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Prolonged Low-Dose Paracetamol Prophylaxis Accelerates Ductal Closure in Extremely Preterm Neonates: A Randomized
Tiina Ukkonen1,2, Eveliina Ronkainen1,2, Aliisa Laitala1,2
1Department of Pediatrics and Adolescent Medicine, Oulu University Hospital, Oulu, Finland.
Insights
Early administration of acetaminophen (paracetamol) significantly shortened the time to ductal closure in extremely preterm infants. This treatment demonstrated safety and efficacy, offering a new therapeutic option for patent ductus arteriosus (PDA).
Area of Science:
- Neonatalogy
- Pediatric Cardiology
- Pharmacology
Background:
- Patent ductus arteriosus (PDA) is a significant concern in extremely preterm infants, linked to increased morbidity and mortality.
- The optimal dosage and safety of early acetaminophen (paracetamol) for PDA treatment in this population remain unclear.
Purpose of the Study:
- To evaluate the efficacy and safety of early intravenous paracetamol administration for the treatment of PDA in extremely low gestational age (ELGA) infants.
- To determine the effective and safe dosage of paracetamol for early PDA intervention.
Main Methods:
- A single-centre, randomized, double-blind, placebo-controlled phase II pilot trial involving ELGA infants (<28 wk gestation or <1000g birth weight).
- Infants received either intravenous paracetamol (20mg/kg loading dose, 7.5mg/kg maintenance every 6 hours for 9 days) or placebo, starting before 96 hours of age.
- Ductal patency was monitored daily using cardiac ultrasound; primary outcome was duration of ductal closure.
Main Results:
- The median ductal closure time was significantly shorter in the paracetamol group (3 days) compared to the placebo group (14 days) (p=0.031).
- Ductal closure was achieved in 75% of infants receiving paracetamol versus 35% in the placebo group (NNT=3).
- Adverse events were similar between groups, and no increase in adverse events was observed with paracetamol treatment.
Conclusions:
- Early, nine-day administration of intravenous paracetamol is effective in shortening ductal closure time in ELGA infants.
- Paracetamol treatment for PDA in this vulnerable population appears safe, with no increase in adverse events compared to placebo.
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.
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