Oral Presentation 46th Annual Meeting of the Fetal and Neonatal Physiological Society 2019

Antenatal sildenafil improves neonatal pulmonary haemodynamics in an ovine model of diaphragmatic hernia (#5)

Aidan J Kashyap 1 , Philip LJ DeKoninck 1 , Karyn A Rodgers 1 , Marta Thio 1 , Erin V McGillick 1 , Alison M Moxham 1 , Benjamin J Amberg 1 , Sasha M Skinner 1 , Stuart B Hooper 1 , Kelly J Crossley 1 , Ryan J Hodges 1
  1. The Ritchie Centre, Hudson Institute of Medical Research, Monash University, Melbourne, Victoria, Australia

Introduction: Congenital diaphragmatic hernia (CDH) is associated with lung hypoplasia that impairs pulmonary vascular development, predisposing these infants to pulmonary hypertension after birth. Antenatal sildenafil treatment attenuates abnormal pulmonary vascular and alveolar development in rodent CDH models. We aimed to evaluate the effect of antenatal sildenafil on pulmonary haemodynamics during the neonatal transition in lambs with a diaphragmatic hernia (DH).

Methods: DH was surgically created at ≈80 days gestational age (GA; term≈147d) in 12 ovine fetuses. From 105d GA, ewes received either sildenafil (5 mg/kg/day intravenously; n=6) or saline infusion (n=6). At ≈138d GA, all lambs were instrumented and then delivered via caesarean section, with physiological (pulmonary and carotid artery blood flows and pressures; cerebral oxygenation) and ventilatory parameters (tidal volume, airway pressure) recorded for 2 hours during the neonatal transition.

Results: Lung-to-body-weight ratio was not significantly greater in DH-sildenafil lambs compared to DH-saline controls (0.016±0.001 vs. 0.013±0.001; p=0.06) and there was no significant difference in dynamic lung compliance (0.8±0.2 vs. 0.7±0.2 mL/cmH2O; p=0.72). Pulmonary vascular resistance (PVR) dramatically decreased in both groups following lung aeration, however subsequently increased in DH-saline lambs after one hour of ventilation. By the end of the 2-hour ventilation period, PVR was 4-fold lower (0.6±0.1 vs. 2.2±0.6 mmHg/(L/min); p=0.002), pulmonary arterial pressure ~10mmHg lower (46±2 vs. 59±2 mmHg; p=0.048) and pulmonary blood flow (PBF) 3-fold greater (25±3 vs. 8±2 mL/min/kg; p=0.02) in DH-sildenafil compared to DH-saline lambs. End-diastolic PBF, which correlates with low PVR and reflects left-to-right shunting across the ductus arteriosus, was greater in DH-sildenafil lambs from 20 minutes into the ventilation period.

Conclusion: In these DH lambs with lung hypoplasia, antenatal sildenafil treatment reduced PVR and increased PBF during the neonatal transition period. These findings suggest that antenatal sildenafil treatment may reduce the likelihood of neonatal pulmonary hypertension in infants with CDH.