Short- and Long-Term Effects of Inhaled Iloprost Therapy in Children With Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is characterized by elevation of pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR), which can lead to progressive right heart failure and death (1–4). Pulmonary arterial hypertension occurs in diverse clinical settings, such as in association with congenital heart disease, chronic lung disease, connective tissue disease, liver disease, and anorexigen use, or could be idiopathic or familial (5,6). Before the development of intravenous (IV) prostacyclin as a chronic therapy for PAH, the National Health Registry estimated that the median survival after diagnosis was 2.8 years for adults and 0.8 years for children with idiopathic PAH (7). Over the past decade, significant advances in the pharmacologic treatment of PAH have improved survival; however, there remains no cure (8–12). On the basis of advances in vascular biology and known pathogenic mechanisms underlying PAH, 3 general classes of therapeutic agents have been developed and are currently available for the treatment of PAH. These include: prostacyclin analogues (epoprostenol, treprostinil, and iloprost), endothelin receptor antagonists (bosentan and ambrisentan), and phosphodiesterase inhibitors (sildenafil) (3,13–24). Until recently, chronic treatment with prostacyclin analogues has required IV or subcutaneous administration, with each approach limited by such problems as line infections, thrombosis, or site pain. Previous studies of inhaled iloprost have been performed in adult patients. In 1 large multicenter, randomized, placebo-controlled trial of iloprost therapy for 3 months, a larger percentage of patients on iloprost demonstrated the combined end point of at least a 10% improvement in the 6-min walk (6MW) distance and improvement in World Health Organization (WHO) functional class, with no deterioration or death versus patients on placebo (16). Most recently, inhaled iloprost has been studied in patients who remain symptomatic (WHO functional class III or IV) on bosentan therapy (25). In this multicenter, randomized, controlled trial, 67 patients with PAH were randomized to receive inhaled iloprost or placebo. There were significant improvements in 6MW distance, WHO functional class, time to clinical worsening, and postinhalation mean PAP and PVR. Combination therapy appeared safe and well tolerated. Although extensively studied in adults with PAH, little is known about efficacy of iloprost in children, especially with regard to long-term therapy (16,17,25–30). Therefore, to determine the potential role for inhaled iloprost therapy in children with PAH, we retrospectively evaluated the acute and chronic effects of inhaled iloprost in children with PAH.