Ronit M Pressler1, Geraldine B Boylan2, Neil Marlow3, Mats Blennow4, Catherine Chiron5, J Helen Cross3, Linda S de Vries6, Boubou Hallberg4, Lena Hellström-Westas7, Vincent Jullien5, Vicki Livingstone2, Barry Mangum8, Brendan Murphy2, Deirdre Murray2, Gerard Pons5, Janet Rennie3, Renate Swarte9, Mona C Toet6, Sampsa Vanhatalo10, Sarah Zohar11. 1. Section of Clinical Neurosciences and Neonatal Unit, University College London, London, UK. Electronic address: r.pressler@ucl.ac.uk. 2. Irish Centre for Fetal and Neonatal Translational Research, University College Cork, Cork, Ireland. 3. Section of Clinical Neurosciences and Neonatal Unit, University College London, London, UK. 4. Neonatology, Karolinska University Hospital, Stockholm, Sweden. 5. Inserm U1129, Paris, France; University Paris Descartes, Paris, France. 6. Neonatology, University Medical Centre Utrecht, Utrecht, Netherlands. 7. Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden. 8. Duke Clinical Research Institute, Duke University, NC, USA. 9. Neonatology, Erasmus University Medical Centre Rotterdam, Rotterdam, Netherlands. 10. Children's Clinical Neurophysiology, Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland. 11. Department for Statistics, Inserm, Inserm U1138, Paris, France.
Abstract
BACKGROUND: Preclinical data suggest that the loop-diuretic bumetanide might be an effective treatment for neonatal seizures. We aimed to assess dose and feasibility of intravenous bumetanide as an add-on to phenobarbital for treatment of neonatal seizures. METHODS: In this open-label, dose finding, and feasibility phase 1/2 trial, we recruited full-term infants younger than 48 h who had hypoxic ischaemic encephalopathy and electrographic seizures not responding to a loading-dose of phenobarbital from eight neonatal intensive care units across Europe. Newborn babies were allocated to receive an additional dose of phenobarbital and one of four bumetanide dose levels by use of a bivariate Bayesian sequential dose-escalation design to assess safety and efficacy. We assessed adverse events, pharmacokinetics, and seizure burden during 48 h continuous electroencephalogram (EEG) monitoring. The primary efficacy endpoint was a reduction in electrographic seizure burden of more than 80% without the need for rescue antiepileptic drugs in more than 50% of infants. The trial is registered with ClinicalTrials.gov, number NCT01434225. FINDINGS: Between Sept 1, 2011, and Sept 28, 2013, we screened 30 infants who had electrographic seizures due to hypoxic ischaemic encephalopathy. 14 of these infants (10 boys) were included in the study (dose allocation: 0·05 mg/kg, n=4; 0·1 mg/kg, n=3; 0·2 mg/kg, n=6; 0·3 mg/kg, n=1). All babies received at least one dose of bumetanide with the second dose of phenobarbital; three were withdrawn for reasons unrelated to bumetanide, and one because of dehydration. All but one infant also received aminoglycosides. Five infants met EEG criteria for seizure reduction (one on 0·05 mg/kg, one on 0·1 mg/kg and three on 0·2 mg/kg), and only two did not need rescue antiepileptic drugs (ie, met rescue criteria; one on 0·05 mg/kg and one on 0·3 mg/kg). We recorded no short-term dose-limiting toxic effects, but three of 11 surviving infants had hearing impairment confirmed on auditory testing between 17 and 108 days of age. The most common non-serious adverse reactions were moderate dehydration in one, mild hypotension in seven, and mild to moderate electrolyte disturbances in 12 infants. The trial was stopped early because of serious adverse reactions and limited evidence for seizure reduction. INTERPRETATION: Our findings suggest that bumetanide as an add-on to phenobarbital does not improve seizure control in newborn infants who have hypoxic ischaemic encephalopathy and might increase the risk of hearing loss, highlighting the risks associated with the off-label use of drugs in newborn infants before safety assessment in controlled trials. FUNDING: European Community's Seventh Framework Programme.
