Pilot Study of Bumetanide for Newborn Seizures

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. The investigators 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 (1). 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 (2).

The investigators will conduct a randomized, double-blind, controlled, dose escalation study
of BTN as add-on therapy to treat refractory seizures caused by HIE, focal or multi-focal
stroke, intracranial hemorrhage, CNS infection, genetic syndrome, focal or diffuse brain
malformation, idiopathic or presumed genetic etiology of seizures, or metabolic disorder
other than electrolyte disturbances or those caused by renal failure not controlled by an
initial loading dose of PB. The trial will test the feasibility of early enrollment of
newborns with HIE, rapid application of a full montage EEG, and continuous review of EEG data
to detect refractory seizures as soon as they occur following an initial loading dose of PB.
When an EEG-proven seizure occurs at least 30 minutes following a loading dose of PB, the
newborn will be randomized to receive either BTN or placebo in conjunction with a loading
dose of PB. Clinical, laboratory and continuous EEG monitoring data obtained after BTN
administration will be analyzed to determine the pharmacokinetics and safety of BTN by
comparing data from treatment and standard therapy groups. This study addresses important
challenges in trial design and sets the stage for trials to improve treatment of neonatal
seizures. Data from this pilot study will be used to guide design of a planned Phase III
multicenter trial to test the efficacy of BTN to control refractory neonatal seizures.

Inclusion Criteria:

- newborns with a post-conceptional age of 33-44 weeks

- condition with risk for seizure:

- asphyxia

- intracranial hemorrhage

- suspected or confirmed stroke

- CNS infection

- genetic syndrome

- focal or diffuse brain malformation

- idiopathic or presumed genetic etiology of seizures

- metabolic disorder other than electrolyte disturbances or those caused by renal
failure

- suspected clinical seizure

Exclusion Criteria:

- have transient metabolic abnormalities (e.g., transient hypocalcemia) as the sole
cause of seizures

- are receiving ECMO (extracorporeal membrane oxygenation) therapy because of alteration
of bumetanide pharmacokinetics by ECMO

- have contraindications to bumetanide (as determined by treating physician)

- have received diuretics such as furosemide or BTN

- newborns with a total serum bilirubin > 15 mg/dL at enrollment

- newborns given ≥ 40mg/kg of phenobarbital

- loading doses of AEDs other than phenobarbital (those who receive levetiracetam are
still eligible since levetiracetam does not affect bumetanide pharmacokinetics)