What is the role of ketamine infusion in treating refractory seizures?

Ketamine Infusion in Refractory Seizures

Direct Recommendation

Ketamine should be used as a third-line anesthetic agent for super-refractory status epilepticus after failure of benzodiazepines and standard second-line agents, with a loading dose of 0.15-0.20 mg/kg IV followed by continuous infusion starting at 1-5 mg/kg/hour, titrated based on EEG response. 1

Treatment Algorithm for Status Epilepticus

First-Line Treatment

• Administer IV lorazepam 4 mg at 2 mg/min immediately for any actively seizing patient, with 65% efficacy in terminating status epilepticus 2
• Check fingerstick glucose and correct hypoglycemia simultaneously 2

Second-Line Treatment (After Benzodiazepine Failure)

• Valproate 20-30 mg/kg IV over 5-20 minutes (88% efficacy, 0% hypotension risk) 2
• Levetiracetam 30 mg/kg IV over 5 minutes (68-73% efficacy, minimal adverse effects) 2
• Fosphenytoin 20 mg PE/kg IV at maximum 50 mg/min (84% efficacy, 12% hypotension risk) 2
• Phenobarbital 20 mg/kg IV over 10 minutes (58.2% efficacy, higher respiratory depression risk) 2

Third-Line Treatment for Refractory Status Epilepticus

Refractory status epilepticus is defined as seizures continuing despite benzodiazepines and one second-line agent. 2 At this stage, initiate continuous EEG monitoring 2 and choose among the following anesthetic agents:

Standard Third-Line Options:

• Midazolam infusion: 0.15-0.20 mg/kg IV load, then 1 mg/kg/min continuous infusion (80% success rate, 30% hypotension risk) 1, 2
• Propofol: 2 mg/kg bolus, then 3-7 mg/kg/hour infusion (73% efficacy, 42% hypotension risk, requires mechanical ventilation) 1, 2
• Pentobarbital: 13 mg/kg bolus, then 2-3 mg/kg/hour infusion (92% efficacy, 77% hypotension risk) 1, 2

Ketamine-Specific Dosing Protocol

For Super-Refractory Status Epilepticus:

• Loading dose: 0.15-0.20 mg/kg IV bolus 1
• Initial infusion: Start at 1 mg/kg/hour 1
• Titration: Increase by 1 mg/kg/hour every 15 minutes as needed based on clinical and EEG response 1
• Maximum range: 1-5 mg/kg/hour per guidelines 1, though research reports use up to 10.5 mg/kg/hour 3

Evidence for Ketamine Efficacy:

• Permanent seizure control achieved in 57% of episodes in a multicenter retrospective study of 60 episodes 4
• Ketamine contributed to control (possible or likely responses) in 32% of cases, with 12% being definitive responses where ketamine was the last drug added 4
• 71.4% response rate in non-intubated patients with refractory seizures, avoiding intubation in the majority 5
• Early initiation (within 5 hours) increases likelihood of success—responders were 80% more likely to have received ketamine earlier than nonresponders 5

Unique Advantages of Ketamine

Hemodynamic Benefits:

Ketamine provides superior cardiovascular stability compared to traditional anesthetics, with 85% of patients on vasopressors being successfully weaned during ketamine infusion. 1 This contrasts sharply with pentobarbital (77% hypotension) and propofol (42% hypotension) 2

Respiratory Advantages:

• Ketamine does not suppress respiratory drive like other continuous infusion anesthetics, potentially avoiding intubation in carefully selected patients 5
• In a case series, 71.4% of non-intubated patients achieved seizure control without requiring mechanical ventilation 5

Mechanistic Rationale:

• Ketamine is a noncompetitive NMDA receptor antagonist that blocks excitatory pathways contributing to ongoing seizures 3, 6
• Demonstrates neuroprotective properties and synergistic effects with other antiseizure medications in animal models 6

Critical Timing Considerations

Ketamine appears most effective when introduced early in the treatment course:

• No likely responses observed when ketamine was introduced 8 or more days after SE onset 4
• No likely responses after failure of 7 or more drugs 4
• Infusion rates below 0.9 mg/kg/hour showed no likely responses 4

Important Safety Considerations and Monitoring

Cardiovascular Effects:

• Hypotension (SBP <90 mmHg) occurred in 31.8% of patients receiving only ketamine, which did not correlate with duration or maximum dose 5
• Hypertension (SBP >180 mmHg) occurred in 39.3% of patients 5
• Continuous blood pressure monitoring is mandatory 2

Metabolic Complications:

High-dose, prolonged ketamine infusions carry risk of metabolic acidosis and cardiovascular collapse, particularly at very high doses. 3 Two fatal cases were reported with metabolic acidosis and cardiovascular collapse during long-term, high-dose infusion 3

Essential Monitoring Parameters:

• Continuous EEG monitoring to guide titration and achieve seizure suppression 2
• Continuous vital sign monitoring, particularly blood pressure and respiratory status 2
• Monitor for metabolic acidosis during prolonged infusions 3
• Be prepared to provide respiratory support if needed 2

Critical Pitfalls to Avoid

• Never use neuromuscular blockers alone (e.g., rocuronium), as they only mask motor manifestations while allowing continued electrical seizure activity and brain injury 2
• Do not skip to third-line agents until benzodiazepines and at least one second-line agent have been tried 2
• Avoid delaying ketamine initiation beyond 8 days or after failure of 7+ drugs, as efficacy diminishes significantly 4
• Do not use infusion rates below 0.9 mg/kg/hour, as no responses were observed at lower rates 4

Guideline Context and Current Status

Ketamine is not specifically mentioned in current major guidelines from the American Academy of Pediatrics or American College of Emergency Physicians for super-refractory status epilepticus, though established third-line agents include midazolam, propofol, and pentobarbital. 1 However, the American College of Emergency Physicians does provide specific dosing recommendations for ketamine based on emerging evidence 1, and research supports its role as an effective alternative with unique advantages 5, 4

Mortality and Outcome Data

• Overall mortality rate in ketamine-treated RSE was 43% 4
• Mortality was significantly lower (16% vs. 56%, p=0.0047) when SE was controlled within 24 hours of ketamine initiation 4
• This emphasizes the importance of early intervention and rapid seizure control for improved outcomes

Concurrent Management

While administering any treatment for status epilepticus, simultaneously search for and treat underlying causes: hypoglycemia, hyponatremia, hypoxia, drug toxicity, CNS infection, ischemic stroke, intracerebral hemorrhage, and withdrawal syndromes. 2