Bosentan as adjunctive therapy in neonates with congenital diaphragmatic hernia-associated pulmonary hypertension: a case series.

Abstract

Congenital diaphragmatic hernia (CDH)-associated pulmonary hypertension (PH) is associated with high morbidity and mortality. Pulmonary vasodilative management is challenging and some patients with CDH are unresponsive to inhaled nitric oxide or sildenafil. Bosentan, an enterally-administered endothelin-1 receptor antagonist, reducing pulmonary vascular resistance may play a role in the treatment of CDH-PH. The aim is to evaluate the efficacy and safety of bosentan as an adjunctive therapy for CDH-PH. We report a case series of all CDH neonates who received oral bosentan as an adjunctive therapy for treatment of PH between 2013 and 2021 at our institution. Bosentan was administered at a median enteral dose of 2 mg/kg/day. Main outcomes were improved PH severity on echocardiography, oxygenation, and respiratory support after starting bosentan. Patients were compared according to improvement in PH after 1 week of treatment (responder vs. non-responder). Fifty CDH neonates received oral adjunctive bosentan therapy. Survival to discharge was 58%. Improved PH was observed in 54 and 72% of patients after 1 and 2 weeks respectively (p < 0.001). Respiratory status ameliorated significantly after 2 weeks compared to baseline, with a reduction of ECMO treatment from 30 to 0% and an increase in patients receiving non-invasive or no respiratory support from 18 to 40%. Oxygenation did not improve over 2 weeks, possibly biased by the changes in the respiratory status and other contributing factors to the pathophysiology of CDH.

Conclusion: Bosentan is effective in the treatment of neonates with CDH-PH and was associated with improved PH severity and respiratory status. Adverse effects were minimal and consistent with previous studies.

What is known: • CDH neonates frequently suffer from pulmonary hypertension with inconclusive evidence regarding the benefit of pulmonary vasodilator treatment. • Increased endothelin-1 plasma levels have been associated with poor outcome in CDH neonates, however, there is minimal data on the use of endothelin receptor blockers, such as bosnetan, in this population.

What is new: • This case series of 50 CDH neonates receiving bosentan demonstrates an improvement in PH severity based on echocardiographic assessment in 54% within one week of treatment. • Respiratory support modus (i.e. ECMO, mechanical ventilation, CPAP) improved significantly within two weeks of bosentan treatment in responders and non-responders.