Efficacy and safety of high versus standard dose ibuprofen for patent ductus arteriosus treatment in preterm infants: A systematic review and meta-analysis

Article type: Review Article

Authors: Yeung, T.^{a; b; d} | Shahroor, M.^{a; c} | Jain, A.^{a; d} | Weisz, D.^{a; c} | Jasani, B.^{a; e; *}

Affiliations: [a] Department of Pediatrics, Division of Neonatology, University of Toronto, Toronto, Canada | [b] Windsor Regional Hospital, Windsor, Canada | [c] Sunny brook Health Sciences Centre, Toronto, Canada | [d] Mount Sinai Hospital, Toronto, Canada | [e] The Hospital for Sick Children, Toronto, Canada

Correspondence: [*] Address for correspondence: Bonny Jasani MD, DM, Hospital for Sick Children, Division of Neonatology, 3rd Floor, 555 University Avenue Toronto, M5G 1X8, Canada. Tel.: +1 416 813 7331; E-mail: [email protected].

Abstract: BACKGROUND:Several small randomized controlled trials (RCTs) and observational studies have compared high (15-20/7.5-10/7.5-10 mg/kg/dose) versus standard dose (10/5/5 mg/kg/dose) ibuprofen for patent ductus arteriosus (PDA) closure, with limited evidence on efficacy and safety. OBJECTIVE:To systematically review and meta-analyze studies of high versus standard dose ibuprofen for the closure of PDA in preterm infants. METHODS:Databases were searched for RCTs and observational studies assessing high compared to standard dose of ibuprofen for PDA closure for preterm infants until August 2021. The primary outcome was failure of PDA closure after the first course of ibuprofen. The secondary outcomes were the failure of PDA closure after a second course of ibuprofen, rates of PDA ligation, all-cause mortality prior to hospital discharge, bronchopulmonary dysplasia, necrotizing enterocolitis, bleeding disorders, oliguria, and serum creatinine after treatment. RESULTS:There were 6 studies with 369 patients (3 RCT, N = 190; 3 observational studies, N = 179). Compared to standard dose, high dose ibuprofen did not significantly decrease the failure rate of PDA closure in preterm infants after the first course (Relative risk (RR) 0.74, 95% confidence interval (CI) 0.53 –1.03, 6 studies, N = 369). High dose ibuprofen significantly decreased the rates of PDA ligation compared to standard dose (RR 0.33, 95% CI 0.16 –0.70, 5 studies, N = 309). INTERPRETATION:Based on low-grade evidence, high dose ibuprofen may more effectively reduce rates of PDA ligation compared to standard dose with no increase in adverse effects, neonatal morbidities and mortality.

Keywords: Ibuprofen, meta-analysis, patent ductus arteriosus, preterm infants

DOI: 10.3233/NPM-210968

Journal: Journal of Neonatal-Perinatal Medicine, vol. 15, no. 3, pp. 501-510, 2022