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Introduction

Status epilepticus (SE)* is characterized by:

>=5 minutes of continuous clinical and/or electrographic seizure, OR

Recurrent seizure activity without recovery to baseline between seizures.

Thirty-day mortality in convulsive SE is 19 to 27%, while non-convulsive SE rates reach 65%.

In one study, patients with treated and resolved SE within 10 hours had 10% mortality compared to 85% mortality in those treated within 20 hours. Remember…. Time is brain!

Definitive SE control should be established within 60 minutes of onset.

*Definitions:

Refractory SE: status epilepticus that continues despite adequate doses of initial benzodiazepines followed by a second acceptable antiepileptic drug

Super-Refractory SE: status epilepticus that continues or recurs >=24 h after the onset of anesthetic therapy, including cases where SE recurs on the reduction or withdrawal of anesthesia

Clinical Detail

Ketamine is a noncompetitive NMDA receptor antagonist. Because NMDA-receptor activity increases as status epilepticus persists, ketamine targets a pathway distinct from the GABAergic agents (benzodiazepines, propofol, midazolam) that lose efficacy over time.

ParameterDetail
Rationale (what happens in SE)GABA (inhibitory) receptors are internalized after ∼1 hour, while NMDA (excitatory) receptors accumulate in the postsynaptic membrane. Consequences: pharmaco-resistance to GABAergic drugs (e.g., benzodiazepines), and NMDA-receptor–driven neuronal excitability → increased epileptiform activity & neuronal death.
Mechanism of actionNoncompetitive NMDA receptor antagonist.
Loading dose1.5 mg/kg (0.5 to 3 mg/kg) slow IV push. Administer over 1 minute or at a rate of 0.5 mg/kg/minute. Repeat 0.5 mg/kg loading dose every 3 to 5 minutes as needed for electrographic/burst suppression, followed by continuous infusion.
Maintenance dose0.3 to 4 mg/kg/h. Titrate as needed for electrographic/burst suppression (usually ≥2 mg/kg/h). Max: 10 mg/kg/h.
PK/PDOnset: within 30 seconds. Metabolism: hepatic (norketamine metabolite 33% as potent as ketamine). Elimination: urine (91% as metabolites). Half-life: 2 to 3 h. Duration: 5 to 10 minutes (recovery 1 to 2 h).
Adverse effectsEmergence reactions – vivid dreams, hallucinations, and/or delirium. Sympathomimetic effect – hypertension, tachycardia, ischemia. Airway complications – increased salivary & tracheobronchial secretions, laryngospasm (0.3%).

Evidence

The evidence base for ketamine in refractory and super-refractory status epilepticus is limited to retrospective studies and case series, summarized below.

Author, YearDesignPurposeOutcome
Alkhachroum, 2020Retrospective study (n=68)IV ketamine in super-refractory SEAverage ketamine dose 2.2 mg/kg/h for 2 days. Associated with ≥50% reduction in seizure burden within 24 h of starting ketamine in 81% of patients; complete cessation of seizures in 63% of patients. Limitation: midazolam 1 mg/kg/h was started 0.4 days before ketamine, possibly confounding the effects of ketamine.
Höfler, 2016Retrospective study (n=42)IV ketamine in super-refractory SEAverage ketamine dose 2.39 mg/kg/h for 4 days. Ketamine was the last drug administered before SE cessation in 64% (27/42) of patients. No adverse effects. Limitation: only 17% of patients received a loading dose.
Sabharwal, 2015Retrospective study (n=67)IV ketamine in super-refractory SEKetamine ranged from 1.5 to 10.5 mg/kg/h. SE was controlled in 91% (61/67) of patients. Ketamine was used in the early phase, within 24–48 h. Infusion duration was 3.6 days, 5.97 days, and 6.5 days for propofol-ketamine, ketamine, and propofol, respectively.
Gaspard, 2013Retrospective study (n=60)IV ketamine in refractory SEAverage load of 1.5 mg/kg, followed by 2.75 mg/kg/h. Likely responsible for SE control in 12% (7/60) of cases, and possibly responsible in 20% (12/20) of cases. Likely response to ketamine if administered within 12 h.
Synowiec, 2013Retrospective study (n=11)IV ketamine in refractory SEAverage load of 2 mg/kg, followed by 1.3 mg/kg/h. In 45% of cases all co-infusions were weaned within 24 h; in 27% of cases all co-infusions were discontinued within 72 h. Refractory SE was terminated in all 11 patients. No adverse effects. Limitation: ketamine administered at sub-anesthetic doses.

Conclusions

Ketamine offers advantages over other anesthetics, as it targets a different pathway and has shown to have more favorable hemodynamic effects.

Ketamine is most effective when a loading dose is administered and a continuous infusion is provided at anesthetic doses of at least 2 mg/kg/hour.

Studies on ketamine for status epilepticus are confounded by many methodological limitations.

There is still debate regarding ketamine’s place in therapy in SE. However, there are trends to starting ketamine earlier in combination with other anesthetics like propofol or midazolam.

References

Alkhachroum A, Der-Nigoghossian CA, Mathews E, et al. Neurology. 2020;95(16):e2286-e2294.

Brophy GM, Bell R, Claassen J, et al. Neurocritical Care Society Status Epilepticus Guideline Writing Committee. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012 Aug;17(1):3-23.

Gaínza-Lein M, Fernández IS, Ulate-Campos A, Loddenkemper T, Ostendorf AP. Seizure. 2019 May;68:22-30.

Gaspard N, Foreman B, Judd LM, Brenton JN, et al. Epilepsia. 2013;54(8):1498-503.

Höfler J, Rohracher A, Kalss G, et al. CNS Drugs. 2016;30(9):869-876.

Legriel S, Oddo M, Brophy GM. Intensive Care Med. 2017;43(4):543-546.

Sabharwal V, Ramsay E, Martinez R, et al. Epilepsy Behav. 2015;52(Pt A):264-6.

Synowiec AS, Singh DS, Yenugadhati V, Valeriano JP, Schramke CJ, Kelly KM. Epilepsy Res. 2013;105(1-2):183-8.

Tags: ketamine status epilepticus GABA NMDA

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