Discussion
PPHN is a common endpoint of several very different pathophysiological 		 mechanisms. It is extremely important to understand the underlying etiology of 		 PPHN, as therapeutic interventions must be tailored to specific circumstances; 		 for example, PPHN associated with hyaline membrane disease should first be 		 treated with surfactant therapy.
Maintenance of adequate circulating blood volume, systemic vascular 		 resistance, and optimal lung inflation are essential for the management of 		 PPHN. High-frequency ventilation has been introduced as a mode of therapy in 		 PPHN. There were no randomized studies of HFOV in the management of infants 		 with PPHN, but attention has been focused on the potential of HFOV to reduce 		 the need for extracorporeal membrane oxygenation (ECMO). A number of reports 		 identify a number of infants who, although referred for ECMO, survived without 		 using this type of intervention [6,7].
A comparison between HFOV and INO in reducing the need for ECMO has 		 been studied. Kinsella et al [8] combined HFOV 		 and INO in the treatment of infants with hypoxic respiratory failure and PPHN 		 who were ECMO candidates. These authors found no difference in the need for 		 ECMO or death in the INO group compared with the HFOV group, and they suggest 		 that combined treatment with INO and HFOV may improve outcome.
In this study, we found that 75% of infants with PPHN who failed HFOV 		 responded to INO therapy and 62.5% survived to discharge. Recently, the NINOS 		 Study Group has conducted a study to evaluate whether INO would reduce the 		 incidence of death or the need for ECMO in infants with hypoxic respiratory 		 failure [9]. HFOV was used in 55% of the infants. The 		 authors found that treatment with INO resulted in a significant reduction in 		 the combined incidence of death in less than 120 days or the need for ECMO. 		 Moreover, Roberts et al [10] studied 58 		 full-term infants with severe hypoxemia and PPHN who were randomized to receive 		 either INO or nitrogen. They found that INO improved systemic oxygenation in 		 these infants and they suggest that INO may reduce the need for more invasive 		 treatment.
In this study, we found that 61.1% of the responders responded within 		 the first 2h after the initiation of INO and their response sustained to the 		 end of the treatment and the remaining neonates showed a gradual response 		 throughout the course of INO. Similarly Goldman et al [11] evaluated INO in a group of 25 severely hypoxic term 		 neonates and identified four patterns of response. Two neonates did not 		 respond, nine neonates who responded well initially then failed within 24 h, 11 		 neonates responded and sustained that response, and three neonates responded to 		 INO but required high doses for prolonged periods of time. We also found that 		 25% failed INO therapy, most likely as a result of severe pulmonary hypoplasia 		 seen in CDH, and severe lung damage due to severe hypoxia as in asphyxia and 		 RDS. A number of studies have noted a general lack of a sustained improvement 		 in oxygenation in response to INO in the management of CDH [12,13,14]. In 		 this study ECMO was not used as an alternative therapy for the INO 		 non-responders because it was not available in our hospital for neonates.
It has been observed that some infants who showed a dramatic response 		 to INO developed a decrease in oxygenation when INO was discontinued. This 		 response may reflect downregulation of endogenous nitric oxide synthase 		 activity secondary to the administration of exogenous nitric oxide [15]. In addition INO may increase the concentration of 		 phosphodiesterase, which then degrades cyclic GMP when INO is discontinued, 		 resulting in vaso-constriction. In this study, four infants became 		 INO-dependent and successfully weaned from INO following the use of 		 phosphodiesterase inhibitor (dipyridamole) [16]. Study 		 of the mechanism of INO dependency may give insight into new therapies that 		 augment the pulmonary vasodilatory effect of INO and the activity of the 		 endogenous NO system.
In conclusion, the administration of INO at 20ppm, following adequate 		 ventilation for a maximum of 2h without significant response could be used to 		 identify the majority of the non-responders. In these situations, other means 		 of therapy, such as ECMO, could be considered.