What is the recommended treatment for a patient with a history of epilepsy experiencing refractory status epilepticus, who has not responded to benzodiazepines and second-line agents?

Ketamine for Refractory Status Epilepticus

Ketamine should be used as a fourth-line anesthetic agent for super-refractory status epilepticus after failure of benzodiazepines, second-line anticonvulsants (valproate, levetiracetam, or fosphenytoin), and third-line GABA-ergic anesthetics (midazolam, propofol, or pentobarbital). 1

Treatment Algorithm for Status Epilepticus

First-Line Treatment (0-5 minutes)

• Administer IV lorazepam 4 mg at 2 mg/min immediately, with 65% efficacy in terminating status epilepticus 1
• Check fingerstick glucose and correct hypoglycemia simultaneously 1

Second-Line Treatment (5-20 minutes after benzodiazepines)

• Valproate 20-30 mg/kg IV over 5-20 minutes demonstrates 88% efficacy with 0% hypotension risk 1, 2
• Levetiracetam 30 mg/kg IV over 5 minutes shows 68-73% efficacy with minimal cardiovascular effects 1, 2
• Fosphenytoin 20 mg PE/kg IV at maximum 50 mg/min has 84% efficacy but 12% hypotension risk requiring cardiac monitoring 1, 2

Third-Line Treatment for Refractory Status Epilepticus (After 20+ minutes)

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

Ketamine as Fourth-Line Therapy

When to Consider Ketamine

• Ketamine is recommended for super-refractory status epilepticus when seizures persist despite benzodiazepines, one second-line agent, and at least one third-line anesthetic agent 1, 4
• Ketamine provides a mechanistically distinct approach through NMDA receptor blockade, complementing GABA-ergic agents 1

Efficacy and Timing

• Early administration is critical: Ketamine demonstrates 64% efficacy when administered within 3 days of refractory status epilepticus onset 1, 5
• Delayed administration reduces efficacy: Efficacy drops dramatically to 32% when ketamine is delayed to mean 26.5 days 1, 5
• In a retrospective series of 11 patients, ketamine successfully terminated refractory status epilepticus in 100% of cases, with seizure cessation occurring within 4-28 days (mean 9.8 days) 6

Dosing Protocol

• Loading and maintenance: 0.45-2.1 mg/kg/hour continuous infusion based on clinical response 1, 6
• Maximal daily doses: Range from 1392-4200 mg depending on patient response 1, 6
• Titrate to achieve seizure suppression on continuous EEG monitoring 1

Advantages Over Traditional Anesthetics

• Hemodynamic stability: Ketamine improves hemodynamic parameters, with 85% of patients able to be weaned from vasopressors during ketamine infusion 6
• Avoids intubation in select cases: In refractory non-convulsive status epilepticus, ketamine avoided endotracheal intubation in 55% of cases when used as the first anesthetic agent 7
• No respiratory depression: Unlike GABA-ergic anesthetics, ketamine does not cause significant cardiorespiratory depression 8, 7

Critical Monitoring Requirements

• Continuous EEG monitoring is mandatory throughout ketamine infusion and for 24-48 hours after discontinuation 1
• Continuous blood pressure monitoring is essential 1
• Prepare for mechanical ventilation despite lower respiratory depression risk, as most patients with super-refractory status epilepticus require airway protection 1

Safety Profile and Adverse Effects

• Common adverse effects: Hypersalivation and pneumonia are most frequently reported 7
• Cardiovascular effects: Monitor for elevated blood pressure and heart rate; use caution in patients with depleted catecholamine reserves as ketamine can suppress myocardial contractility 8, 1
• Psychiatric effects: Higher risk of delirium compared to dexmedetomidine, with adverse psychiatric events potentially persisting days to weeks after exposure 8
• Contraindications: Avoid in patients with elevated intracranial pressure concerns, though ketamine can decrease cerebrospinal fluid pressure when combined with hypocarbia 3

Important Caveats

Do Not Skip Treatment Steps

• Never bypass second-line agents (valproate, levetiracetam, fosphenytoin) to jump directly to ketamine 1
• Never bypass third-line anesthetics (midazolam, propofol, pentobarbital) before considering ketamine 1

Simultaneous Actions Required

• Search for and treat underlying causes including hypoglycemia, hyponatremia, hypoxia, drug toxicity, CNS infection, stroke, and withdrawal syndromes throughout treatment 1, 2
• Load with long-acting anticonvulsants (phenytoin, valproate, levetiracetam, or phenobarbital) during ketamine infusion to ensure adequate levels before tapering 1

Emerging Evidence

• Increasing support for earlier use: There is growing evidence supporting ketamine not only in stage 3 status epilepticus but potentially as a second-line treatment option, though this is not yet standard practice 4
• Pediatric considerations: Ketamine has been used successfully in pediatric refractory status epilepticus, including a 9-month-old who achieved seizure cessation after ketamine 1 mg/kg IV when other agents failed 9