J Neurocrit Care.  2023 Jun;16(1):1-9. 10.18700/jnc.230003.

Refractory and super-refractory status epilepticus and evidence for the use of ketamine: a scope review

• Espinosa L
• Gomez M
• Zamora A
• Molano-Franco D

• KMID: 2543386
• DOI: http://doi.org/10.18700/jnc.230003

Abstract

Status epilepticus (SE) is a neurological emergency with serious consequences for neuronal tissues, therefore, it is considered the most serious manifestation of epilepsy. The response to treatment, its evolution time and duration, and the need to use one or more antiseizure drugs define SE as refractory or super-refractory. Ketamine has been used in SE management since the 90s when an article describing its use in treating SE was published. Since then, at least 24 publications have reported the use of ketamine for the treatment of SE in both adult and pediatric patients. This scoping review seeks to synthesize information on the use of drugs in super-refractory SE, specifically ketamine. Twenty articles were chosen for the final document construction. Few studies have investigated the use of ketamine in refractory status epilepticus (RSE) and super-refractory status epilepticus (SRSE). Most of the information comes from retrospective case series studies, mostly with small sample sizes, and although the information is heterogeneous, it points to the efficacy of ketamine as a third-line drug in RES and SRSE, in controlling seizures.

Keyword

Ketamine; Anticonvulsants; Epileptic status; Treatment; Diagnosis

Figure

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  Fig. 1. N-methyl-D-aspartate (NMDA) receptors regulate, through a complex mechanism, calcium entry into the cell from the extracellular compartment. The entry of this cation translates into calcium-dependent intracellular excitability mediated by second and third messengers. Ketamine antagonizes NMDA receptors which are located at the medullary, thalamic, limbic, and cortical levels. Thanks to the multiplicity of NMDA receptors, ketamine interferes with the sensory afferent flow to the central nervous system's higher centers, affecting pain, emotional responses, and memory, which is why it is referred to as a "dissociative anesthetic." Ketamine also has some side effects on opioid receptors which helps propagate its analgesic effect, as well as in alpha- and beta-adrenergic receptors, which gives it some cardiovascular actions.

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  Fig. 2. Systematic review flowchart.

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  Fig. 3. Receptor trafficking theory. Seizures produce many physiological effects and biochemical changes in the brain; within minutes, the trafficking of receptors causes some key adaptations. (A) Arrangement of γ-aminobutyric acid (GABA) receptors under normal conditions. (B) After recurrent seizures, GABA receptors in the synaptic membrane undergo a process of internalization. These membrane proteins are directed to endosomes in the cytosol or to the Golgi apparatus, where they are recycled to the cellular membrane. (C) Arrangement of N-methyl-D-aspartate (NMDA) receptors under normal conditions. (D) In synapses, unlike GABA receptors, NMDA receptors are mobilized towards the synaptic membrane from amino acids located in the Golgi apparatus and are assembled into receptors that are transported in endosomes to the cell membrane. As a result of this trafficking, the number of functional NMDA receptors per synapse increases while the number of functional GABA receptors decreases [53].

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