The primary or idiopathic type of PPHN accounts for only 10 to 20% of all PPHN cases, while 80 to 90% of PPHN cases are secondary to an underlying disorder(1). Many studies include both primary and secondary PPHN in their reports; while in our study, we included primary PPHN cases; Therefore, it can be stated that the present study had a more homogeneous statistical population eliminating the cofounding factor of etiology in the results. Also, secondary PPHN has a worse prognosis than primary PPHN. Also, there was no significant difference among our groups regarding sex, gestational age, and mothers' history of diabetes, which are all risk factors for PPHN(18). Also, we performed serial echocardiography among our patients since studies have linked repeated echocardiographic findings to the prognosis of PPHN (19). According to the results, inhaled milrinone can have similar effects with injected milrinone as an adjunct in the management of PPHN. Also, the results indicate similar safety for both intravenous and inhaled prescriptions.
Therapeutic effects of injectable milrinone as an adjuvant to other therapies (including iNO) have been reviewed and validated in previous studies. In a review article, Qasim et al(4) .reviewed six studies on the effect of injectable milrinone in the management of PPHN, in which all reported a positive effect of injectable milrinone in the treatment of PPHN. The dose of milrinone in three of the studies was 50 µg / kg bolus and then 0.33 µg / kg/min infusion, while in three studies without bolus and with an infusion rate of 0.99 − 0.33 µg / kg. Injectable milrinone in our study was administered as an intravenous infusion at a dose of 0.5 − 0.3 µg / kg/min. Furthermore, all of these studies examined term neonates, with a limited sample size of 4 to 17 neonates (20–23).
Although the standard treatment for PPHN in reference books includes iNO (5, 6), PPHN is resistant to iNO in some cases. Mat Bah et al. reported that iNO resistance worsens the prognosis of PPHN, especially if the PPHN is idiopathic (primary) (24). Also, the management of primary PPHN is still a controversial issue that in many cases requires combination therapy with multiple drugs. Therefore, many studies are still evaluating the suitable drug combination to improve the management of primary PPHN, such as sildenafil (25), surfactant (26), and adenosine (27). However, some studies have also reported a poorer prognosis by adding supplemental treatment, such as hydrocortisone (28).
Many previous studies have evaluated the efficacy of milrinone as an adjuvant treatment. El-Ghandour et al. (29) showed that the combination of oral sildenafil and intravenous milrinone did not increase the side effects and was more effective than monotherapy with any of the drugs. Also, previous studies have shown that injectable milrinone may improve prognosis in infants with iNO-resistant PPHN (24, 30). Mat Bah et al reported a worse prognosis among iNO-resistant PPHN neonates, especially in the idiopathic type(24). Also, Dillard et al. reported that infants who were non-respondent to iNO and received adjuvant milrinone had a better prognosis, better oxygenation, and less hemodynamic change (30). However, in some cases, the addition of milrinone to iNO has shown no significant effect in improving treatment (31). Finally, injectable milrinone, which demonstrated a satisfactory outcome in our study, can also be utilized as an adjuvant or alternative in PPHN management, especially in centers with limited access to iNO.
Studies have shown that milrinone can also be given by inhalation and has similar effects to injectable milrinone(17, 32, 33). However, none of these studies have been performed in infants with primary PPHN, which points to the novelty of our study compared to previous studies. In the present study, although the frequency of clinical improvement in the inhaled milrinone group was slightly higher than the injected milrinone group, this difference was not statistically significant. A study by Abd Elbaser et al. compared the effect of intravenous and inhaled milrinone in the management of pulmonary artery hypertension after heart surgery in children with congenital heart disease, which showed superior efficacy of inhaled milrinone in reducing pulmonary artery pressure and heart rate and increasing arterial blood pressure than injectable milrinone (17). Patel et al. investigated the effect of inhaled milrinone in patients with mitral valve stenosis with pulmonary hypertension, which showed that administration of inhaled milrinone before and after heart surgery in these patients, although it is easier to administer than an injection, can improve right ventricular hemodynamics, right ventricular function and systemic hemodynamics (33). Our study, like the previously mentioned reports, showed that inhaled milrinone could have a similar effect to injectable milrinone, however, inhaled milrinone was used as an adjuvant treatment in the management of early PPHN in our study. Neonatal hemodynamic parameters were not significantly different between the injected and inhaled milrinone groups, and even in cases such as clinical improvement, neonatal oxygen demand, and mortality, inhaled milrinone had a slightly better outcome (18%) than injectable milrinone. Although the two groups were not statistically significant, these findings are clinically noticeable.
The method of inhaled drug administration has become more and more considered today due to its ease of administration and direct effectiveness on pulmonary arteries. Several previous studies have examined the effect of inhaled administration of other drugs on the management of PPHN, such as magnesium sulfate (34) and iloprost (35), and reported this method as a safe treatment with low systemic side effects.
Among our study limitations is that we evaluated this clinical trial without using the gold standard therapy for severe PPHN (iNO and ECMO) as a comparator, and was designed to compare the effects of the milrinone. These findings, however, are critical for developing countries that do not have access to the gold standard therapy.