HYPOTHERMIA REDUCES MORTALITY AND MORBIDITY FROM STATUS EPILEPTICUS

Virginia Commonwealth University, Richmond VA

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Abstract

? DESCRIPTION (provided by applicant): The goal of this project is to demonstrate that hypothermia given after survival of the status epilepticus (SE) and organophosphate (OP) pesticide and nerve agent induced SE is a safe and effective non-pharmaceutical treatment to prevent or decrease SE induced mortality and morbidity, including behavioral abnormalities and cognitive impairment and acquired epilepsy (AE) and mossy fiber sprouting. SE is a major medical emergency in clinical practice and SE is a major complication from exposure to OPs from chemical threats from terrorist attacks or from exposure by accident or natural disasters. Advances have been made to treat the seizures associated with SE and the cholinergic crisis from OP exposure, but at present there are no therapies available to prevent mortality and the long term morbidities associated with SE and OP SE. Our research has made a major advance in understanding how SE and OP SE cause mortality. Our PR indicate that cardiac irritability in the first 2 weeks after SE is the major cause of mortality and this can be prevented by treatment up to 3 h after SE with hypothermia. We made a breakthrough in our preliminary research and discovered that hypothermia treatment following SE can prevent the development of the Ca2+ plateau and neuronal loss providing a mechanism for the effect of hypothermia in reducing the chronic morbidity associated with SE. This study will use pilocarpine, the OP pesticide paraoxon (POX), and OP nerve agent surrogate diisopropyl- fluorophosphate (DFP) to induce SE in rats. Our laboratory is ideally suited to conduct these studies and has developed the necessary skills to carry out the following specific aims: Aim 1: Determine whether effects of different times after SE and durations of hypothermia treatment can reduce or prevent mortality and cardiac irritability (prolongation of the QT interval) following survival from pilocarpine, POX and DFP induced SE. Aim 2: Evaluate the effects of different times after SE and durations of hypothermia treatment on the maintenance of the Ca2+ plateau and neuronal loss after SE. Aim 3: Determine whether hypothermia can prevent the development of behavioral abnormalities (depression) after survival from pilocarpine, POX and DFP induced SE. Aim 4: Evaluate whether hypothermia can prevent the development of cognitive impairment and the development of AE and mossy fiber sprouting following survival from pilocarpine, POX and DFP induced SE. The PR demonstrates the feasibility of these studies and underscores the potential significance of conducting this research. Hypothermia is a routine effective treatment for cardiac arrest and anoxic brain injury that is widely used in hospitals. If these preliminary findings are documented, this study may provide the experimental data needed to develop clinical trials and protocols to employ hypothermia in hospital settings to treat SE and in the every expanding terrorist threats or accidental exposures to pesticide and nerve agent induced SE.