Keywords
ketamine
NMDA receptors
epilepsy
neuroprotection
How to Cite
Abstract
Refractory status epilepticus remains one of the most challenging neurological emergencies in clinical practice, carrying high rates of morbidity and mortality and posing a significant risk of permanent neurological damage. Despite the widespread use of conventional antiepileptic drugs and anesthetic agents, a substantial proportion of patients fail to achieve adequate seizure control, highlighting the need for alternative therapeutic approaches that target different pathophysiological mechanisms. In this context, ketamine has gained increasing attention as a potential treatment option for refractory and superrefractory status epilepticus. The aim of this study was to review and synthesize the available evidence regarding the use of ketamine in the management of refractory status epilepticus, with particular focus on its mechanism of action, clinical effectiveness, and practical implications for neurological care. A systematic review of the literature was conducted, including studies that evaluated the administration of ketamine in adult patients with refractory or superrefractory status epilepticus. The selected studies comprised a variety of designs, including retrospective analyses, prospective registries, case series, and narrative reviews. The evidence indicates that ketamine has been associated with partial or complete seizure control in a considerable proportion of patients, especially when introduced early during the course of refractory status epilepticus. Its non-competitive antagonism of N-methyl-D-aspartate (NMDA) receptors allows modulation of sustained glutamatergic hyperexcitability, a key mechanism underlying seizure persistence when GABAergic therapies become less effective. In addition, ketamine demonstrated a favorable hemodynamic profile and a low incidence of severe adverse effects in critically ill neurological patients. Overall, the findings suggest that ketamine represents a valuable therapeutic option in refractory status epilepticus and support its consideration within individualized treatment strategies, while further prospective studies are needed to better define optimal dosing, timing, and patient selection.
References
1. Flórez J, Armijo JA, Mediavilla A, editors. Human Pharmacology. 6th ed. Barcelona: Elsevier; 2013.
2. Farreras P, Rozman C, editors. Internal Medicine. 16th ed. Barcelona: Elsevier; 2009.
3. Fauci AS, Kasper DL, Braunwald E, Hauser SL, Longo DL, Jameson JL, Loscalzo J, editors. Harrison’s Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008.
4. Cruz JM, Giraldo CE, Fernández EF, Tovar OE. Clinical indication and pharmacology of ketamine. [Place of publication and publisher not specified].
5. Godoy JF, Uribes R. Status epilepticus in adults. Rev Med Clin Condes. 2013;24(6):912-920.
6. Rodríguez García PL. Diagnosis and treatment of status epilepticus. Rev Cubana Neurol Neurocir. [Year, volume, and pages not specified].
7. Mion G. Ketamine. EMC Anesthesia-Resuscitation. 2012;38(1):1-12.
8. Hidalgo Downing E. Review of the recreational use of ketamine. [Academic work or article; editorial data not specified].
9. Fernández EI. Enantiomers: S(+) ketamine. Rev Argentina Anestesiol. 2002;60(2):85-92.
10. Díaz M, Rubio M, Espinosa D. Treatise on internal medicine. [Edition, place, and publisher not specified].
11. Caranzano L, Nový J, Rossetti AO. Ketamine in super-refractory status epilepticus in adults: efficacy analysis in a prospective registry. Rev Neurol. 2022;74(5):165-172.
12. Alkhachroum A, Der-Nigoghossian CA, Mathews E, Massad N, Letchinger R, Doyle K, et al. Ketamine to treat super-refractory status epilepticus. Neurology 2020;95:E2286–94. https://doi.org/10.1212/WNL.0000000000010611
13. Aurangzeb S, Prisco L, Adcock J, Speirs M, Raby S, Westbrook J, et al. New-onset super refractory status epilepticus: A case-series. Seizure 2020;75:174–84. https://doi.org/10.1016/j.seizure.2019.10.005.
14. Beuchat I, Rosenow F, Kellinghaus C, Trinka E, Unterberger I, Rüegg S, et al. Refractory Status Epilepticus: Risk Factors and Analysis of Intubation in the Multicenter SENSE Registry. Neurology 2022;99:E1824–34. https://doi.org/10.1212/WNL.0000000000201099.
15. Buratti S, Giacheri E, Palmieri A, Tibaldi J, Brisca G, Riva A, et al. Ketamine as advanced second-line treatment in benzodiazepine-refractory convulsive status epilepticus in children. Epilepsia 2023;64:797–810. https://doi.org/10.1111/epi.17550.
16. Caranzano L, Novy J, Rossetti AO. Ketamine in adult super-refractory status epilepticus: Efficacy analysis on a prospective registry. Acta Neurologica Scandinavica 2022;145:737–42. https://doi.org/10.1111/ane.13610.
