Ketamine controls prolonged status epilepticus

Abstract

New treatments are needed to control prolonged status epilepticus given the high failure rate of current therapies. In an animal model of status epilepticus based on electrical stimulation of the hippocampus, rats demonstrate at least 5 five-hours of seizure activity following stimulation. Phenobarbital (70 mg/kg) administered 15 min after stimulation effectively controlled seizures in 66% of animals (n=6). When phenobarbital (70 mg/kg) was administered 60 min after stimulation, seizures were controlled in 25% of animals (n=4). Ketamine (100 mg/kg) administered 15 min after stimulation did not control seizures in any animal (n=4). But when ketamine was administered one hour after stimulation it effectively controlled seizures in all animals (n=4). Increasing doses of ketamine were administered 60 min after stimulation to generate a dose-response curve. The ketamine dose response (fraction of seizure free rats) data were fit to a sigmoid curve to derive an ED(50) of 58 mg/kg. These findings suggest that prolonged status epilepticus becomes refractory to phenobarbital but can be effectively controlled by ketamine. For patients experiencing prolonged status epilepticus that is refractory to phenobarbital, ketamine may be an alternative to general anesthesia.

Fig. 1

EEG recording from the cortex and hippocampus of an animal subjected to continuous hippocampal stimulation. Ten second samples of the continuous record are displayed from a period just before stimulation (baseline), at the beginning of spontaneous seizures, and after 2 and 5 h of spontaneous seizures. Note that a persistent electrographic seizure (status epilepticus) lasted five hours after termination of stimulation. The pattern of electrographic seizure changed with time as demonstrated by a reduction in frequency of the discharges and changes in their morphology.

Fig. 2

Prolonged status epilepticus renders phenobarbital less effective. Phenobarbital (70 mg/kg, i.p.) was administered after 15, 30, and 60 min of spontaneous seizures. Arrows mark the time of administration of phenobarbital. Animals were considered seizure-free based on EEG criteria. In all animals behavioral sedation preceded termination of electrographic seizures. The percentage of animals not having electrographic seizures was plotted over time.

Fig. 3

EEG recording from the cortex and hippocampus of a rat in status epilepticus and treated with ketamine (100 mg/kg). Samples (10 s) of the continuous EEG record are displayed from a period just before stimulation (baseline), during spontaneous status epilepticus, and after ketamine administration. Ketamine was administered after 60 min of status epilepticus.

Fig. 4

Ketamine treatment of prolonged (60 min) status epilepticus. Increasing doses of ketamine were administered after 60 min of spontaneous seizures (arrow). The percentage of animals not having electrographic seizures was plotted over time for each dose. One animal that received ketamine (150 mg/kg) died and was not included in the analysis.