Paracetamol Treatment of the Borderline Significant PDA

TIME TO RE-EVALUATE THE KINDER GENTLER APPROACH TO PATENT DUCTUS ARTERIOSUS (PDA) IN THE PRETERM NEONATE

The therapeutic approach to the patent ductus arteriosus (PDA) in the premature neonate remains controversial. Currently it is generally accepted to treat only hemodynamically significant PDAs. The current investigation aims to study the effect of treatment on PDAs of borderline significance via a prospective, randomized controlled trial of paracetamol in this group.

In the neonatal intensive care unit of the Shaare Zedek Medical Center, preterm babies <30 wks. GA, are studied echocardiographically on day of life 3-4. Pending parental informed consent, those diagnosed with a PDA of borderline significance will be randomized to receive either paracetamol or placebo for three days, followed by a repeat echocardiogram. If the PDA remains of borderline significance, the treatment will be continued for an additional 4 days (1 week total). Paracetamol levels and liver functions will be assessed after the third day. Babies will be followed until discharge for subsequent PDA pathology; respiratory distress and chronic lung disease [CLD]; necrotizing enterocolitis [NEC]; retinopathy of prematurity [ROP]. The investigators' primary goal is to demonstrate a decrease in the composite outcome of death or severe morbidity chronic lung disease [CLD], as shown by decreased time on supplemental oxygen and assisted ventilation. Secondary goals: To demonstrate a decrease in subsequently diagnosed hs PDA, including Decrease in the need for subsequent therapy for PDA closure Decrease in surgical PDA ligations To demonstrate a decrease in necrotizing enterocolitis (NEC) and/or ROP with treatment. To demonstrate no adverse effect on blood flow in anterior cerebral, superior mesenteric and renal arteries.

Treatment with placebo at a volume of 2.25 cc/kg/dose x 4/day to be given with feeds, or in place of feed when baby is receiving <2 cc/kg/feed.

Treatment with paracetamol drops at 15 mg/kg/dose x 4/day. Drops will be diluted 1:15 in order to reduce osmolality. This will yield a dose of 2.25 ml/kg/dose, to be given with feeds, or in place of feed when baby is receiving <2 cc/kg/feed.

Study infants will be followed clinically and any occurrence of NEC or ROP will be recorded with its level of significance (Bell staging for NEC and Stage of ROP)

Inclusion Criteria: Preterm neonates < 30 weeks' gestational age PDA of borderline significance Exclusion Criteria: Infants not deemed likely to survive more than one week Infants with congenital heart malformations Infants with pulmonary hypertension and right to left ductal shunting

Terrin G, Conte F, Oncel MY, Scipione A, McNamara PJ, Simons S, Sinha R, Erdeve O, Tekgunduz KS, Dogan M, Kessel I, Hammerman C, Nadir E, Yurttutan S, Jasani B, Alan S, Manguso F, De Curtis M. Paracetamol for the treatment of patent ductus arteriosus in preterm neonates: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2016 Mar;101(2):F127-36. doi: 10.1136/archdischild-2014-307312. Epub 2015 Aug 17.

Hammerman C, Bin-Nun A, Markovitch E, Schimmel MS, Kaplan M, Fink D. Ductal closure with paracetamol: a surprising new approach to patent ductus arteriosus treatment. Pediatrics. 2011 Dec;128(6):e1618-21. doi: 10.1542/peds.2011-0359. Epub 2011 Nov 7.