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

Prolonged, self-sustaining seizures are commonly referred to as status epilepticus (SE). Benzodiazepines are currently the mainstay of treatment of SE. In randomized clinical trials of treatment of convulsive SE, benzodiazepines such as lorazepam and diazepam are effective in terminating seizures in 59–78% of patients (Leppik et al., 1983; Treiman et al., 1998; Alldredge et al., 2001). Currently, there are no therapies that have been demonstrated to control seizures in 22–41% of the patients who were refractory to benzodiazepines. Therapies such as phenobarbital and phenytoin were ineffective in controlling SE refractory to first line treatment in the Veteran’s Administration cooperative trial. It is a common practice to use general anesthetics such as midazolam, propofol, or pentobarbitone, etc. to terminate refractory SE. These treatments terminate SE but require prolonged hospitalization and intensive care (Bleck 2005). N-methyl-d-aspartate (NMDA) antagonists are candidate treatments for refractory SE. Some of these compounds, such as ketamine and MK-801 (dizocilpine), have been demonstrated to terminate prolonged, GABA-refractory SE induced by electrical stimulation in experimental animals (Bertram & Lothman 1990; Mazarati & Wasterlain 1999; Borris et al., 2000). In addition, NMDA receptor antagonists offer the possibility of protecting neurons from seizure-induced neuronal damage and the development of epilepsy (Fujikawa et al., 1994; Prasad et al., 2002). However, in contrast to their efficacy in terminating SE in an electrical stimulation model, NMDA receptor antagonists are not effective in terminating cholinergic stimulation-induced diazepam-refractory SE. In addition, one study found that NMDA receptor antagonists were ineffective in controlling SE induced by organophosphate cholinesterase inhibitors, also known as nerve agents (Shih et al., 1999). In commonly used cholinergic models of SE induced by pilocarpine or lithium followed by pilocarpine, NMDA receptor antagonists were effective in terminating SE only if administered prior to the induction of SE (Ormandy et al., 1989). However, they were less effective in terminating ongoing SE when administered 30 or 60 min following administration of pilocarpine. Another study found that a combination of a single dose (4 mg/kg) of noncompetitive NMDA receptor antagonist, MK 801, with diazepam (10 mg/kg) was superior to diazepam alone in terminating SE when administered 60 min postseizure onset (Rice & DeLorenzo 1999). Several issues related to the treatment of diazepam-refractory SE with NMDA receptor antagonists remain to be explored. For example, the drug efficacy is in part influenced by the dose used. The efficacy of various doses of NMDA receptor antagonists administered alone has not been investigated in the cholinergic activation model of SE. Previous studies on the treatment of SE caused by electrical stimulation have demonstrated that increasing doses of NMDA receptor antagonists control SE in a larger fraction of animals up to a peak effective dose; further increases diminished the efficacy (Yen et al., 2004). Therefore, it is possible that the efficacy of NMDA receptor antagonists in treating refractory SE could be improved by varying its dose. Additionally, the combination therapy of NMDA antagonist and diazepam was not systematically explored. The doses of NMDA receptor antagonist, MK-801(dizocilpine), and diazepam were not varied and this could impact the efficacy of the combination therapy. Importantly, NMDA receptor antagonist dizocilpine is not clinically available. In this study, we examined the efficacy of clinically-available NMDA receptor antagonist (ketamine) in terminating diazepam-refractory SE induced by cholinergic stimulation. Multiple doses of ketamine ranging from ineffective to toxic were examined for their efficacy in terminating diazepam-refractory SE. Furthermore, the same range of ketamine doses was used in combination with two doses of diazepam. These studies provide a comprehensive evaluation of a therapy for refractory SE by a combination of two clinically available drugs.