Which anticonvulsant best terminates benzodiazepine-refractory status epilepticus?

  • Kapur J & al.
  • N Engl J Med
  • 28 Nov 2019

  • International Clinical Digest
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  • Levetiracetam, fosphenytoin, and valproate were similarly efficacious and safe for stopping seizures and improving level of consciousness in patients with benzodiazepine-refractory convulsive status epilepticus.

Why this matters

  • Early seizure termination reduces complications, mortality.

Key results

  • Trial stopped early for futility.
  • Main efficacy outcome:
    • 47% with levetiracetam (95% credible interval [CrI], 39%-55%),
    • 45% with fosphenytoin (95% CrI, 36%-54%), and
    • 46% with valproate (95% CrI, 38%-55%).
  • Posterior probability that drug was the most effective:
    • 0.41 for levetiracetam,
    • 0.24 for fosphenytoin, and
    • 0.35 for valproate.
  • Groups also similar on:
    • ICU admission;
    • Median lengths of ICU, hospital stay; and
    • Median time to seizure termination when treatment was successful.
  • Numeric but nonsignificant differences:
    • More episodes of hypotension, intubation with fosphenytoin.
    • More deaths with levetiracetam.

Expert comment

  • In an editorial, Phil E. Smith, MD, writes, “Having three equally effective second-line intravenous medications means that the clinician may choose a drug that takes into account individual situations that may be modified by factors such as the presumed underlying cause of status epilepticus; coexisting conditions, including allergy, liver and renal disease, hypotension, propensity to cardiac arrhythmia, and alcohol and drug dependence; the currently prescribed antiepileptic treatment; the cost of the medication; and governmental agency drug approval.”

Study design

  • Randomized adaptive trial comparing 3 drugs in 384 children and adults with convulsive status epilepticus unresponsive to treatment with benzodiazepines (ESETT trial).
  • Main outcome: absence of clinically evident seizures and improvement in level of consciousness 60 minutes after start of drug infusion, without additional anticonvulsant medication.
  • Funding: National Institute of Neurological Disorders and Stroke.


  • Need for unblinding in some cases.
  • Reliance on clinical vs electroencephalographic criteria for main outcome.
  • Only single dose of each drug tested.
  • Late nonserious adverse events not collected.