17. Cornwall CD, Krøigård T, Skovbo JSS, Edemann-Callesen HE, Beier CP. Outcomes and Treatment Approaches for Super-Refractory Status Epilepticus: A Systematic Review and Meta-Analysis. JAMA Neurology 2023;80:959–68. https://doi.org/10.1001/jamaneurol.2023.2407.
18. Girardin M-L, Flamand T, Roignot O, Abi-Wardé M-T, Mutschler V, Voulleminot P, et al. Treatment of new onset refractory status epilepticus/febrile infection-related epilepsy syndrome with tocilizumab in a child and a young adult. Epilepsia 2023;64:e87–92. https://doi.org/10.1111/epi.17591.
19. Hanin A, Muscal E, Hirsch LJ. Second-line immunotherapy in new onset refractory status epilepticus. Epilepsia 2024;65:1203–23. https://doi.org/10.1111/epi.17933.
20. Kirmani BF, Au K, Ayari L, John M, Shetty P, DeLorenzo RJ. Super-refractory status epilepticus: Prognosis and recent advances in management. Aging and Disease 2021;12:1097–119. https://doi.org/10.14336/AD.2021.0302.
21. Koh S, Wirrell E, Vezzani A, Nabbout R, Muscal E, Kaliakatsos M, et al. Proposal to optimize evaluation and treatment of Febrile infection-related epilepsy syndrome (FIRES): A Report from FIRES workshop. Epilepsia Open 2021;6:62–72. https://doi.org/10.1002/epi4.12447.
22. Lumley L, Niquet J, Marrero-Rosado B, Schultz M, Rossetti F, de Araujo Furtado M, et al. Treatment of acetylcholinesterase inhibitor-induced seizures with polytherapy targeting GABA and glutamate receptors. Neuropharmacology 2021;185. https://doi.org/10.1016/j.neuropharm.2020.108444.
23. Marrero-Rosado B, de Araujo Furtado M, Kundrick ER, Walker KA, Stone MF, Schultz CR, et al. Ketamine as adjunct to midazolam treatment following soman-induced status epilepticus reduces seizure severity, epileptogenesis, and brain pathology in plasma carboxylesterase knockout mice. Epilepsy and Behavior 2020;111. https://doi.org/10.1016/j.yebeh.2020.107229.
24. Rosenow F, Weber J. S2k guidelines: status epilepticus in adulthood: Guidelines of the German Society for Neurology. Der Nervenarzt 2021;92:1002–30. https://doi.org/10.1007/s00115-020-01036-2.
25. Rubin DB, Angelini B, Shoukat M, Chu CJ, Zafar SF, Brandon Westover M, et al. Electrographic predictors of successful weaning from anesthetics in refractory status epilepticus. Brain 2020;143:1143–57. https://doi.org/10.1093/brain/awaa069.
26. Samanta D, Garrity L, Arya R. Refractory and Super-refractory Status Epilepticus. Indian Pediatrics 2020;57:239–53. https://doi.org/10.1007/s13312-020-1759-0.
27. Stetefeld HR, Schaal A, Scheibe F, Nichtweiß J, Lehmann F, Müller M, et al. Isoflurane in (Super-) Refractory Status Epilepticus: A Multicenter Evaluation. Neurocritical Care 2021;35:631–9. https://doi.org/10.1007/s12028-021-01250-z.
28. Vossler DG, Bainbridge JL, Boggs JG, Novotny EJ, Loddenkemper T, Faught E, et al. Treatment of Refractory Convulsive Status Epilepticus: A Comprehensive Review by the American Epilepsy Society Treatments Committee. Epilepsy Currents 2020;20:245–64. https://doi.org/10.1177/1535759720928269.
29. Gautam C, Mahajan S, Sharma J, Singh H, Singh J. Repurposing potential of ketamine: Opportunities and challenges. Indian Journal of Psychological Medicine 2020;42:22–9. https://doi.org/10.4103/IJPSYM.IJPSYM_228_19.
30. Jaafar F, Haddad L, Koleilat N, Sharara-Chami R, Shbarou R. Super refractory status epilepticus secondary to anti-GAD antibody encephalitis successfully treated with aggressive immunotherapy. Epilepsy and Behavior Reports 2020;14. https://doi.org/10.1016/j.ebr.2020.100396.
31. Niquet J, Lumley L, Baldwin R, Rossetti F, Suchomelová L, Naylor D, et al. Rational polytherapy in the treatment of cholinergic seizures. Neurobiology of Disease 2020;133. https://doi.org/10.1016/j.nbd.2019.104537.
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Copyright (c) 2023 Ahmad Rizky Pratama, Siti Nur Aisyah, Muhammad Fajar Hidayat (Author)