Ketamine Infusion for Status Epilepticus
Direct Recommendation
Ketamine should be reserved as a third-line agent for refractory status epilepticus (RSE) that has failed benzodiazepines, second-line anticonvulsants (valproate, levetiracetam, fosphenytoin, or phenobarbital), AND initial anesthetic agents (midazolam, propofol, or pentobarbital). 1, 2
Treatment Algorithm for Status Epilepticus
First-Line: Benzodiazepines
- Administer IV lorazepam 4 mg at 2 mg/min immediately for any actively seizing patient, with 65% efficacy in terminating status epilepticus 1
- Alternative routes include IM midazolam or intranasal midazolam if IV access unavailable 1
- Check fingerstick glucose simultaneously and correct hypoglycemia 1
Second-Line: Anticonvulsants (if seizures persist after benzodiazepines)
Select ONE of the following 3, 1:
- Valproate 20-30 mg/kg IV over 5-20 minutes (88% efficacy, 0% hypotension risk—preferred for cardiovascular safety) 1, 2
- Levetiracetam 30 mg/kg IV over 5 minutes (68-73% efficacy, minimal adverse effects) 1, 2
- Fosphenytoin 20 mg PE/kg IV at max 50 mg/min (84% efficacy, but 12% hypotension risk requiring continuous ECG/BP monitoring) 1, 2
- Phenobarbital 20 mg/kg IV over 10 minutes (58.2% efficacy, higher respiratory depression risk) 1
Third-Line: Anesthetic Agents for Refractory Status Epilepticus
Refractory status epilepticus is defined as seizures continuing despite benzodiazepines AND one second-line agent 1
Initiate continuous EEG monitoring at this stage 1
Select ONE of the following anesthetic agents 1, 2:
- Midazolam infusion: 0.15-0.20 mg/kg IV load, then 1 mg/kg/min continuous infusion (80% efficacy, 30% hypotension risk) 1
- Propofol: 2 mg/kg bolus, then 3-7 mg/kg/hour infusion (73% efficacy, 42% hypotension, requires mechanical ventilation but shorter ventilation time than barbiturates at 4 vs 14 days) 1, 2
- Pentobarbital: 13 mg/kg bolus, then 2-3 mg/kg/hour infusion (92% efficacy—highest success rate—but 77% hypotension risk) 1
Ketamine's Role: Fourth-Line for Super-Refractory Cases
When to Consider Ketamine
Only after failure of benzodiazepines, a second-line anticonvulsant, AND at least one anesthetic agent (midazolam, propofol, or pentobarbital) 4, 5
Evidence Supporting Ketamine Use
- Ketamine acts on NMDA receptors, which become upregulated during prolonged status epilepticus, providing a mechanistically distinct approach from GABA-ergic agents 4, 6
- A systematic review of 248 patients showed 64% efficacy when ketamine was administered early in RSE (within 3 days), but efficacy dropped to 32% when delayed to mean 26.5 days 5
- In a retrospective series of 11 patients, ketamine successfully terminated RSE in 100% of cases, with seizure cessation occurring within 4-28 days (mean 9.8 days) 7
- Ketamine improved hemodynamic stability, with 85% of patients weaned from vasopressors during infusion 7
Dosing and Administration
- Dosing ranges from 0.45-2.1 mg/kg/hour, with maximal daily doses of 1392-4200 mg based on clinical response 7
- No standardized dosing protocol exists; titrate based on EEG suppression and clinical response 5, 7
- Can be administered IV or orally (oral route used successfully in 10 children with non-convulsive status epilepticus, avoiding intubation) 5
Safety Profile
- No acute adverse effects reported in case series 7
- Associated with hemodynamic improvement rather than deterioration, unlike traditional anesthetics 7
- May allow avoidance of intubation in select cases, particularly non-convulsive status epilepticus 5
Critical Pitfalls to Avoid
Do NOT Use Ketamine Prematurely
Never skip second-line anticonvulsants or initial anesthetic agents to jump directly to ketamine 1. The established treatment algorithm must be followed sequentially because:
- Second-line agents (valproate, levetiracetam, fosphenytoin) have 68-88% efficacy with well-established safety profiles 1, 2
- Initial anesthetic agents (midazolam, propofol, pentobarbital) have 73-92% efficacy 1
- Ketamine evidence comes only from case reports and case series—no randomized controlled trials exist 4, 5
Do NOT Use Neuromuscular Blockers Alone
Never administer rocuronium or other paralytics without anticonvulsants, as they only mask motor manifestations while allowing continued electrical seizure activity and ongoing brain injury 1
Simultaneous Evaluation Required
While administering anticonvulsants, actively search for and treat reversible causes 1, 2:
- Hypoglycemia (check fingerstick immediately) 1
- Hyponatremia 1
- Hypoxia 1
- Drug toxicity or withdrawal syndromes 1
- CNS infection 1
- Ischemic stroke or intracerebral hemorrhage 1
Monitoring Requirements
For All Anesthetic Agents (Including Ketamine)
- Continuous EEG monitoring to guide titration and detect ongoing electrical seizure activity 1, 5
- Continuous blood pressure monitoring (hypotension occurs in 30-77% depending on agent) 1
- Prepare for mechanical ventilation and respiratory support regardless of agent chosen 1
Load Long-Acting Anticonvulsants During Infusion
Administer phenytoin/fosphenytoin, valproate, levetiracetam, or phenobarbital during the anesthetic infusion to ensure adequate levels before tapering 1
Emerging Evidence and Future Directions
There is increasing evidence supporting ketamine not only in super-refractory status epilepticus but potentially as an earlier second-line option 4. However, current guidelines do not yet support this practice, and two ongoing randomized controlled trials (NCT02431663 and NCT03115489) will hopefully provide definitive evidence 5. Until these results are available, ketamine should remain a fourth-line agent reserved for cases refractory to all standard therapies 1, 4, 5.