What is the recommended dose of ketamine (intravenous anesthetic) for a patient with refractory seizures and a history of epilepsy or other neurological conditions?

Ketamine Dosing for Refractory Status Epilepticus

For refractory status epilepticus that has failed benzodiazepines and at least one second-line agent, initiate ketamine with a loading dose of 1-3 mg/kg IV followed by continuous infusion starting at 0.9-2.1 mg/kg/hour (approximately 15-35 mcg/kg/min), titrating to seizure suppression under continuous EEG monitoring. 1, 2, 3

Treatment Algorithm and Positioning

Ketamine is recommended as a fourth-line agent for super-refractory status epilepticus after failure of:

• First-line: Benzodiazepines (lorazepam 4 mg IV) 1
• Second-line: One agent among valproate (20-30 mg/kg), levetiracetam (30 mg/kg), fosphenytoin (20 mg PE/kg), or phenobarbital (20 mg/kg) 1
• Third-line: Anesthetic agents (midazolam infusion, propofol, or pentobarbital) 1

Ketamine should be considered earlier in the treatment sequence (as early as third-line) when traditional anesthetic agents are contraindicated or when hemodynamic instability precludes their use. 2, 4

Specific Dosing Protocol

Loading Dose

• 1-3 mg/kg IV bolus over 60 seconds 5, 6
• The FDA label specifies 1-4.5 mg/kg for anesthetic induction, but 1-3 mg/kg is appropriate for seizure management based on animal-to-human conversion studies 5, 6
• Approximately 24% of patients in clinical practice receive an initial bolus (median 95 mg) 7

Continuous Infusion

• Initial rate: 0.9-2.1 mg/kg/hour (15-35 mcg/kg/min) 2, 3
• Most commonly initiated at 10 mcg/kg/min (0.6 mg/kg/hour) 4
• Titrate upward by 10 mcg/kg/min increments every 15 minutes based on EEG response 7, 4
• Maximum rates used clinically: 30-50 mcg/kg/min (1.8-3 mg/kg/hour) 7, 4
• Maximal daily doses reported: 1392-4200 mg 2

Duration

• Median infusion duration: 39-40 hours 7, 4
• Continue until seizure cessation, then maintain for 24-48 hours before tapering 1

Efficacy Data

Ketamine demonstrates 64% efficacy when used early in refractory status epilepticus (within 3 days), but efficacy drops to 32% when delayed beyond 8 days. 1, 3

Specific outcomes from clinical studies:

• 57% permanent seizure control in multicenter retrospective review 3
• 84% of patients achieved ≥50% seizure reduction at 24 hours 7
• 43% complete seizure cessation 7
• 71.4% response rate when used without intubation in carefully selected patients 4

No likely responses were observed when infusion rates were <0.9 mg/kg/hour, when introduced ≥8 days after SE onset, or after failure of ≥7 drugs. 3

Critical Timing Considerations

Early initiation is crucial for success. Responders were 80% more likely to have received ketamine ≥5 hours earlier than nonresponders. 4 The number of antiseizure medications tried before ketamine was associated with seizure cessation (OR 2.6,95% CI 0.9-6.9, p=0.05), suggesting earlier use may improve outcomes. 7

Unique Advantages Over Other Anesthetic Agents

Hemodynamic Profile

Ketamine improves hemodynamic stability rather than causing hypotension. 2 This contrasts sharply with other anesthetic agents:

• Midazolam: 30% hypotension risk 1
• Propofol: 42% hypotension risk 1
• Pentobarbital: 77% hypotension risk 1

85% of patients requiring vasopressors during early RSE treatment were successfully weaned from vasopressors during ketamine infusion. 2

Respiratory Profile

Ketamine does not suppress respiratory drive like other continuous infusion anesthetics, potentially avoiding intubation in 71.4% of carefully selected patients. 4, 6 This represents a major advantage, as propofol and pentobarbital require mechanical ventilation with mean durations of 4 and 14 days respectively. 1

Mechanistic Advantage

Ketamine acts on NMDA receptors, providing a mechanistically distinct approach from GABA-ergic agents (benzodiazepines, propofol, pentobarbital), which may explain its efficacy in benzodiazepine-refractory cases. 1, 6

Preparation and Administration

Dilution (per FDA label)

