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We tested bumetanide added to phenobarbital to treat neonatal seizures in the first trial to include a standard\u2010therapy control group.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A randomized, double\u2010blind, dose\u2010escalation design was employed. Neonates with postmenstrual age 33 to 44\u2009weeks at risk of or with seizures were eligible. Subjects with electroencephalography (EEG)\u2010confirmed seizures after \u226520 and &lt;40mg\/kg phenobarbital were randomized to receive additional phenobarbital with either placebo (control) or 0.1, 0.2, or 0.3mg\/kg bumetanide (treatment). Continuous EEG monitoring data from \u22652\u2009hours before to \u226548\u2009hours after study drug administration (SDA) were analyzed for seizures.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Subjects were randomized to treatment (n = 27) and control (n = 16) groups. Pharmacokinetics were highly variable among subjects and altered by hypothermia. The only statistically significant adverse event was diuresis in treated subjects (48% vs 13%,\n                      <jats:italic>p<\/jats:italic>\n                      =\u20090.02). One treated (4%) and 3 control subjects died (19%,\n                      <jats:italic>p<\/jats:italic>\n                      =\u20090.14). Among survivors, 2 of 26 treated subjects (8%) and 0 of 13 control subjects had hearing impairment, as did 1 nonrandomized subject. Total seizure burden varied widely, with much higher seizure burden in treatment versus control groups (median = 3.1 vs 1.2\u2009min\/h,\n                      <jats:italic>p<\/jats:italic>\n                      =\u20090.006). There was significantly greater reduction in seizure burden 0 to 4\u2009hours and 2 to 4\u2009hours post\u2010SDA (both\n                      <jats:italic>p<\/jats:italic>\n                      &lt;\u20090.01) compared with 2\u2010hour baseline in treatment versus control groups with adjustment for seizure burden.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>Although definitive proof of efficacy awaits an appropriately powered phase 3 trial, this randomized, controlled, multicenter trial demonstrated an additional reduction in seizure burden attributable to bumetanide over phenobarbital without increased serious adverse effects. Future trials of bumetanide and other drugs should include a control group and balance seizure severity. ANN NEUROL 2021;89:327\u2013340<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.25959","type":"journal-article","created":{"date-parts":[[2020,11,17]],"date-time":"2020-11-17T09:21:41Z","timestamp":1605604901000},"page":"327-340","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":96,"title":["A Pilot Randomized, Controlled, Double\u2010Blind Trial of Bumetanide to Treat Neonatal Seizures"],"prefix":"10.1002","volume":"89","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6998-7753","authenticated-orcid":false,"given":"Janet S.","family":"Soul","sequence":"first","affiliation":[{"name":"Department of Neurology, Boston Children's Hospital Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann M.","family":"Bergin","sequence":"additional","affiliation":[{"name":"Department of Neurology, Boston Children's Hospital Harvard Medical School  Boston MA 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