The New England Journal of Medicine © Copyright, 2000, by the Massachusetts Medical Society VOLUME 343 S EPTEMBER 7, 2000 NUMBER 10 674 · September 7, 2000 A COMPARISON OF IBUPROFEN AND INDOMETHACIN FOR CLOSURE OF PATENT DUCTUS ARTERIOSUS BART VAN OVERMEIRE, M.D., PH.D., KOEN SMETS, M.D., DOMINIEK LECOUTERE, M.D., HILDE VAN DE BROEK, M.D., JOOST WEYLER, M.D., PH.D., KATYA DE GROOTE, M.D., AND JEAN-PAUL LANGHENDRIES, M.D. ABSTRACT Background Indomethacin is the conventional treatment for patent ductus arteriosus in preterm in- fants. However, its use is associated with various side effects. In a prospective study, we compared ibu- profen and indomethacin with regard to efficacy and safety for the early treatment of patent ductus arte- riosus in preterm infants. Methods We studied 148 infants (gestational age, 24 to 32 weeks) who had the respiratory distress syndrome and an echocardiographically confirmed patent ductus arteriosus. The infants were randomly assigned at five neonatal intensive care centers to re- ceive three intravenous doses of either indometha- cin (0.2 mg per kilogram of body weight, given at 12- hour intervals) or ibuprofen (a first dose of 10 mg per kilogram, followed at 24-hour intervals by two doses of 5 mg per kilogram each), starting on the third day of life. The rate of ductal closure, the need for addi- tional treatment, side effects, complications, and the infants’ clinical course were recorded. Results The rate of ductal closure was similar with the two treatments: ductal closure occurred in 49 of 74 infants given indomethacin (66 percent), and in 52 of 74 given ibuprofen (70 percent) (relative risk, 0.94; 95 percent confidence interval, 0.76 to 1.17; P=0.41). The numbers of infants who needed a second phar- macologic treatment or surgical ductal ligation did not differ significantly between the two groups. Oli- guria occurred in 5 infants treated with ibuprofen and in 14 treated with indomethacin (P=0.03). There were no significant differences with respect to other side effects or complications. Conclusions Ibuprofen therapy on the third day of life is as efficacious as indomethacin for the treatment of patent ductus arteriosus in preterm infants with the respiratory distress syndrome and is significantly less likely to induce oliguria. (N Engl J Med 2000;343: 674-81.) ©2000, Massachusetts Medical Society. From the Department of Pediatrics, Division of Neonatology, University Hospital Antwerp (B.V.O., K.D.); the Department of Pediatrics, Division of Neonatology, Ghent University Hospital (K.S.); the Neonatal Intensive Care Unit, Sint Jan Ziekenhuis, Bruges (D.L.); the Neonatal Intensive Care Unit, Queen Paola Children’s Hospital, Antwerp (H.V.B.); the Department of Epidemiology and Community Medicine, University of Antwerp (J.W.); and the Neonatal Intensive Care Unit, Clinique Saint Vincent, Rocourt (J.-P.L.) — all in Belgium. Address reprint requests to Dr. Van Overmeire at the Department of Pediatrics, Division of Neonatology, University Hos- pital Antwerp, Wilrijkstraat 10, B-2650 Edegem, Belgium, or at bart.van. overmeire@uza.uia.ac.be. ATENT ductus arteriosus remains a frequent problem in premature infants with the respi- ratory distress syndrome. 1-3 In a large network of neonatal intensive care units, the frequen- cy of patent ductus arteriosus in infants weighing 501 to 1500 g was 31 percent. 3 Substantial left-to-right shunting through the ductus may increase the risk of intraventricular hemorrhage, necrotizing enterocoli- tis, bronchopulmonary dysplasia, and death. 4,5 There- fore, closure of the ductus is indicated. Intravenous indomethacin is the conventional pharmacologic treat- ment for promoting closure of a patent ductus in pre- mature infants. However, concern remains regarding the safety of indomethacin, which affects renal, gas- trointestinal, and cerebral perfusion and may lead to complications such as transient or permanent renal dysfunction, 6,7 necrotizing enterocolitis, gastrointesti- nal hemorrhage, 8 and reduced cerebral intracellular oxygenation. 9,10 Ibuprofen has been shown to close the ductus in animals 11 without affecting basal cerebral blood flow and intestinal or renal hemodynamics during positive- pressure ventilation, 12 and it has been shown to have different effects on regional circulation from those of indomethacin. 13-15 Furthermore, ibuprofen enhanced cerebral blood-flow autoregulation and had some neu- roprotective effects in animals subjected to oxidative stress. 16,17 More recently, ibuprofen has been shown to be effective for the closure of patent ductus arteriosus in premature infants, 18-20 without reducing mesenteric, P Copyright © 2000 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at UNIVERSITEIT GENT on May 12, 2005 .