• The primary outcome is determination of the pharmacokinetics of bumetanide in newborns with refractory seizures. [ Time Frame: Two years are anticipated for collection of the neonatal data ] [ Designated as safety issue: No ]
  

• A secondary outcome is determination of the safety and tolerability of bumetanide as add-on therapy in newborns with refractory seizures. [ Time Frame: Two years is anticipated ] [ Designated as safety issue: Yes ]
  
• The secondary outcome will be to determine whether there is a dose-dependent effect of bumetanide compared with standard therapy alone for the control of seizures, quantified by EEG measures of seizure activity. [ Time Frame: Two and a half years is anticipated ] [ Designated as safety issue: No ]
  

Seizures occur more often during the newborn period (2-3.5 per 1000 live births) than at any later age. Neonatal seizures can lead to frequent and serious long-term consequences in survivors, such as later epilepsy and significant cognitive and motor disabilities. Unfortunately there are no completely effective drugs to treat neonatal seizures. Anti-epileptic drugs (AEDs) currently used to treat neonatal seizures are generally ineffective and have significant potential for side effects. Furthermore, many of these AEDs have never been tested in a randomized study. Numerous experts have thus emphasized in the last few years the urgent need for randomized trials of potential new treatments for neonatal seizures. We are conducting a pilot study of the drug bumetanide as one such potential and novel treatment. Bumetanide is a commercially available drug that has been used safely in newborns as a diuretic for many years with minimal side effects. Recent basic science research in animals has shown bumetanide to be very effective in reducing seizures in neonatal animals by blocking a specific chloride importer which is highly expressed in neonates but not in children and adults.

Moreover, these experimental studies have shown bumetanide to be particularly effective against seizures when used in combination with phenobarbital (PB), which is the standard first drug given to treat neonatal seizures.

We will conduct a randomized, double-blinded, controlled trial enrolling newborns who manifest seizures related to acute neurologic disorders. These are the newborns whose seizures are commonly drug-resistant and who are likely to develop later neurologic sequelae such as epilepsy and cognitive and motor disabilities. When seizures persist in our subjects despite an initial loading dose of PB, we will administer one of two doses of bumetanide with the usual second dose of PB, or PB alone (standard therapy, or control group). We will use laboratory tests and clinical monitoring to determine how bumetanide is metabolized by our subjects and how well they tolerate the drug. We will use continuous electroencephalogram (EEG) monitoring of our subjects to determine whether and to what extent the addition of bumetanide reduces seizures compared with control. We anticipate that this pilot study will lead to a large multicenter trial of bumetanide for the treatment of neonatal seizures.