Safety and Feasibility of Intravenous Paracetamol for Patent Ductus Arteriosus in Indomethacin-/Ibuprofen-Resistant or -Contraindicated Preterm Infants: A Case Series

Abstract

Background Although indomethacin and ibuprofen are the standard treatments for hemodynamically significant patent ductus arteriosus (hsPDA), they are associated with renal impairment and gastrointestinal complications. Paracetamol for hsPDA closure does not provoke a peripheral vasoconstrictive effect and seems to have effects similar to those of indomethacin and ibuprofen. We have previously reported the safety of low-dose (7.5 mg/kg) intravenous paracetamol for preterm infants with hsPDA, who were indomethacin-resistant or -contraindicated but did not affect the need for surgical PDA ligation. However, reports considering the use of higher-dose (15 mg/kg) paracetamol for hsPDA have not been published in Japan.

Cases In 16 premature infants in whom indomethacin or ibuprofen was contraindicated or ineffective, 15 mg/kg of paracetamol was intravenously administered every 6 hours for 3 days after obtaining parental consent. hsPDA closure or narrowing was observed in 14 infants (88%), with the need for surgical closure totally avoided in nine cases (56%). High plasma paracetamol levels were observed in three cases. No paracetamol-related side effects or adverse events were reported.

Conclusion The intravenous administration of higher dose paracetamol was safe and feasible in premature infants with hsPDA. Future clinical trials to explore the optimized dose and timing of administration are needed.

Keywords

ibuprofen - indomethacin - paracetamol - patent ductus arteriosus - premature infant - surgical closure

• References

• 1 Gentile R, Stevenson G, Dooley T, Franklin D, Kawabori I, Pearlman A. Pulsed Doppler echocardiographic determination of time of ductal closure in normal newborn infants. J Pediatr 1981; 98 (03) 443-448
• 2 Clyman RI, Couto J, Murphy GM. Patent ductus arteriosus: are current neonatal treatment options better or worse than no treatment at all?. Semin Perinatol 2012; 36 (02) 123-129
• 3 Liu H, Manganiello V, Waleh N, Clyman RI. Expression, activity, and function of phosphodiesterases in the mature and immature ductus arteriosus. Pediatr Res 2008; 64 (05) 477-481
• 4 Itabashi K, Ohno T, Nishida H. Indomethacin responsiveness of patent ductus arteriosus and renal abnormalities in preterm infants treated with indomethacin. J Pediatr 2003; 143 (02) 203-207
• 5 Hamrick SE, Hansmann G. Patent ductus arteriosus of the preterm infant. Pediatrics 2010; 125 (05) 1020-1030
• 6 Johnston PG, Gillam-Krakauer M, Fuller MP, Reese J. Evidence-based use of indomethacin and ibuprofen in the neonatal intensive care unit. Clin Perinatol 2012; 39 (01) 111-136
• 7 Oncel MY, Yurttutan S, Degirmencioglu H. , et al. Intravenous paracetamol treatment in the management of patent ductus arteriosus in extremely low birth weight infants. Neonatology 2013; 103 (03) 166-169
• 8 Oncel MY, Yurttutan S, Erdeve O. , et al. Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a randomized controlled trial. J Pediatr 2014; 164 (03) 510-4.e1
• 9 Ohlsson A, Shah PS. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants. Cochrane Database Syst Rev 2015; DOI: 10.1002/14651858.CD010061.pub3.
• 10 Terrin G, Conte F, Oncel MY. , et al. Paracetamol for the treatment of patent ductus arteriosus in preterm neonates: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 2016; 101 (02) F127-F136
• 11 El-Mashad AE, El-Mahdy H, El Amrousy D, Elgendy M. Comparative study of the efficacy and safety of paracetamol, ibuprofen, and indomethacin in closure of patent ductus arteriosus in preterm neonates. Eur J Pediatr 2017; 176 (02) 233-240
• 12 Härkin P, Härmä A, Aikio O. , et al. Paracetamol accelerates closure of the ductus arteriosus after premature birth: a randomized trial. J Pediatr 2016; 177: 72-77.e2
• 13 Matsumura S, Oshima A, Fujinuma S. , et al. Low-dose intravenous paracetamol for patent ductus arteriosus in indomethacin-resistant or contraindicated preterm infants: three cases reports. AJP Rep 2017; 7 (04) e230-e233
• 14 Prescott LF, Illingworth RN, Critchley JA, Stewart MJ, Adam RD, Proudfoot AT. Intravenous N-acetylcystine: the treatment of choice for paracetamol poisoning. BMJ 1979; 2 (6198): 1097-1100
• 15 Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med 1988; 319 (24) 1557-1562
• 16 Bauer AZ, Kriebel D, Herbert MR, Bornehag CG, Swan SH. Prenatal paracetamol exposure and child neurodevelopment: a review. Horm Behav 2018; 101: 125-147
• 17 Oncel MY, Eras Z, Uras N, Canpolat FE, Erdeve O, Oguz SS. Neurodevelopmental outcomes of preterm infants treated with oral paracetamol versus ibuprofen for patent ductus arteriosus. Am J Perinatol 2017; 34 (12) 1185-1189