A Randomised Controlled Trial of Early Targeted Patent Ductus Arteriosus Treatment Using a Risk Based Severity Score

Introduction: The ductus arteriosus is an essential component of the fetal circulation. In over 60% of babies under 28 week’s gestation, the ductus maintains its patency. Epidemiological studies have found a patent ductus arteriosus (PDA) to be associated, among other outcomes, with chronic lung disease (CLD) and death.

Objectives: I aim to identify infants at high risk of developing CLD/Death by utilising the PDA risk-based severity score (PDAsc). Those infants are then randomised to early treatment with Ibuprofen versus placebo. I hypothesise that in preterm infants less than 29 weeks gestation who are at high risk of developing chronic lung disease or death based on a PDAsc ≥ 5.0, obtained using echocardiography carried out between 36 and 48 hours of life, early treatment with non-steroidal anti-inflammatory drugs (Ibuprofen) compared with placebo will result in a reduction of CLD/Death by 36 weeks post menstrual age (PMA). I also aim to describe the influence of left ventricular diastolic function on right ventricular and pulmonary vascular coupling and respiratory morbidity in the premature population, and I aim to assess left ventricular circumferential and radial deformation in premature infants.

Methods: This was a single centre double-blind, two arm randomised control trial with a balanced (1:1) allocation that was carried out in the neonatal intensive care unit in the Rotunda Hospital, Dublin between April 2017 and April 2020. An echocardiogram was carried out in the first 36-48 hours of life to identify preterm infants with a PDAsc ≥ 5.0 and these infants were randomised to intravenous Ibuprofen or placebo. Assessment at 36 weeks post menstrual age occurred for the composite primary outcome of CLD/Death. A post-hoc efficacy analysis was also performed comparing infants in the Ibuprofen group with successful closure of the ductus to infants in the Placebo group who maintained ductal patency.

Results: 60 infants were recruited into the PDA RCT; 30 received Ibuprofen and 30 received placebo. There was no difference in the composite primary outcome between the groups (odds ratio 0.8, 95% confidence interval 0.3 – 2.1) or its individual components (death; OR 2.4, 95% CI 0.6 – 8.9, CLD; OR 0.5, 95% CI 0.2 – 1.6). The secondary analysis revealed a lower rate of CLD/Death and CLD alone in the infants whose ductus successfully closed in the Ibuprofen group compared to those whose ductus remained patent in the Placebo group.

Conclusion: The PDA RCT did not show any significant reduction in the composite primary outcome following early targeted treatment of a HsPDA as identified by a PDAsc in premature infants. The secondary analysis reveals an interesting link between duration of ductal exposure and respiratory morbidity. Evaluation of RV PV coupling, LV diastolic function and respiratory morbidity gives further clarity to cardiorespiratory disease in premature neonates.