Conference: 2010 International PHA Conference and Scientific Sessions
Release Date: 06.24.2010
Presentation Type: Abstracts
Bagby M, Zussman M, Hirsch R.
The Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
BACKGROUND: Patients with congenital diaphragmatic hernia (CDH) have complex functional and structural alterations in their pulmonary vasculature that may lead to severe pulmonary hypertension (PH). Survival in large part depends on alleviation of the PH, and frequently involves composite therapeutic approaches. Bosentan is a non-selective endothelin receptor antagonist with, to date, limited use in this population. This report summarizes the experience at our center using this drug in infants with CDH and severe PH.
METHODS: Thirteen patients (8 male, mean age at commencement 64 days (range 25–188)) with CDH and PH who received bosentan were identified from an institutional database. Demographics, clinical status, concomitant therapies, adverse drug effects and outcomes were reviewed.
RESULTS: At commencement of bosentan therapy, 9 subjects had been surgically repaired. All were mechanically ventilated, 5 were receiving inhaled nitric oxide, and 2 inhaled epoprostenol. Eleven were receiving enteral sildenafil. Echocardiographic evaluation in all 13 subjects, and cardiac catheterization in 8 revealed right ventricular (RV) pressures that were supra-systemic in 4 patients, systemic in 6 patients, and greater than half systemic in the remainder. Drug related data were as follows: i) Dosing: The average bosentan commencement dose was 3.75mg/kg daily (range 2 – 5.4). Two patients had their dose increased to twice daily after 9 and 30 days respectively. The mean duration of therapy was 32 days (range 4 – 123), although two patients required recommencement of therapy for recurrent pulmonary hypertension. Only 1 subject was discharged home on bosentan. ii) Safety: Liver transaminase and hemoglobin were monitored at least weekly in all patients. Bosentan was discontinued in 3 patients before 1 month: 1 patient died (severe right heart failure); 1 had elevated transaminases; and in the third it was discontinued after end-organ damage (including hepatic) was evident after a prolonged episode of accelerated junctional tachycardia following repair of a congenital heart defect. Four subjects required single isolated blood transfusions, felt to be clinically independent of bosentan therapy. There were no other adverse effects in the remaining 10 patients. iii) Efficacy: The drug was stopped in one subject, 3 weeks after commencement when the RV pressure decreased to less than 40% systemic. RV pressure declined in the other 8 patients who were able to have the drug discontinued prior to discharge. In those subjects, the RV to systemic pressure ranged from 26 – 59%.
CONCLUSION: Despite the potential toxic adverse effects, bosentan was well tolerated in this neonatal population with severe PH. Given the complex pathogenesis of PH in CDH patients, with appropriate monitoring, bosentan offers a safe and important additional therapeutic option.