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

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.

• Traditional Treatment (Group T) (Drug), also known as benzodiazepines, barbiturates, propofol: Patients will receive traditional drug infusions
• Ketamine Infusion (Group K) (Drug), also known as Ketalar: 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

Primary outcomes

• Time taken for burst suppression [Baseline to 1 hr]: Average time for burst suppression
• Time taken for termination of seizures [Baseline to 24 hrs]: Average time for seizures to terminate

Secondary outcomes

• Use of vasopressors [baseline to 72 hrs]: The need of vasopressors
• Number of days on ventilator [Baseline to 72 hrs]: Total number of days patient is on the ventilator
• Length of stay in ICU [Baseline to 72 hrs postoperatively]: Total number of days in the ICU
• Use of parenteral or enteral nutrition [Baseline to 72 hrs postoperatively]: Nutrition provided through a feeding tube or catheter
• Medical imaging results [Post-op Day 2 to Post-op day 10]: MRI scans 7 to 10 days after burst suppression
• Mortality [baseline to post-op day 10]: death

Sex: All, ages: 18 Years to 100 Years, accepts healthy volunteers

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

• Results publication: 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. PMID 30232735

• Vinodkumar Singh, MD, Principal investigator, University of Alabama at Birmingham