Abstracts

Rationale: Organophosphorus nerve agents like sarin (GB) and VX are highly toxic chemicals that have been used as weapons by militant governments and terrorist organizations. The most life-threatening effect of nerve agents on the central nervous system is the irreversible blockade of acetylcholinesterase activity, which results in accumulation of excess acetylcholine at neural synapses. This, in turn, leads to status epilepticus. In the event of a civilian nerve agent exposure, it is likely that children would represent a large proportion of the casualties because they are particularly susceptible to seizures compared to adults (Haut et al., 2004; Rakhade & Jensen, 2009; Sidell et al., 2008). Here we determined the ED50 of five traditional and investigational anticonvulsant drugs in both male and female pediatric and adult rats with the intent of guiding clinical treatment options for nerve agent-induced status epilepticus across the population. Methods: Female and male postnatal day 21, 28, and 70 (adult control) rats were implanted with electroencephalographic (EEG) headpieces for monitoring of cortical seizure activity. Rats were exposed to either GB or VX, and then treated five minutes post-seizure onset with varying doses of diazepam, midazolam, phenobarbital, sec-Butyl-propylacetamide (SPD), or propofol. The up-down method (Dixon & Massey, 1983) was used to determine the median effective dose (ED50) for each treatment drug against each agent for each sex within each age group. A three-factor ANOVA was used to compare age, sex, and agent for each treatment drug. Results: No significant differences were observed between males and females for any treatment. All drugs also showed similar efficacy against both GB and VX. A significant effect of age was observed on the ED50 of diazepam (p = 0.0224), phenobarbital (p = 0.0142), and propofol (p = 0.0492). Younger animals stopped seizing with lower doses of these drugs than adults. Conclusions: Out of all of the variables tested in this study, age had the most influence on anticonvulsant efficacy. Our results suggest that pediatric patients may benefit from lower doses of diazepam than adults, allowing maximum use of available resources in field hospitals. Children also may respond to therapies such as phenobarbital that do not work well in adults. Additionally, our work supports the use of emerging therapies like propofol in both adult and pediatric populations. Funding: This research was supported by an Inter-Agency Agreement between NIH/NINDS (Y1-06-9613-01) and USAMRICD (A120-B.P2009-2). Support was also provided by appointments to the Research Participation Program for the U.S. Army Medical Research Institute of Chemical Defense administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and U.S. Army Medical Research and Materiel Command. The views expressed in this abstract are those of the authors and do not reflect the official policy of the Department of Army, Department of Defense, or the U.S. Government. The experimental protocol was approved by the Animal Care and Use Committee 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. 89-544), as amended.