 months) who had previously failed to wean from iNO (Lee et al.
2008
).
Namachivayam et al. delivered enteral sildenafil (
n
¼
15) or placebo (
n
¼
14) to
a total of 29 infants with critical illness (most with congenital heart disease), who
were breathing 2 ppm iNO in preparation for a discontinuation trial. Ten out of 14
patients (71%) receiving placebo experienced rebound pulmonary hypertension
after iNO was stopped. In contrast, administration of a single dose of oral sildenafil
(0.4 mg/kg) prevented rebound pulmonary hypertension in all 15 treated patients.
The authors also noted a significant reduction in the duration of mechanical ventila-
tion and ICU length of stay in the group that received sildenafil (Namachivayam
et al.
2006
).
Some data raise specific concerns regarding the use of sildenafil in combination
with iNO. In piglets with meconium aspiration, intravenous sildenafil in combina-
tion with iNO enhanced the decrease in pulmonary artery pressure and pulmonary
