Abstracts

Rationale: Clinical studies have shown 43% of status epilepticus (SE) cases are pharmacoresistant to 1st and 2nd lines of treatments. These refractory status epilepticus (RSE) cases are associated with higher mortality and morbidity rates. Multiple types of treatment options are tried; however, it is not clear which method of treatment is more efficacious as compared to the others. In the lithium-pilocarpine SE rat model, we have found that EEG stage III pattern is highly refractory to standard treatments (i.e. diazepam and phenobarbital). Using this model of RSE, we prospectively tested the comparative abortive efficacy of 3 commonly used agents – propofol, midazolam, and pentobarbital.Methods: 23 adult male Sprague-Dawley rats were each implanted with 4 stainless steel epidural electrodes for EEG recording. Status epilepticus was induced by 3 mmol/kg intraperitoneal (IP) lithium chloride followed 24 hrs later by 30 mg/kg pilocarpine subcutaneously. EEG was continuously recorded and at SE EEG stage III onset, diazepam (10mg/kg IP), phenobarbital (25mg/kg IP), and a test agent were given. The treatment arms consisted of: midazolam intramuscularly at 1, 5, 10, 15, & 20 mg/kg; propofol IP at 40, & 55 mg/kg; and pentobarbital IP at 20, & 30 mg/kg. Treatment success was defined as the cessation of all clinical and electrographic seizure activity for 30 minutes. Efficacy, mean time to abort SE, and mortality rates were compared between treatment arms and doses.Results: Pentobarbital stopped 100% of seizure activity at the 20 and 30 mg/kg doses. However the mortality rate was higher in the later group (100% of 3 animals) compared with the former (25% of 4). Propofol, at 40 mg/kg, successfully stop the seizure activity in 75% of 4 animals with a 0% mortality rate. At the 55 mg/kg dose, it had a 100% abortive rate with a 67% percent mortality rate in 3 animals. Midazolam was unsuccessful in aborting SE at any of the tested doses. Mean time to SE abortion ranged from 5-8 minutes after medication injection for all successful cases.Conclusions: The current study demonstrates the ability to prospectively compare 3rd and 4th line treatments for RSE using a reliable animal model of pharmacoresistant SE. Although pentobarbital and propofol successfully aborted episodes of RSE, high mortality rates still existed, in spite of optimized treatment times. The lack of an abortive response from midazolam doses may reflect the nature of this RSE model, a need for higher dosing, or a need for a different route of administration. These results reveal the need for a more effective and safe treatment for RSE. Further studies should include other potential drugs and dosings. (Funding support from the Barrow Neurological Foundation.)