Ketamine for Refractory Status Epilepticus

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

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.

Pharmacology of Ketamine | Pharmacology of Ketamine

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 = 🡹 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

GHS 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%)

Evidence

Author, Year | Design | Purpose | Outcome

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 🡻 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

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.