title: Paracetamol Accelerates Closure of the Ductus Arteriosus after Premature Birth: A Randomized Trial.
abstract: OBJECTIVE
  To study the biologic effect of paracetamol, an inhibitor of prostaglandin synthase, on early closure of ductus arteriosus, and to evaluate possible adverse effects associated with the drug.
  
  
  METHODS
  In a controlled, double-blind, phase I-II trial, very low gestational age (<32 weeks) infants requiring intensive care were randomly assigned to intravenous paracetamol or placebo (0.45% NaCl). A loading dose of 20 mg/kg was given within 24 hours of birth, followed by 7.5 mg/kg every 6 hours for 4 days. Daily cardiac ultrasound examinations of ductal calibers were performed before the first dose, and until 1 day after the last dose. The main outcome was a decrease in the ductal caliber without side effects.
  
  
  RESULTS
  Of 63 screened infants, 48 were randomized: 23 were assigned to paracetamol and 25 to placebo. Before the intervention, their ductal calibers were similar. During the intervention, the ductus closed faster in the paracetamol group (hazard ratio 0.49, 95% CI 0.25-0.97, P = .016). The mean (95% CI) postnatal ages for ductal closure were 177 hours (31.1-324) for the paracetamol-treated vs 338 hours (118-557) for controls (P = .045). Paracetamol serum levels were within the therapeutic range, and no adverse effects were evident.
  
  
  CONCLUSIONS
  Prophylactic paracetamol induced early closure of the ductus arteriosus without detectable side effects. Further trials are required to determine whether intravenous paracetamol may safely prevent symptomatic patent ductus arteriosus.
  
  
  BACKGROUND
  ClinicalTrials.gov: NCT01938261; European Clinical Trials Database: EudraCT 2013-008142-33.
authors.affiliation: PEDEGO Research Center, and MRC Oulu, University of Oulu, and the Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
authors.forename: Pia
authors.initials: P
authors.lastname: Härkin
authors.affiliation: PEDEGO Research Center, and MRC Oulu, University of Oulu, and the Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Härmä
authors.affiliation: PEDEGO Research Center, and MRC Oulu, University of Oulu, and the Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland. Electronic address: outi.aikio@ppshp.fi.
authors.forename: Outi
authors.initials: O
authors.lastname: Aikio
authors.affiliation: PEDEGO Research Center, and MRC Oulu, University of Oulu, and the Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
authors.forename: Marita
authors.initials: M
authors.lastname: Valkama
authors.affiliation: PEDEGO Research Center, and MRC Oulu, University of Oulu, and the Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Leskinen
authors.affiliation: PEDEGO Research Center, and MRC Oulu, University of Oulu, and the Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Saarela
authors.affiliation: PEDEGO Research Center, and MRC Oulu, University of Oulu, and the Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Hallman
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects / Q000627:therapeutic use*; D061605:Administration, Intravenous; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D004374:Ductus Arteriosus, Patent / Q000188:drug therapy*; D005260:Female; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D019102:Infant, Very Low Birth Weight; D008297:Male; D047928:Premature Birth; D016896:Treatment Outcome
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen
keywords: acetaminophen; intravenous; patent ductus arteriosus; preterm infant