Month: December 2020

ESETT Trial

  • ESETT = Established Status Epilepticus Treatment Trial
    • Randomized, blinded, adaptive trial
  • GOAL: compare efficacy of 3 intravenous AEDs in children and adults with convulsive status epilepticus unresponsive to treatment with benzos.
    • Levetiracetam
    • Fosphenytoin
    • Valproate
  • OUTCOME:
    • Primary outcome:
      • absence of clinical seizures + level of consciousness at 60 mins
    • Safety outcomes:
      • life-threatening hypotension
      • cardiac arrhythmia
      • intubation
      • seizure recurrence
      • death
  • RESULTS:
    • 384 patients
    • Primary outcome of cessation of status epilepticus
      • levetiracetam 47%
      • fosphenytoin 45%
      • valproate 46%
    • Safety outcomes
      • more episodes of hypotension and intubation with fosphenytoin (not significant)
      • more deaths in levetiracetam (not significant)
    • time to cessation of seizures favored valproate but not subjected to formal analsyis
  • CONCLUSION:
    • Each of the three seizure meds led to cessation of status epilepticus and improved alertness by 60 mins in ~half of patients, with similar incidences of adverse events.

NOTES:

  1. Eligibility: 2 years or older, treated with generally accepted cumulative dose of benzos lasting >5mins and with persistent or recurrent convulsions at least 5 mins after last dose of benzos and no more than 30 mins after last dose of benzos
  2. “Minimal adequate cumulative dose” defined in the study as:
    1. diazepam at 10mg (IV or per rectum)
    2. lorazepam at 4mg (IV)
    3. midazolam at 10mg (IV or IM)
  3. After 10 mins, infusion of trial drug discontinued; rescue therapy given as needed for persistent or recurrent seizures after 20 mins from start of drug infusion.
  4. “clinically apparent seizure” defined as visually observed focal or generalized tonic-clonic movements or generalized or segmental myoclonus.
  5. “improved responsiveness” defined as purposeful responses to noxious stimuli, ability to follow commands, verbalization
  6. Planned interim analysis (at n=400) met predefined futility criterion, and trial was stopped.

LIMITATIONS:

  1. need for unblinding in some instances
  2. 10% of patients had psychogenic nonepileptic seizures
  3. clinical rather than EEG criteria was used to determine primary outcome
  4. fosphenytoin restrictions on maximal rate of infusion, so constraint of 10-minute infusion limited maximal dose to 1500mg PE which may be submaximal dose
  5. adverse events >24h not collected – may have missed other events such as rashes or elevated liver enzymes or delayed presentations
  6. high percentage of patients had deviations related to benzodiazepine dosing

TAKE HOME: Fosphenytoin, valproate, and levetiracetam are effective in approximately half of patients with benzo-refractory status epilepticus. These 3 intravenous meds did not differ significantly with regard to effectiveness and safety.

Reference:

Brown, J., & Jones, J. (2020). Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus. The Journal Of Emergency Medicine, 58(6), 980-981. doi: 10.1016/j.jemermed.2020.05.027