Antenatal sildenafil treatment improves neonatal pulmonary hemodynamics and gas exchange in lambs with diaphragmatic hernia.

OBJECTIVES: Infants with congenital diaphragmatic hernia (CDH) are predisposed to pulmonary hypertension after birth, owing to lung hypoplasia that impairs fetal pulmonary vascular development. Antenatal sildenafil treatment attenuates abnormal pulmonary vascular and alveolar development in rabbit and rodent CDH models, but whether this translates to functional improvements after birth remains unknown. We aimed to evaluate the effect of antenatal sildenafil on neonatal pulmonary hemodynamics and lung function in lambs with diaphragmatic hernia (DH). METHOD(S): DH was surgically induced at approximately 80days' gestation in 16 lamb fetuses (term in lambs is approximately 147days). From 105days' gestation, ewes received either sildenafil (0.21mg/kg/h intravenously) or saline infusion until delivery (n=8 fetuses in each group). At approximately 138days' gestation, all lambs were instrumented and then delivered via Cesarean section. The lambs were ventilated for 120min with continuous recording of physiological (pulmonary and carotid artery blood flow and pressure; cerebral oxygenation) and ventilatory parameters, and regular assessment of arterial blood gas tensions. Only lambs that survived until delivery and with a confirmed diaphragmatic defect at postmortem examination were included in the analysis; these comprised six DH-sildenafil lambs and six DH-saline control lambs. RESULT(S): Lung-to-body-weight ratio (0.016+/-0.001 vs 0.013+/-0.001; P=0.06) and dynamic lung compliance (0.8+/-0.2 vs 0.7+/-0.2mL/cmH2 O; P=0.72) were similar in DH-sildenafil lambs and controls. Pulmonary vascular resistance decreased following lung aeration to a greater degree in DH-sildenafil lambs, and was 4-fold lower by 120min after cord clamping than in controls (0.6+/-0.1 vs 2.2+/-0.6mmHg/(mL/min); P=0.002). Pulmonary arterial pressure was also lower (46+/-2 vs 59+/-2mmHg; P=0.048) and pulmonary blood flow higher (25+/-3 vs 8+/-2mL/min/kg; P=0.02) in DH-sildenafil than in DH-saline lambs