NEMO

Neonatal hypoxic ischaemic encephalopathy (HIE) occurs in 2-3/1000 live births and is a major cause of both acute mortality and long-term neurodisability. Seizures are the hallmark of HIE. The clinical and electrographic seizure burden in babies with HIE can be siderable and is often not reduced by current antiepileptic drugs. Phenobarbitone remains the first line drug for neonatal seizures despite the fact that it has limited efficacy. Better treatments for neonatal seizures, particularly in asphyxiated babies, are a high research priority with the ultimate aim to improve long-term outcome. The aim of NEMO is to develop an effective treatment regimen for neonatal seizures using innovative strategies, targeted specifically to the needs and peculiarities of babies. An age dependent high expression of neuronal co-transporter resulting in excitatory rather than inhibitory function of GABA is believed to be responsible for the high incidence of seizures in the neonatal period. By blocking this co-transporter with bumetanide, a loop diuretic, the depolarizing action of GABA will be reversed resulting in reduced neuronal firing. Intensive EEG monitoring will enable us to accurately identify seizures and monitor treatment effect. A European-wide multicentre approach would for the first time allow performing a RCT with enough statistical power in this age-group. By solidating efforts from basic science, pharmacology and clinical centres, we propose: 1. to perform a European-wide, multicentre, randomised, placebo-trolled, double-blind trial to evaluate the efficacy and safety of bumetanide in neonatal seizures, including the effect on neurodevelopment 2. to perform pharmacokinetic and pharmcodynamic studies of bumetanide 3. to further investigate the mechanisms of action in non-clinical experiments 4. to develop and adapt a bumetanide formulation suitable for newborns in order to apply for a Paediatric Use Marketing Authorization (PUMA).