Prolonged Low-Dose Paracetamol Prophylaxis Accelerates Ductal Closure in Extremely Preterm Neonates: A Randomized Trial

INTRODUCTION: Patent ductus arteriosus (PDA) is associated with increased morbidities and mortality in extremely preterm infants. The biological effect of acetaminophen on the closure of ductus has been shown; however, the effective and safe dosage for early treatment of the most preterm infants remains unknown. METHODS: In a single-centre, randomised, controlled, double-blind, phase II pilot trial, extremely low gestational age (ELGA, <28 wk) and/or birth weight (<1,000 g) infants were randomized to intravenous paracetamol or 0.45% saline-placebo. The treatment started before 96 h age, with loading dose of 20 mg/kg and maintenance of 7.5 mg/kg every 6 h for 9 days. Ductal patency was assessed prior to trial initiation and monitored daily, using cardiac ultrasound. Primary outcome was the duration of ductal closure. Secondary outcomes included ductal closure rates, treatment of symptomatic PDA, serum paracetamol levels, long-term morbidities, and mortality. RESULTS: After consent, 40 infants were randomly allocated soon after birth. The intention-to-treat analysis included 39 infants; 19 had paracetamol and 20 placebos. The median (IQR) ductal closure time was 3 (10) days in the paracetamol group, versus 14 (20) days in the placebo group (p = 0.031). Ductus was closed in 15 (75%) vs. 7 (35%) infants, respectively, p = 0.016 (number needed to treat = 3). Three infants in the placebo group received post-study treatment for PDA. The numbers of adverse events were similar in both study groups. CONCLUSION: Early, 9-day paracetamol administration, compared to placebo, significantly shortened the ductal closure time without increase in adverse events in ELGA infants.