Efficacy of Ketamine Infusion Compared With Traditional Anti-epileptic Agents in Refractory Status Epilepticus

Efficacy of Ketamine Infusion Compared With Traditional Anti-epileptic Agents in Refractory Status Epilepticus

Efficacy of Ketamine Infusion Compared With Traditional Anti-epileptic Agents in Refractory Status Epilepticus- a Pilot Study

The study will investigate the efficacy of the N-methyl-D-aspartate receptor antagonist ketamine as a first line agent in refractory status epilepticus versus traditional general anesthetic agents used for burst suppression that target the gamma-aminobutyric acid adrenergic receptors.

The traditional treatment for refractory status epilepticus includes diazepam, midazolam, valproic acid, thiopental and propofol. These medications fail to control seizure activity in 20-40% of patients. This is attributed to decrease in activity of gamma-aminobutyric acid receptors along with reciprocal up regulation of N-Methyl-D-aspartate receptors. Glutamate activation of N-methyl-D-aspartate receptors promotes calcium influx and excitotoxicity. Ketamine, an intravenous anesthetic agent which is a non-competitive antagonist of N-methyl-D-aspartate receptors can block the flow of Ca and Na and by combining with phencyclidine binding sites inside the ion channel of N-methyl-D-aspartate receptors, reduce the epileptiform burst discharges and after potential. Therefore, targeting the N-methyl-D-aspartate receptors with ketamine may provide a novel approach to control refractory seizures. Moreover, by blocking glutamate mediated N-methyl-D-aspartate receptor induced neurotoxicity, ketamine may render neuroprotection. Ketamine also provides additional advantage of hemodynamic stability. Currently, ketamine is used as a last resort drug in the treatment of refractory status epilepticus. The specific aim is to determine whether continuous infusion of ketamine as a first line agent for refractory status epilepticus is effective in controlling seizures. The central hypothesis of our proposal is that early treatment with ketamine will be much more efficacious in controlling refractory status compared to the traditional treatment.

Group T patients will be placed into burst suppression with the traditional drug infusions which include any single or combination of drugs; usually benzodiazepines, barbiturates and or propofol.

Patients in the group K arm will receive a loading dose of 2.5 mg/kg of ketamine followed by a continuous infusion with a starting dose of 3mg/kg/hr with titration in 1mg/kg/hr increments until burst suppression is achieved or a maximum dose of 10mg/kg/hr is reached. After 48 hours of burst suppression the ketamine dosage will be reduced by 2mg/kg/hr in a stepwise fashion to evaluated for EEG or clinical evidence of seizure recurrence.

Patients will receive loading dose of 2.5 mg/kg of ketamine followed by a continuous infusion with a starting dose of 3mg/kg/hr with titration in 1mg/kg/hr increments until burst suppression is achieved or a maximum dose of 10mg/kg/hr is reached

Inclusion Criteria: Patients more than 18 years of age with a diagnosis of status epilepticus Considered for burst suppression therapy after failing 2 or 3 anti-epileptic medications Exclusion Criteria: Post anoxic status epilepticus Pregnant women, as confirmed by urine, or blood human chorionic gonadotropin, ultrasound or physical exam Prisoners Age less than 18 years Allergy or sensitivity to the drug in question

Rosati A, De Masi S, Guerrini R. Ketamine for Refractory Status Epilepticus: A Systematic Review. CNS Drugs. 2018 Nov;32(11):997-1009. doi: 10.1007/s40263-018-0569-6.