Ketamine Reduces Seizure Burden in Super-Refractory Status Epilepticus

Jan Claassen, MD, FNCS

Results from a retrospective study of patients with super-refractory status epilepticus (SRSE) treated with ketamine infusion showed that they experienced a decrease in seizure burden, supporting the notion that high-dose ketamine infusions are associated with decreased vasopressor requirements without intracranial pressure.

Among a consecutive series of 68 SRSE patients admitted between 2009 and 2018 and treated with ketamine and monitored with scalp electroencephalogram (EEG), seizure burden decreased by at least 50% within 24 hours of starting treatment in 55 (81%) patients, with complete cessation in 43 (63%).

Senior author Jan Claassen, MD, FNCS, associate professor of neurology, director, clinical care neurology, Columbia University, and colleagues found that 54 (79%) patients achieved at least 50% decrease in seizure burden and 44 (65%) patients had complete seizure cessation after stopping ketamine treatment.

Claassen and co-investigators used a generalized linear mixed effect model to find that ketamine was associated with a stable mean arterial pressure (odds ratio [OR], 1.39; 95% CI, 1.38–1.40), and with decreased in vasopressor requirements over time. Longer administration time (OR, 0.9; 95% CI, 0.8–1) was also associated with a stable mean arterial pressure.

Claassen and colleagues found no effect of a higher dose of ketamine (OR, 0.1; 95% CI, 0–0.12) and longer administration on (OR, –0.33; 95% CI –0.32 to –0.34) on intracranial pressure (ICP), cerebral blood flow (CBF; OR, –0.03; 95% CI, –0.02 to –0.04) and (OR, –0.4; 95% CI, –0.44 to –.44) nor cerebral perfusion pressure (CPP; OR, –0.13; 95% CI, –0.12 to –0.14) and (OR, –0.3; 95% CI, –0.3 to –0.3).

The average dose of ketamine infusion was 2.2 mg/kg/h (±1.8), with median duration of 2 days (range 1–4). All patients received midazolam infusions in addition to ketamine, with an average dose of 1.0 mg/kg/h (±0.8) at the time of ketamine infusion and was started at a median of 0.4 (range, 0.1–1.0) days before ketamine.

“In summary, this study supports the use of ketamine infusions for the treatment of SRSE and suggests that high doses of ketamine are associated with improved hemodynamics without an increase in intracranial pressure. Prospective studies are needed starting ketamine infusions early in the treatment of status epilepticus,” the Claassen et al. concluded.

SRSE, often defined by the failure of seizures to stop despite administration of dosed antiepileptic drugs (AEDs) has no current data to support optimal management, but midazolam, propofol, and pentobarbital are gamma-aminobutyric acid (GABAa) receptor anesthetics that are among the most commonly used. Ketamine, meanwhile, is designed to antagonize N-methyl-D-aspartate (NMDA) receptors and inhibit glutamatergic transmission. Receptor trafficking occurs in the setting of status epilepticus whereby intrasynaptic membrane GABAa receptors are internalized and NMDA receptors are upregulated.

Mean status epilepticus severity score (STESS) was 4 (±1), and in-hospital mortality rate was 46%. Claassen and colleagues noted that 18 (41%) patients with seizure cessation after starting ketamine died and 13 (54%) patients without seizure cessation died after stopping ketamine. On average, 2 (±1) concurrent anesthetics (propofol in 36 patients and pentobarbital in 10 patients) were used for SRSE treatment.

The average age of the patients included in the analysis was 53 years old (±19) and 46 (68%) were women. Cardiac arrest was the most common etiology (27%) followed by new onset refractory status epilepticus (NORSE) (18%).

REFERENCE

Alkhachroum A, Der-Nigoghossian CA, Mathews E, et al. Ketamine to treat super-refractory status epilepticus. Neurology. Published September 1, 2020. doi: 10.1212/WNL.0000000000010611.