Ketamine in Status Epilepticus

Problem:  prolonged status epilepticus leads to upregulation of NMDA receptors, glutamate-mediated excitotoxicity and resistance to conventional antiepileptics.
Ketamine-A-Miracle-Drug-for-Depression-or-Not-RM-1440x810.jpg
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Definitions:

1.  Refractory status epilepticus – either generalized or complex partial status epilepticus that fails to respond to first and second line therapies

2.  Superrefractory status epilepticus – status epilepticus that remains unresponsive despite 24 hours of therapy with general anesthesia
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Mechanisms of conventional AEDs:
  1. GABA agonist – cortical inhibition / reduction of epileptogenicity and lateral spread; e.g. benzodiazeipne, valproate, propofol, barbiturates, clonazepam, clobazam, vigabatrin, and topiramate
  2. Na blockers – phenytoin, carbamazepine, lamotrigine, oxcarbazepine, zonisamide, and rufinamide
  3. Ca blockers – gabapentin and pregabalin,

 

Molecular Changes in Prolonged Status Epilepticus:

  1. GABA A downregulation – depletes receptors for benzodiazepines, etc, also subunit alterations in GABAA receptor lead to impaired binding –> resistance to GABA-mediated AEDs
  2. p-glycoprotein molecular transporter upregulation – occurs at the level of BBB ~20 to 30 minutes into status epilepticus; these transporters export phenytoin and phenobarbital molecules and efficacy of phenytoin and phenobarbital is greatly diminished
  3. upregulation of NMDA receptors – leads to glutamate-mediated activation of these receptors, leads to intracellular calcium influx and excitotoxicity
  4. proinflammatory mediators can also alter BBB permeability and induce neuronal damage which can lead to AED resistance and excitotoxicity

 

Advantages of Ketamine in RSE / SRSE:

  • NMDA receptor antagonists target a receptor known to be upregulated during SE/RSE/SRSE
  • NMDA receptor antagonists provide neuroprotection (studied in TBI population)
  • drug is readily available and cheap
  • sympathomimetic properties = vasopressor sparing effects
  • side effect profile low

 

Possible Complications:

  • arrhythmias
  • hypersalivation
  • mild hypertension
  • hallucinations
  • ICP elevation? – old literature, should not be factored in

 

Notes:

  • Effectivity:  110 patients = 56.5% responded (cessation of SE)
  • Duration of Treatment:  16 hours to 140 days
  • Usual dosing: bolus 0.5 to 5 mg/Kg then continuous infusion 0.12 to 10mg/kg/hr, duration of 2h to 27d
  • most common duration: 7 days, most responding within 48-72h
  • Start ketamine within 24-48 hours of SE onset, after failure of first trial with anesthetics of choice (midazolam, propofol, pentobarbital)
  • Suggested dosing:  bolus 3mg/kg, followed by continuous infusion up to 10mg/kg/hr, duration up to 7 days

 

Reference:

Zeiler, F. A. “Early Use Of The NMDA Receptor Antagonist Ketamine In Refractory And Superrefractory Status Epilepticus”. Critical Care Research and Practice 2015 (2015): 1-5.

 

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