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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.
Highlights
Acts of terrorism and warfare by hostile governments and militant groups have extended beyond the battlefield environment into civilian spaces, often with explicit intent to cause the greatest level of destruction, chaos, and harm possible
This study was approved by the Institutional Animal Care and Use Committee (IACUC) at the United States Army Medical Research Institute of Chemical Defense, and all procedures were conducted in accordance with the principles stated in the Guide for the Care and Use of Laboratory Animals, and the Animal Welfare Act of 1966 (P.L. 84-544)
Consistent with numerous other preclinical experiments, benzodiazepines were ineffective even at doses that scale to roughly four times the effective dose levels from the RAMPART study (Jackson et al, 2019; Marrero-Rosado et al, 2018; McDonough et al, 2010; Niquet et al, 2020; Shih et al, 1999; Silbergleit et al, 2012; U.S Food and Drug Administration (USFDA), 2005)
Summary
Acts of terrorism and warfare by hostile governments and militant groups have extended beyond the battlefield environment into civilian spaces, often with explicit intent to cause the greatest level of destruction, chaos, and harm possible. Nerve agents (NAs) have been used to execute these types of attacks because they are disseminated, fast acting, and highly potent chemical. Developed during World War II, and subsequently banned nearly three decades ago, NAs have continued to make global headlines for their use in targeted political assassinations and mass terrorist attacks (Chai et al, 2017, 2018; Stone, 2018). NAs are organophosphate compounds that cause toxicity by directly inhibiting acetylcholinesterase. This inhibition leads to a prominent, systemic hyper-concentration of the neurotransmitter acetylcholine (ACh) within synapses. Excessive ACh can result in miosis, hypersecretions, fasciculations, pulmonary edema, centrally-induced apnea, and seizures that, if left untreated, can rapidly progress to status epilepticus (SE)
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