Neonatal pulmonary hypertension or persistent pulmonary hypertension of the newborn (PPHN) are terms used interchangeably to describe a neonate who has cyanosis due to a respiratory cause in the first few days of life in the absence of a structural congenital cardiac lesion (Gersony 1984). Pulmonary hypertension is defined clinically when there is hypoxemia refractory to oxygen therapy or lung recruitment strategies (PaO₂ < 55 despite FiO₂ of 1.0) (Roberts 1997; Shah 2004) associated with preductal to postductal oxygen gradient > 20 mm Hg (Walsh‐Sukys 2000). Echocardiographic diagnosis is by demonstration of the presence of extrapulmonary right to left shunting at the ductal or atrial level in the absence of severe pulmonary parenchymal disease with Doppler evidence of tricuspid regurgitation (Shah 2004; Wessel 1997). During cardiac catheterization pulmonary hypertension is defined as pulmonary arterial pressure > 25 ‐ 30 mm Hg (Adatia 2002). The incidence of pulmonary hypertension in newborns has been reported as approximately 2/1000 live births, with reported mortality rates of 4 ‐ 33% among various centres in the US (Walsh‐Sukys 2000). Pulmonary hypertension in the neonate could be primary (idiopathic) or secondary to pulmonary parenchymal disease (such as meconium aspiration syndrome, surfactant deficiency or alveolocapillary dysplasia), severe pulmonary hypoplasia, polycythemia, hypoglycemia, sepsis and maternal ingestion of prostaglandin inhibitors (Adatia 2002; Gersony 1984). Inhaled nitric oxide, by virtue of its selective pulmonary vasodilator effects, is considered the mainstay in the treatment of pulmonary hypertension in term or near term neonates (Barrington 2001). A certain proportion of neonates fail to respond to nitric oxide (Goldman 1996). Nitric oxide therapy is also associated with rebound pulmonary hypertension when therapy is discontinued in some patients due to suppression of endogenous nitric oxide production (Kinsella 2000). Development of methemoglobinemia and cost (Subhedar 2002) are other important considerations for the use of nitric oxide. The role of inhaled nitric oxide in preterm neonates is not clear (Finer 2001).

Advances in the understanding of the physiology of vasoactive mediators have revealed that there is a high concentration of phosphodiesterases in the pulmonary vasculature (Rabe 1994). Inhibition of phosphodiesterase 5 leads to increased concentration of cyclic‐AMP and GMP locally which in turn leads to relaxation of pulmonary vascular smooth muscles (Humbert 2004). Phosphodiesterase 5 inhibitors include dipyridamole, zaprinast, pentoxiphylline and sildenafil (Travadi 2003). Dipyridamole has significant systemic vasodilatory effect (Dukarm 1998). Zaprinast and pentoxiphylline have not been adequately studied. Sildenafil has been studied in neonatal animal models. In a neonatal pig model of pulmonary hypertension induced secondary to meconium aspiration (Shekerdemian 2002), there was marked improvement in pulmonary vascular resistance and cardiac output without deterioration in systemic oxygenation one hour after intravenous infusion of sildenafil compared to control animals. In a separate experiment, Shekerdemian 2004 observed improvement in pulmonary vascular resistance, however, it was associated with systemic vasodilation and deterioration of oxygenation when sildenafil (0.5 mg/kg) was administered along with 20 ppm of inhaled nitric oxide. The interaction of sildenafil with other selective pulmonary vasodilators warrants further studies.

Sildenafil has been used for the treatment of pulmonary hypertension in adults in controlled and uncontrolled settings (Kanthapillai 2004; Sastry 2004). It has been used in intravenous, oral (Ikeda 2005) or inhalational (Ichinose 2001) form. In uncontrolled experiments in children, sildenafil was shown to reduce pulmonary vascular resistance (Abrams 2000; Carroll 2003; Erickson 2002) and improved exercise capacity. Non‐approved and uncontrolled use of sildenafil in neonates has been reported to improve pulmonary vascular resistance and survival of neonates (Erickson 2002; Kumar 2002). However, this has evoked mixed reaction from the scientific community (Kumar 2002; Lewin 2002; Oliver 2002; Patole 2002). Marsh (Marsh 2004) reported severe retinopathy of prematurity following the use of sildenafil in a neonate with severe pulmonary hypertension; however, this was questioned by Pierce (Pierce 2005). Sildenafil use in adults is suspected to worsen the proliferative diabetic retinopathy (Burton 2000; Behn 2001) and thus retinal vascular growth needs to be carefully observed, especially for preterm neonates. Sastry 2004 reported slightly higher incidence of backache, headache, numbness of feet and hands and constipation among patients who received sildenafil for primary pulmonary hypertension compared to placebo in adults.

Systematic review of sildenafil for pulmonary hypertension in adults and children identified four eligible studies of 77 patients and concluded that more studies of adequate size were necessary (Kanthapillai 2004). The neonatal population was not included in this review. In neonates the disease is more prevalent and, in the majority of cases, has a different pathophysiology (failure of natural drop in pulmonary vascular resistance as opposed to children and adults where pulmonary hypertension is either primary or secondary to various chronic illnesses such as collagen vascular disease, left heart disease, chronic obstructive pulmonary disease, interstitial diseases or chronic thromboembolic disorders). The use of sildenafil for the treatment of pulmonary hypertension in neonates has not been evaluated systematically.