• Do NOT inject the 100 mg/mL concentration IV without dilution 5
• For loading dose: Dilute with equal volume of Sterile Water, Normal Saline, or D5W 5
• For infusion: Add 10 mL of 50 mg/mL vial (or 5 mL of 100 mg/mL vial) to 500 mL D5W or NS to create 1 mg/mL solution 5
• For fluid restriction: Add to 250 mL to create 2 mg/mL solution 5
• Use immediately after dilution 5

Administration Rate

• Loading dose: Administer slowly over 60 seconds to avoid respiratory depression and enhanced vasopressor response 5
• Continuous infusion: Use infusion pump with precise rate control 5

Essential Monitoring Requirements

Continuous Monitoring

• Continuous EEG monitoring to guide titration and detect nonconvulsive seizures 1, 7
• Continuous blood pressure monitoring (though hypotension is rare with ketamine) 1
• Continuous oxygen saturation monitoring 1
• Airway equipment must be immediately available despite lower respiratory depression risk 5, 4

EEG-Guided Titration

Titrate ketamine to achieve seizure suppression on EEG, not to burst suppression pattern required with barbiturates. 1 Continue EEG monitoring for at least 24-48 hours after complete ketamine discontinuation, as late seizure recurrence is common and often nonconvulsive. 1

Adverse Effects and Safety Profile

Common Adverse Effects

• Hypertension (SBP >180 mmHg): 39.3% of patients 4
• Hypotension (SBP <90 mmHg): 31.8% when ketamine used alone (significantly lower than other anesthetics) 4
• Neuropsychological manifestations during emergence (consider benzodiazepine co-administration) 5
• Increased salivation (consider antisialagogue prior to induction) 5

Serious Adverse Effects

No acute serious adverse effects were noted in the largest case series. 2 Ketamine was discontinued due to possible adverse events in only 5 of 58 patients (8.6%) in multicenter review. 3

Genitourinary pain has been reported with chronic ketamine use for off-label indications—consider cessation if genitourinary pain develops with other urinary symptoms. 5

Contraindications and Precautions

• Not recommended for patients who have not followed NPO guidelines due to vomiting/aspiration risk 5
• Use with caution in patients with depleted catecholamine reserves, as ketamine can suppress myocardial contractility in this setting 8
• Higher risk of delirium compared to dexmedetomidine (though lower than benzodiazepines) 8

Concurrent Therapy Considerations

Loading Long-Acting Anticonvulsants

Load with phenytoin/fosphenytoin, valproate, levetiracetam, or phenobarbital during ketamine infusion to ensure adequate levels before tapering. 1 This prevents seizure recurrence when ketamine is discontinued.

Drug Interactions

Concurrent propofol infusions were inversely associated with seizure cessation (OR 0.02,95% CI 0.001-0.43, p=0.01), suggesting propofol may antagonize ketamine's efficacy. 7 Consider discontinuing propofol when initiating ketamine if hemodynamically tolerated.

Patient Selection for Non-Intubated Ketamine Use

Ketamine can be safely used without intubation in carefully selected patients with refractory seizures, achieving 71.4% response rate. 4 Selection criteria should include:

• Adequate baseline respiratory function
• Ability to protect airway (intact gag reflex)
• Hemodynamic stability
• Immediate availability of intubation equipment and personnel
• Continuous monitoring capability

Six of eight nonresponders (75%) ultimately required intubation and additional anesthetic agents, so have a low threshold to intubate if seizures persist. 4

Outcomes and Prognosis

Mortality was significantly lower (16% vs 56%, p=0.0047) when status epilepticus was controlled within 24 hours of ketamine initiation, emphasizing the importance of early aggressive treatment. 3

Overall mortality in refractory status epilepticus treated with ketamine was 43%, but this reflects the severity of underlying conditions rather than ketamine toxicity. 3

Common Pitfalls to Avoid

1. Starting ketamine too late: Efficacy drops dramatically after 8 days or failure of ≥7 drugs 3
2. Using inadequate infusion rates: No responses observed at <0.9 mg/kg/hour 3
3. Injecting 100 mg/mL concentration IV without dilution: This is explicitly contraindicated 5
4. Failing to load long-acting anticonvulsants: Seizures will recur when ketamine is tapered 1
5. Continuing propofol concurrently: May antagonize ketamine efficacy 7
6. Inadequate EEG monitoring: Nonconvulsive seizures occur in >50% of cases and are only detectable by EEG 1
7. Premature discontinuation of EEG: Continue for 24-48 hours after ketamine stopped 1