Refractory and Super-Refractory Status Epilepticus in Nerve Agent-Poisoned Rats Following Application of Standard Clinical Treatment Guidelines

Abstract

Nerve agents (NAs) induce a severe cholinergic crisis that can lead to status epilepticus (SE). Current guidelines for treatment of NA-induced SE only include prehospital benzodiazepines, which may not fully resolve this life-threatening condition. This study examined the efficacy of general clinical protocols for treatment of SE in the specific context of NA poisoning in adult male rats. Treatment with both intramuscular and intravenous benzodiazepines was entirely insufficient to control SE. Second line intervention with valproate (VPA) initially terminated SE in 35% of rats, but seizures always returned. Phenobarbital (PHB) was more effective, with SE terminating in 56% of rats and 19% of rats remaining seizure-free for at least 24 h. The majority of rats demonstrated refractory SE (RSE) and required treatment with a continuous third-line anesthetic. Both ketamine (KET) and propofol (PRO) led to high levels of mortality, and nearly all rats on these therapies had breakthrough seizure activity, demonstrating super-refractory SE (SRSE). For the small subset of rats in which SE was fully resolved, significant improvements over controls were observed in recovery metrics, behavioral assays, and brain pathology. Together these data suggest that NA-induced SE is particularly severe, but aggressive treatment in the intensive care setting can lead to positive functional outcomes for casualties.

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“…Nerve agents cause a severe cholinergic crisis that can induce RSE. In animal studies, nerve agents and OPNA intoxication with pesticides have been shown to elicit benzodiazepine RSE ( Morgan et al, 2021 ; Reddy et al, 2021 ). Second-line ASMs were not able to terminate such SE, and no current drug therapy is effective against RSE and SRSE.…”

“…With the exception of PB, there is no record of the FDA approving an MC via the Animal Rule pathway, which is a very complex and nearly implausible regulatory strategy for new nerve agent MCs. Nerve agent–induced RSE is very resistant to current and new anticonvulsants as seen in experimental rodent model outcomes showing minimal responses to second-line antiseizure medications such as valproate, levetiracetam, and phenytoin ( Morgan et al, 2021 ). There may be a disparity between the PK results of medications in animal RSE models and those in patients with RSE, which may appear as poor efficacy or suboptimal protection if the PK-PD relationship is not clear.…”

“…Nerve agents cause a severe cholinergic crisis that can induce RSE. In animal studies, nerve agents and OPNA intoxication with pesticides have been shown to elicit benzodiazepine RSE (Morgan et al, 2021;Reddy et al, 2021).…”