LOW-DOSE INDOMETHACIN AND PREVENTION OF INTRAVENTRICULAR HEMORRHAGE -A MULTICENTER RANDOMIZED TRIAL

Objectives. Parenchymal involvement of intraventricular hemorrhage (IV H) is a major risk factor for neurodevelopmental handicap in very low birth weight neonates. Previous trials have suggested that indomethaci n would lower the incidence and severity of IVH in very low birth weig ht neonates. Methods. We enrolled 431 neonates of 600- to 1250-g birth weight with no evidence for IVH at 6 to 11 hours of age in a prospect ive, randomized, placebo-controlled trial to test the hypothesis that low-dose indomethacin (0.1 mg/kg intravenously at 6 to 12 postnatal ho urs and every 24 hours for two more doses) would lower the incidence a nd severity of IVH. Serial cranial ultrasound examinations and echocar diographs were performed. Results. There were no differences in the bi rth weight, gestational age, sex, Apgar scores, and percent of neonate s treated with surfactant between the indomethacin and placebo groups. Within the first 5 days, 25 (12%) indomethacin-treated and 40 (18%) p lacebo-treated neonates developed IVH (P = .03, trend test). Only one indomethacin-treated patient experienced grade 4 IVH compared with 10 placebo-treated neonates (P = .01). Sixteen indomethacin-treated neona tes and 29 control neonates died (P = .08); there was a difference fav oring indomethacin with respect to survival time (P = .06). Eighty-six percent of all neonates had a patent ductus arteriosus on the first p ostnatal day; indomethacin was associated with significant ductal clos ure by the fifth day of life (P < .001). There were no differences in adverse events attributed to indomethacin between the two treatment gr oups. Conclusions. Low-dose prophylactic indomethacin significantly lo wers the incidence and severity of IVH, particularly the severe form ( grade 4 IVH). In addition, indomethacin closes the patent ductus arter iosus and is not associated with significant adverse drug events in ve ry low birth weight neonates.