- 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.
|Rationale||What happens during SE? |
GABA (inhibitory) receptors are internalized after ~1 hour NMDA (excitatory) receptors accumulate in the postsynaptic membrane
What are the consequences?
Pharmaco-resistance to GABAergic drugs, such as benzodiazepines NMDA receptors facilitate neuronal excitability = increased eptileptiform activity & neuronal death
|Mechanism of Action||Noncompetitive NMDA receptor antagonist|
|Dosing & Administration||Loading Dose: 1.5 mg/kg (0.5 to 3 mg/kg) |
slow IV push Administer over 1 minute or 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 Dose: 0.3 to 4 mg/kg/h
Titrate as needed for electrographic/burst suppression (usually ≥2 mg/kg/h)
Max: 10 mg/kg/h
|Formulations||Standard concentration: 500 mg in 250 mL NS; 1,000 mg in 500 mL NS |
Double concentration: 1,000 mg in 250 mL NS; 2,000 mg in 500 mL of NS
|PK/PD||Onset: 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 Effects||Emergence reactions – vivid dreams, hallucinations, and/or delirium|
Sympathomimetic effect – hypertension, tachycardia, ischemia
Airway complications – increased salivary & tracheobronchial secretions, laryngospasm (0.3%)
- 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
Review of Evidence
|Alkhachroum 2020||Retrospective study (n=68)||IV ketamine in super-refractory SE|| -Average dose of ketamine 2.2 mg/kg/h for 2 days |
-Associated with increased seizure burden by ≥ 50% within 24 h of starting ketamine in 81% of patients
-Associated with complete cessation of seizures in 63% of patients
-Limitation: midazolam 1 mg/kg/h was started 0.4 days before ketamine possibly confounding effects of ketamine
|Höfler 2016||Retrospective study (n=42)||IV ketamine in super-refractory SE|| -Average dose of ketamine 2.39 mg/kg/h for 4 days |
–Ketamine last drug administered in 64% (27/42) of patients before SE cessation –No adverse effects
-Limitation: only 17% of patients received a loading dose
|Sabharwal 2015||Retrospective study (n=67)||IV ketamine in super-refractory SE|| -Ketamine 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 2013||Retrospective study (n=60)||IV ketamine in refractory SE|| -Average load with1.5 mg/kg, followed by 2.75mg/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 2013||Retrospective study (n=11)||IV ketamine in refractory SE|| -Average load with 2 mg/kg, followed by 1.3 mg/kg/h |
–45% of cases all co-infusions were weaned within 24 h –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
- 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.
- 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.