A combination of ketamine and diazepam synergistically controls refractory status epilepticus induced by cholinergic stimulation

Abstract

Purpose: New treatments are needed for status epilepticus (SE) that is refractory to drugs modulating GABA(A) receptors, and NMDA receptor antagonists are candidate drugs.

Methods: Clinically available NMDA receptor antagonist ketamine was tested for effectiveness in terminating prolonged SE induced by a combination of lithium and pilocarpine. Animals were treated 10 min after first grade 5 behavioral seizure (Racine scoring scale) by intraperitoneal administration of ketamine, diazepam, or saline. Seizure termination was determined by electroencephalogram (EEG) recordings from the hippocampus and the cortex.

Results: Animals treated with normal saline or either 20 mg/kg diazepam, or 50 mg/kg ketamine continued in SE for the next 300 min. However, combined treatment with diazepam and ketamine rapidly terminated prolonged cholinergic stimulation-induced SE. Detailed study of dose response relationships demonstrated that diazepam enhanced efficacy and potency of ketamine in terminating SE.

Discussion: This study demonstrated synergistic action of diazepam and ketamine in terminating SE. It suggests that a ketamine-diazepam combination might be a clinically useful therapeutic option for the treatment of refractory SE.

Conflict of interest statement

Conflict of interest: Authors have no conflicts of interest to report. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Figures

Figure 1

EEG tracings recorded from the hippocampus and cortex of an animal in SE treated with 50 mg/kg ketamine. Baseline recording was obtained prior to the administration of pilocarpine, animal was considered in SE when it experienced first stage 5 seizure. Ketamine was administered 10 min after first class 5 seizure and the tracing was obtained 5 min after ketamine treatment. Note that ketamine initially increased the frequency and amplitude of epileptiform activity which continued unabated for 5 h.

Figure 2

Relationship between various doses of ketamine administered alone or in combination with diazepam and percentage of animals seizure-free at a time 60 min following drug administration. Note left and upward shift of curves as diazepam is combined with ketamine and its dose is increased.

Figure 3

Time course of ketamine control of electrographic seizures is displayed. The onset of ketamine action and persistence of seizure freedom were studied by analyzing seizure freedom at various time points following drug administration. When ketamine was administered alone (top panel), it acted slowly taking from 45 min to 1 h to terminate SE. In combination with 10 mg/kg diazepam (middle panel), the action became faster and more persistent. A combination of 20 mg/kg diazepam and ketamine was rapidly acting and its effect was persistent (bottom panel).

Figure 4

EEG tracings recorded from the hippocampus and cortex of an animal in SE treated with 50 mg/kg ketamine and 20 mg/kg diazepam. Baseline recording was obtained prior to the administration of pilocarpine, animal was considered in SE when it experienced first stage 5 seizure. A combination of ketamine 50 mg/kg with 20 mg/kg diazepam abolished SE. Compare this response to that shown in Fig. 1.