What is the recommended ketamine dosing protocol (loading dose and infusion rates) for refractory or super‑refractory status epilepticus in adults and children?

Ketamine Dosing in Status Epilepticus

Positioning in Treatment Algorithm

Ketamine is recommended as a fourth-line agent for super-refractory status epilepticus after failure of benzodiazepines, second-line anticonvulsants (valproate, levetiracetam, fosphenytoin, or phenobarbital), and third-line anesthetic agents (midazolam, propofol, or pentobarbital). 1

The American Academy of Neurology and other guideline societies position ketamine specifically for super-refractory cases, with evidence showing 64% efficacy when administered early in refractory status epilepticus (within 3 days), but efficacy drops dramatically to 32% when delayed to a mean of 26.5 days. 1, 2

Dosing Protocol

Loading Dose

• No specific loading dose is established in current guidelines; most protocols initiate continuous infusion directly. 1, 3

Continuous Infusion Rates

Adult Dosing:

• Initial rate: 0.45–1.0 mg/kg/hour 3
• Titration: Increase by 0.5–1.0 mg/kg/hour increments based on clinical response and EEG monitoring 3
• Maximum reported rates: 2.1 mg/kg/hour 3
• Maximal daily doses: 1392–4200 mg depending on patient weight and clinical response 3

Pediatric Dosing:

• Initial rate: 1 mg/kg/hour 4
• Titration: Up to 6 mg/kg/hour has been safely used in young infants 4
• Alternative bolus dosing: 1–3 mg/kg IV has been proposed based on animal-to-human conversion studies, though this is investigational 5

Clinical Evidence and Efficacy

The strongest clinical evidence comes from a retrospective case series showing 100% seizure termination in 11 patients with refractory status epilepticus treated with ketamine infusion. 3 Time from ketamine initiation to seizure cessation ranged from 4 to 28 days (mean 9.8 days), with 7 of 11 patients (64%) achieving seizure control within one week. 3

A systematic review of 248 individuals (including 29 children) demonstrated that timing is critical: early ketamine administration (within 3 days of refractory status epilepticus onset) achieved 64% efficacy, while delayed administration (mean 26.5 days) dropped to 32% efficacy. 2

Monitoring Requirements

• Continuous EEG monitoring is mandatory to guide titration and detect ongoing electrical seizure activity 1
• Continuous blood pressure monitoring is essential, though ketamine uniquely improves hemodynamic stability compared to other anesthetic agents 3
• Mechanical ventilation preparation should be available, though ketamine does not suppress respiration like GABA-ergic agents 5

Unique Advantages Over Standard Anesthetic Agents

Hemodynamic Stability:

• Ketamine was associated with improved hemodynamic stability in all reported cases 3
• 6 of 7 patients (85%) requiring vasopressors during early refractory status epilepticus treatment were successfully weaned from vasopressors during ketamine infusion 3
• This contrasts sharply with pentobarbital (77% hypotension risk), propofol (42% hypotension risk), and midazolam (30% hypotension risk) 1

Mechanistic Advantage:

• Ketamine acts on NMDA receptors, providing a mechanistically distinct approach from GABA-ergic agents (benzodiazepines, barbiturates, propofol) 1
• This is critical because prolonged status epilepticus causes GABA receptor internalization and NMDA receptor upregulation, making GABA-ergic agents progressively less effective 6, 5

Respiratory Safety:

• Ketamine does not suppress respiration when used for sedation and anesthesia, unlike all other anesthetic agents used in status epilepticus 5
• 12 individuals (10 children) were successfully treated without requiring endotracheal intubation, seven of whom received oral ketamine for non-convulsive status epilepticus 2

Pediatric Considerations

Ketamine has been successfully used in young infants with refractory and super-refractory status epilepticus. 4 In a case series of three young infants, ketamine was initiated at 1 mg/kg/hour with one patient requiring titration to 6 mg/kg/hour. 4 All cases tolerated ketamine well, particularly in the setting of hemodynamic instability, and concomitant ketamine use allowed reduction in benzodiazepine infusion rates. 4

Critical Pitfalls and Practical Considerations

Timing is Everything:

• Do not delay ketamine initiation in super-refractory status epilepticus—efficacy drops by 50% when delayed beyond 3 days 2
• Ketamine should be considered before prolonged courses of barbiturates that require 14 days of mechanical ventilation versus 4 days with propofol 1

Dosing Heterogeneity:

• Ketamine doses in published literature are extremely heterogeneous and do not appear to be an independent prognostic factor 2
• Titrate based on EEG response and clinical seizure cessation, not arbitrary dose limits 3

Combination Therapy:

• Ketamine is used as an adjunctive agent in conjunction with other antiseizure medications, not as monotherapy 4, 3
• Ensure adequate loading of long-acting anticonvulsants (phenytoin/fosphenytoin, valproate, levetiracetam, or phenobarbital) before tapering ketamine 1

Contraindications:

• Use ketamine with caution in patients with depleted catecholamine reserves, as it can suppress myocardial contractility in this setting 1
• Ketamine has a higher risk of delirium compared to dexmedetomidine (though lower than benzodiazepines) 1

Evidence Limitations

Current evidence is limited to case reports and case series; no randomized controlled trials have been completed. 2 The strongest available evidence comes from retrospective case series showing consistent efficacy and safety, but methodological limitations prevent firm conclusions. 2, 3 Two ongoing clinical trials (NCT02431663 and NCT03115489) may provide higher-quality evidence in the future. 2