BACKGROUND: Preclinical data suggest that the loop-diuretic bumetanide might be an effective treatment for neonatal seizures. We aimed to assess dose and feasibility of intravenous bumetanide as an add-on to phenobarbital for treatment of neonatal seizures. METHODS: In this open-label, dose finding, and feasibility phase 1/2 trial, we recruited full-term infants younger than 48 h who had hypoxic ischaemic encephalopathy and electrographic seizures not responding to a loading-dose of phenobarbital from eight neonatal intensive care units across Europe. Newborn babies were allocated to receive an additional dose of phenobarbital and one of four bumetanide dose levels by use of a bivariate Bayesian sequential dose-escalation design to assess safety and efficacy. We assessed adverse events, pharmacokinetics, and seizure burden during 48 h continuous electroencephalogram (EEG) monitoring. The primary efficacy endpoint was a reduction in electrographic seizure burden of more than 80% without the need for rescue antiepileptic drugs in more than 50% of infants. The trial is registered with ClinicalTrials.gov, number NCT01434225. FINDINGS: Between Sept 1, 2011, and Sept 28, 2013, we screened 30 infants who had electrographic seizures due to hypoxic ischaemic encephalopathy. 14 of these infants (10 boys) were included in the study (dose allocation: 0·05 mg/kg, n=4; 0·1 mg/kg, n=3; 0·2 mg/kg, n=6; 0·3 mg/kg, n=1). All babies received at least one dose of bumetanide with the second dose of phenobarbital; three were withdrawn for reasons unrelated to bumetanide, and one because of dehydration. All but one infant also received aminoglycosides. Five infants met EEG criteria for seizure reduction (one on 0·05 mg/kg, one on 0·1 mg/kg and three on 0·2 mg/kg), and only two did not need rescue antiepileptic drugs (ie, met rescue criteria; one on 0·05 mg/kg and one on 0·3 mg/kg). We recorded no short-term dose-limiting toxic effects, but three of 11 surviving infants had hearing impairment confirmed on auditory testing between 17 and 108 days of age. The most common non-serious adverse reactions were moderate dehydration in one, mild hypotension in seven, and mild to moderate electrolyte disturbances in 12 infants. The trial was stopped early because of serious adverse reactions and limited evidence for seizure reduction. INTERPRETATION: Our findings suggest that bumetanide as an add-on to phenobarbital does not improve seizure control in newborn infants who have hypoxic ischaemic encephalopathy and might increase the risk of hearing loss, highlighting the risks associated with the off-label use of drugs in newborn infants before safety assessment in controlled trials. FUNDING: European Community's Seventh Framework Programme.
Authors: Ronit M Pressler; Geraldine B Boylan; Neil Marlow; Linda S de Vries; Mats Blennow; Catherine Chiron; J Helen Cross; Boubou Hallberg; Lena Hellström-Westas; Vincent Jullien; Barry Mangum; Brendan Murphy; Deirdre Murray; Gerard Pons; Janet Rennie; Mona C Toet; Sarah Zohar Journal: Nat Rev Neurol Date: 2015-11-03 Impact factor: 42.937
Authors: Maria D Donovan; Geraldine B Boylan; Deirdre M Murray; John F Cryan; Brendan T Griffin Journal: Br J Clin Pharmacol Date: 2015-11-04 Impact factor: 4.335
Authors: Gregory A Chinn; Jennifer M Sasaki Russell; Nicole A Yabut; Deenu Maharjan; Jeffrey W Sall Journal: Anesthesiology Date: 2020-10-01 Impact factor: 7.892
Authors: Yogendra H Raol; Srdjan M Joksimovic; Dayalan Sampath; Brock A Matter; Philip M Lam; Uday B Kompella; Slobodan M Todorovic; Marco I González Journal: Neurosci Lett Date: 2020-08-26 Impact factor: 3.046