Discussion
Despite the critical nature of PPHN, a paucity of evidenceābased
therapeutic interventions for this disorder remains (8, 9). Although
there are no randomized control trials for the use of prostanoids or
their analogues as pulmonary vasodilators and sole therapeutic agents
for the treatment of PPHN in neonates (8), this report, along with
others suggest that inhaled iloprost, single or combined, is useful and
effective in neonates with PPHN. It is readily available and has
comparable clinical effects to iNO (17-32). As the iNO is only approved
therapy for PPHN, it would be unethical not to use it for PPHN where
available (8). In Turkey, iNO is delivered by a private company, and
sometimes the device is simply occupied. That is why we had to use
inhaled iloprost for PPHN. Feasibility of randomized trials of inhaled
iloprost seems problematic for now, so clinical experience rise to
prominence.
There are no spesific guidelines for inhaled iloprost treatment in terms
of dosage and the timing. Iloprost has a biological half-life of 20-30
minutes in humans (33). Using a dose of 2.5-7.5 mcg, 6-9 times a day,
with a maximal dose of 45 mcg per day, was approved in 2004, for the
treatment of adult PAH (34). Same doses were used in children with
success (35). For neonates, different doses are used in the literature;
0.2-2.5 mcg/kg/dose, every 1-6 hours in general (17-32). Continuous
inhalation is also reported (30). Delivering one dose of inhalation
lasts approximately 5 minutes in our setting, and the clinical effect at
the beginning of the therapy last 1-2 hours at most in our experience.
Unfortunately, this causes unstable oxygen saturations. To avoid this
instability, the care-giver has to react quickly to FiO2and oxygen saturation, and decide the dosing interval. Although
preferable, continuous inhalation was impossible in this setting.
Technics are needed to be developed to give continuous inhalation and
increasing the dosage just like iNO, which could provide a more stable
oxygen saturation and hemodynamics. Another issue to consider is, the
way inhaled iloprost is used; using an integrated nebulizer to
ventilator setting. How much of the drug is actually delivered to the
baby? Is some lost in the setting? There are no answers to these
questions for now. Also, all the patients mentioned here have somewhat
gone through acute or chronic hypoxia, and developed PPHN due to
mechanisms of acute pulmonary vasoconstruction or pulmonary vascular
remodeling, it is not clear if it works in PPHN caused by other reasons
and mechanisms (1, 4-6).
As for the side effects; headache, cough, and dizziness were reported in
adults and children receiving inhaled iloprost and also intravenous
iloprost was reported to cause hypotension (36, 37). No side effects
attributable to inhaled iloprost were observed in neonates (17-32, 37).
A maximal dose of 192 mcg/day and a cumulative dose of 510 mcg caused no
side effect in our patients, which means very high maximal doses
compared to adults are well tolerated in neonates. Two of our patients
received inotrop therapy for hypotension, but was already on inotrop
support before iloprost therapy. Another two had inotrops to raise the
mean arteriel pressure to pulmonary arteriel pressure, not because of
iloprost induced hypotension. Probably, adverse effects of inhaled
iloprost are negligible in neonatal population (17-32).
Inhaled iloprost seems to be a reliable alternative for infants with
persistent pulmonary hypertension, when iNO is not available and may be
used as an adjunctive therapy along with other pulmonary vasodilators.
(17-32). Compared to iNO, the pros of inhaled iloprost are being cheaper
and readily available and cons are swings in oxygenation (Figures 1-6)
as there is no setting of continuous inhalation, and also the lack of a
spesific guideline. In conclusion, our clinical experience supports that
inhaled iloprost might be an alternative drug treatment for PPHN and
provides safety and efficacy data which is insufficient for now in the
literature. Well-designed trials are warranted to remedy the paucity of
evidence.