Pia Härkin1, Antti Härmä1, Outi Aikio2, Marita Valkama1, Markku Leskinen1, Timo Saarela1, Mikko Hallman1. 1. PEDEGO Research Center, and MRC Oulu, University of Oulu, and the Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland. 2. 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.
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. STUDY DESIGN: 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. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01938261; European Clinical Trials Database: EudraCT 2013-008142-33.
RCT Entities:
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. STUDY DESIGN: 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. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01938261; European Clinical Trials Database: EudraCT 2013-008142-33.
Authors: Christina Schreiner; Maria Sappler; Michaela Höck; Marlene Hammerl; Vera Neubauer; Ursula Kiechl-Kohlendorfer; Elke Griesmaier Journal: Front Pediatr Date: 2022-05-23 Impact factor: 3.569
Authors: Shannon E G Hamrick; Hannes Sallmon; Allison T Rose; Diego Porras; Elaine L Shelton; Jeff Reese; Georg Hansmann Journal: Pediatrics Date: 2020-11 Impact factor: 7.124