Endothelin receptor antagonists for persistent pulmonary hypertension in term and late preterm infants

Background Endothelin, a powerful vasoconstrictor, is one of the mediators in the causation of persistent pulmonary hypertension of the newborn (PPHN). Theoretically, endothelin receptor antagonists (ETRA) have the potential to improve the outcomes of infants with PPHN. Objectives To assess the efficacy and safety of ETRA in the treatment of PPHN in full‐term, post‐term and late preterm infants. To assess the efficacy and safety of selective ETRAs (which block only the ETA receptors) and non‐selective ETRAs (which block both ETA and ETB receptors) separately. Search methods CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, EMBASE and CINAHL databases were searched until December 2015. Selection criteria Randomised, cluster‐randomised or quasi‐randomised controlled trials were eligible. Data collection and analysis Two review authors independently searched the literature, selected the studies, assessed the risk of bias and extracted the data. A fixed‐effect model was used for meta‐analysis. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence. Main results Two randomised controlled trials of ETRA met the inclusion criteria. Both studies utilized oral Bosentan. The first study was done in a setting where inhaled nitric oxide (iNO) therapy was not available. Forty‐seven infants (≥ 34 weeks' gestation) were randomised to receive either Bosentan or placebo. The second study was a multicentre study where iNO therapy was the standard of care for PPHN. Twenty‐one infants were randomised to receive either 'iNO plus Bosentan' or 'iNO plus placebo'. In the first study, there was no significant difference in the incidence of death before hospital discharge between the Bosentan and placebo groups (1/23 vs 3/14; RR 0.20, 95% CI 0.02 to 1.77; RD −0.17, 95% CI −0.40 to 0.06). A higher proportion of infants in the Bosentan group showed improvement in oxygenation index (OI) at the end of therapy (21/24 vs 3/15; RR 4.38, 95% CI 1.57 to 12.17; RD 0.68, 95% CI 0.43 to 0.92; number needed to treat for a beneficial outcome (NNTB) 1.5). The duration of mechanical ventilation was lower in the Bosentan group (4.3 ± 0.9 vs 11.5 ± 0.6 days; MD −7.20, 95% CI −7.64 to −6.76). There was no significant difference in adverse neurological outcomes at six months (0/23 vs 4/14; RR 0.07, 95% CI 0.00 to 1.20; RD −0.29, 95% CI −0.52 to ‐0.05). The study suffered from a high risk of attrition bias since