Pulmonary hypertension (PH) is rare but serious and potentially a life-threatening disease characterized by an elevation in mean pulmonary artery pressure and pulmonary vascular resistance . In severe cases, PH leads to right heart failure, clinical worsening, and death. Despite an estimated annual incidence rate of approximately 3 cases of PH per million children, PH remains an important cause of morbidity and mortality among children [1, 2]. Etiologies are numerous and include chronic infections, lung disease and chronic hypoxemia, thromboembolic disease, and genetic and metabolic abnormalities, but it is most commonly idiopathic or associated with congenital heart disease [3,4,5,6,7,8,9,10]. In children, untreated PH carries a grim prognosis, with subtypes such as idiopathic PH predicting a median survival of just 10 months . PH has been reported in 23 to 37% of premature infants with chronic lung disease in multiple retrospective studies, and carries a 2-year mortality rate as high as 48% [12,13,14,15]. In addition to substantial mortality risk, PH associated with chronic lung disease is associated with increased morbidity such as prolonged mechanical ventilation, need for supplemental oxygen, and increased hospital length of stay [12,13,14,15,16,17,18,19].
Despite recent developments in PH-specific therapies, survival of patients with idiopathic PH remains poor and appears to be worse in children compared to adults . PH has primarily been characterized and studied among adults and therefore the development of treatment therapies has also targeted this population . An array of pharmacologic treatments are available and approved for use in adults, but studies evaluating therapeutic dosing, side effects, and outcome for pediatric patients are lacking. PH clinicians are nonetheless prescribing these medications off-label in children as part of standard practice, often with guidance from only small cohort studies or past clinical experience . However, benefit is frequently seen . Combination drug therapy is increasing in frequency, again, backed by large adult studies [20, 23]. Many factors such as disease severity, side effect profile, drug interaction, cost, and impact on quality of life must be considered when prescribing for the pediatric population. Three classes of drugs have been extensively evaluated for the pharmacologic treatment of pediatric PH: prostanoids (epoprostenol, treprostinil, iloprost, beraprost), endothelin receptor antagonists (ERAs) (bosentan, ambrisentan), and type-5 phosphodiesterase (PDE5) inhibitors (sildenafil, tadalafil). Because vasoconstriction is an important component in the development of PH, vasodilator drugs are also frequently used to decrease pulmonary arterial pressure, to improve cardiac output, and to potentially reverse pulmonary vascular changes in the lungs [23,24,25,26,27,28]. However, the adverse effects of these drugs have often been studied in isolation and in clinical trial settings [23, 27, 28]. With increased usage of novel PH treatment therapies (such as Treprostinil and Selexipag), there is a urgent need to better understand the adverse effects experienced by pediatric patients in every day settings where complex combined therapy regimens are commonplace .
In addition to the physiological burdens and side effects of PH treatment therapies, there are social, economic, emotional and health access implications for children living with PH, their families, and their caregivers. Children who live in remote settings have limited access to emergency and specialty care . Accessing care is even more limited for children living with PH as specialty PH care centers and physicians with specialized PH training are much more sparse than general clinics and hospitals . This is of particular interest as PH treatment therapies side effects may greatly affect a family’s ability to thrive while caring for a child living with PH .
The purpose of our study was to estimate the side effect profiles of the most commonly prescribed PH therapies among children and to understand the burdens placed upon families to access care for children living with PH.