Novel Treatment of Status Epilepticus

Status epilepticus patients are often refractory to treatment and continue to have seizures despite aggressive management. Treatment resistance results from functional and molecular changes in neurons that lead to downregulation of inhibitory gamma-aminobutyric acid (GABA) receptors and upregulation of excitatory N-methyl-D-aspartate (NMDA) glutamate receptors. These neuronal changes reduce the efficacy of GABAergic drugs (eg, phenobarbital, propofol) commonly used to treat status epilepticus. Drugs with different mechanisms of action are therefore essential for treatment. 

This report describes a case series of 3 epileptic dogs with long-lasting super-refractory status epilepticus treated with a combination of ketamine and dexmedetomidine along with controlled mild hypothermia. Ketamine is an NMDA-receptor antagonist that decreases glutamate activity, which is overexpressed with status epilepticus, causing glutamate excitotoxicity and cell death. Dexmedetomidine is an alpha-2 adrenoceptor agonist that suppresses sympathetic stimulation and noradrenaline release, lowering brain excitatory neurotransmitters. Dexmedetomidine also has neuroprotective effects due to vasoconstrictive properties that may aid in controlling cerebral edema. 

All 3 dogs were initially treated with a benzodiazepine (midazolam or diazepam), followed by a 12-hour, anesthesia-inducing propofol infusion. Phenobarbital, with or without levetiracetam, was also administered to 2 dogs. Seizure activity resumed after anesthesia was discontinued. All dogs were then treated with an IV bolus of ketamine (1 mg/kg), followed by an IV bolus of dexmedetomidine (3 µg/kg), after which an infusion of ketamine (1 mg/kg/hour) and dexmedetomidine (3-7 µg/kg/hour) at a variable rate was administered. This ketamine and dexmedetomidine combination resulted in moderate to deep sedation; however, endotracheal intubation was not necessary. Body temperature was maintained between 98.1°F to 99.9°F (36.7°C-37.7°C). The ketamine and dexmedetomidine infusion was discontinued after 12 hours; seizure activity stopped in all 3 dogs. 

This is the first study in which a combination of ketamine and dexmedetomidine was used to successfully treat refractory status epilepticus in dogs.

Key pearls to put into practice:

Refractory status epilepticus and super-refractory status epilepticus involve downregulation of GABA receptors; therefore, drugs that target a receptor with a different mechanism of action are needed.

Ketamine can decrease the excitatory activity of glutamate by blocking NMDA receptors, which minimizes glutamate excitotoxicity and neuronal cell death. Dexmedetomidine can decrease sympathetic activity via attenuating noradrenaline release, which lowers excitation and metabolic demand in the brain.

Because NMDA receptors are not activated in the initial phase of seizures, NMDA antagonists are only recommended for prolonged status epilepticus.