Ultrasound Obstet Gynecol. 2019 Jul 31. doi: 10.1002/uog.20415. [Epub ahead of print]
Antenatal sildenafil treatment improves neonatal pulmonary hemodynamics and gas exchange in lambs with diaphragmatic hernia.
Kashyap AJ1,2, DeKoninck PLJ1,2,3, Rodgers KA1,2, Thio M4,5, McGillick EV1,2, Amberg BJ1,2, Skinner SM1,2, Moxham AM1,2, Russo FM6, Deprest JA6,7, Hooper SB1,2, Crossley KJ1,2, Hodges RJ1,2,8.
Author information
The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia.
Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia.
Department of Obstetrics and Gynaecology, Erasmus MC, Rotterdam, The Netherlands.
Newborn Research Centre, The Royal Women's Hospital, Melbourne, Australia.
Department of Obstetrics and Gynaecology, The University of Melbourne, Australia.
Department of Obstetrics and Gynaecology, Division Woman and Child, University Hospitals Leuven, Leuven, Belgium.
Institute for Women's Health, University College London Hospital, London, United Kingdom.
Monash Women's Service, Monash Health, Melbourne, Australia.
Infants with congenital diaphragmatic hernia (CDH) are predisposed to pulmonary hypertension after birth, due 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 haemodynamics and lung function in lambs with a diaphragmatic hernia (DH).

A DH was surgically created at ≈80 days gestational age (GA; term≈147d) in 16 fetal lambs. From 105d GA, ewes received either sildenafil (0.21 mg/kg/hr intravenously) or saline infusion. At ≈138d GA, all lambs were instrumented and then delivered via caesarean section. Lambs were ventilated for 120 min with continuous recording of physiological (pulmonary and carotid artery blood flows and pressures; cerebral oxygenation) and ventilatory parameters, and regular assessment of arterial blood gas tensions.

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  0.2 mL/cmH2O, p=0.72) were similar in DH-sildenafil lambs (n=6) and DH-saline controls (n=6). Pulmonary vascular resistance decreased following lung aeration to a greater degree in DH-sildenafil lambs and was 4-fold lower by 120 min after cord clamping (0.6  0.1 vs. 2.2  0.6 mmHg/(L/min); p=0.002). Pulmonary arterial pressure was also lower (46  2 vs. 59  2 mmHg; p=0.04 and pulmonary blood flow higher (25  3 vs. 8  2 mL/min/kg; p=0.02) in DH-sildenafil compared to DH-saline lambs. Throughout the 120 min ventilation period, PaCO2 tended to be lower in DH-sildenafil lambs (63  8 vs. 87  8 mmHg, p=0.057), and there was no significant difference in PaO2 .

Sustained maternal antenatal sildenafil infusion reduced pulmonary arterial pressure and increased pulmonary blood flow in DH lambs for the first 120 min after birth. These findings of improved pulmonary vascular function are consistent with improved pulmonary vascular structure seen in two previous animal models. The data support the rationale for a clinical trial with antenatal sildenafil to reduce the risk of neonatal pulmonary hypertension in infants with CDH. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Congenital abnormalities; fetal therapy; neonatal transition; pulmonary hypertension; pulmonary vascular development

PMID: 31364206 DOI: 10.1002/uog.20415