Phenobarbital as alternate anticonvulsant for organophosphate-induced benzodiazepine-refractory status epilepticus and neuronal injury.
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OBJECTIVE: Organophosphates (OPs) such as diisopropylfluorophosphate (DFP) and soman are lethal chemical agents that can produce seizures, refractory status epilepticus (SE), and brain damage. There are few optimal treatments for late or refractory SE. Phenobarbital is a second-line drug for SE, usually after lorazepam, diazepam, or midazolam have failed to stop SE. Practically, 40minutes or less is often necessary for first responders to arrive and assist in a chemical incident. However, it remains unclear whether administration of phenobarbital 40minutes after OP intoxication is still effective. Here, we investigated the efficacy of phenobarbital treatment at 40minutes postexposure to OP intoxication. METHODS: Acute refractory SE was induced in rats by DFP injection as per a standard paradigm. After 40minutes, subjects were given phenobarbital intramuscularly (30-100mg/kg) and progression of seizure activity was monitored by video-EEG recording. The extent of brain damage was assessed 3days after DFP injections by neuropathology analysis of neurodegeneration and neuronal injury by unbiased stereology. RESULTS: Phenobarbital produced a dose-dependent seizure protection. A substantial decrease in SE was evident at 30 and 60mg/kg, and a complete seizure termination was noted at 100mg/kg within 40minutes after treatment. Neuropathology findings showed significant neuroprotection in 100mg/kg cohorts in brain regions associated with SE. Although higher doses resulted in greater protection against refractory SE and neuronal damage, they did not positively correlate with improved survival rate. Moreover, phenobarbital caused serious adverse effects including anesthetic or comatose state and even death. SIGNIFICANCE: Phenobarbital appears asan alternate anticonvulsant for OP-induced refractive SE in hospital settings. A careful risk-benefit analysis is required because of negative outcomes on survival and cardio-respiratory function. However, the need for sophisticated support and critical monitoring in hospital may preclude its use as medical countermeasure in mass casualty situations.
