Discussion
Despite the critical nature of PPHN, a paucity of evidence‐based 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.