Biology Reference
In-Depth Information
When supportive treatment is insufficient, the only FDA-approved pulmonary
vasodilator in neonates is iNO. Multicenter randomized, placebo-controlled,
blinded trials of iNO in term and near-term infants with PPHN demonstrated that
iNO significantly decreased the need for ECMO in newborns with PPHN (Clark
et al.
2000
; Group
1997
). However, up to 40% of infants do not respond or sustain
their response to iNO, and it does not reduce mortality, duration of mechanical
ventilation, or length of hospitalization. Follow-up studies to 12-24 months also
show that iNO does not significantly decrease the incidence of chronic lung disease
or adverse neurodevelopmental sequelae (Clark et al.
2003
; Group
2000
).
In addition to the problem of inadequate response to iNO, many infants will
acutely develop “rebound” pulmonary hypertension upon its discontinuation
(Atz et al.
1996
; Farrow et al.
2005
). As noted above, this finding was first described
in young infants receiving inhaled NO after surgery for congenital heart disease,
although the phenomenon frequently occurs in infants with PPHN as well. Rebound
pulmonary hypertension tends to be most severe if discontinuation occurs when
infants are breathing higher concentrations of iNO, but may also occur even after
more gradual iNO weaning. It is important for clinicians to understand that rebound
pulmonary hypertension can occur even in infants who were apparent nonresponders
to iNO therapy, particularly after treatment has been delivered for more than an hour.
While rebound pulmonary hypertension typically responds to reinstitution of iNO, it
represents a significant limitation of this therapy (Atz et al.
1996
; Farrow et al.
2005
).
Additional pulmonary vasodilators are urgently needed for infants with pulmo-
nary hypertension. Inhibition of PDEs represents a potentially powerful and novel
way to achieve safe, sustained, and even selective pulmonary vasodilation in these
infants.
2.1 PDE5 Inhibitors
PDE5 is by far the best studied of the PDEs for involvement in the pathophysiology
of neonatal pulmonary hypertension. Its dysregulation has been implicated in most
of the major causes of neonatal pulmonary hypertension including PPHN, CDH,
BPD, and congenital heart disease. The PDE5 inhibitor sildenafil has been shown
to be an effective treatment in adult pulmonary arterial hypertension (Galie et al.
2005
) and is now marketed as Revatio for this purpose. Not surprisingly, PDE5
inhibitors have been among the first PDE inhibitors used in neonates. While many
have proposed their use to augment iNO therapy, there is some evidence to suggest
that PDE5 inhibitors may serve as effective vasodilators in their own right.
2.1.1 Dipyridamole
One of the earliest drugs used to manipulate the pulmonary circulation was
the nonspecific PDE5 inhibitor dipyridamole (Persantin) (al-Alaiyan et al.
1996
;
