Combined Ketamine and Midazolam for Generalized Convulsive Status Epilepticus
NCT ID: NCT05779657
Last Updated: 2024-10-29
Study Results
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Basic Information
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COMPLETED
PHASE2/PHASE3
144 participants
INTERVENTIONAL
2023-03-21
2024-08-30
Brief Summary
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Detailed Description
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According to most guidelines, benzodiazepines are the recommended first line antiseizure medication (ASMs). Second-line ASMs for benzodiazepines-refractory GCSE include multiple options, such as fosphenytoin/phenytoin, valproic acid, or levetiracetam. Last, refractory GCSE requires treatment with third-line ASMs, such as another second-line ASMs or infusion with thiopental, midazolam, pentobarbital, propofol, or ketamine.
However, about 35% of cases with GCSE are not controlled by benzodiazepines, and up to 40% of benzodiazepines-refractory GCSE don't respond to second-line ASMs. As GCSE persists for a longer time, it becomes more difficult to control with worse prognosis. Indeed, the effectiveness of benzodiazepines to control seizures decreases by 50% when given after 10-15 minutes of continuous seizures. Therefore, new ASMs or combinations are required for earlier control of seizures, which will contribute to better outcome. Combination of benzodiazepines with another ASM that has a different mechanism of action may be a promising option for faster control of GCSE. One of the potential drugs for such combination is ketamine.
Several adult and pediatric studies have shown effectiveness of ketamine in refractory and super-refractory GCSE. Unlike benzodiazepines that act through inhibitory Gamma-aminobutyric acid (GABA), ketamine is a non-competitive antagonist for N- methyl- d- aspartate (NMDA) receptors, which mediates excitatory glutamate action. Continuous seizure activity is associated with internalization of GABA receptors and upregulation of NMDA receptors.
A number of animal studies have demonstrated synergistic action of combined ketamine and benzodiazepines for status epilepticus. While combined ketamine and benzodiazepines have been used in pediatric sedation/analgesia, there are limited studies on such combination for children with GCSE.
In this study, the investigators aim to evaluate the efficacy and safety of ketamine plus midazolam versus midazolam alone as first-line therapy of pediatric GCSE.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
Study group (Ket-Mid): will receive intravenous ketamine 2 mg/kg (max 60 mg) over 2 minutes.
Control group (Pla-Mid): will receive intravenous isotonic saline (as a placebo) in the same way.
At the same time, both groups will receive intravenous midazolam 0.2 mg/kg (maximum 10 mg) over 2 minutes.
TREATMENT
QUADRUPLE
Study Groups
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Study group (Ket-Mid)
Children receiving ketamine + midazolam
Ketamine
Intravenous ketamine 2 mg/kg (max 60 mg) over 2 minutes (diluted with isotonic saline to 5 mg/ml concentration)
Midazolam
Intravenous midazolam 0.2 mg/kg (maximum 10 mg) over 2 minutes
Control group (Pla-Mid)
Children receiving placebo + midazolam
Midazolam
Intravenous midazolam 0.2 mg/kg (maximum 10 mg) over 2 minutes
Placebo
Intravenous isotonic saline 0.4 ml/kg (max 12 ml) over 5 minutes
Interventions
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Ketamine
Intravenous ketamine 2 mg/kg (max 60 mg) over 2 minutes (diluted with isotonic saline to 5 mg/ml concentration)
Midazolam
Intravenous midazolam 0.2 mg/kg (maximum 10 mg) over 2 minutes
Placebo
Intravenous isotonic saline 0.4 ml/kg (max 12 ml) over 5 minutes
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Generalized convulsive status epilepticus, defined as \> 5 minutes of clinically observed continuous or recurrent generalized, tonic-clonic seizure activity without regaining of consciousness.
Exclusion Criteria
* Previous treatment with any antiseizure medication for the presenting seizure episode.
* Hypertension
* Alcohol intake
* Conditions associated with increased intracranial pressure (e.g., central nervous system mass lesions, hydrocephalus)
* Glaucoma
* Known allergy or contraindications to any of the study drugs.
* End-stage kidney disease.
* End stage liver disease
* Arrhythmia, severe heart disease, or pulmonary hypertension.
* Hyperthyroidism
* Pheochromocytoma
* Hypoglycemia or hyperglycemia.
* Inborn errors of metabolism.
* Known or suspected psychiatric disorder.
* Failure to obtain intravenous access in the first 5 minutes of stabilization phase.
* Cessation of seizures during the stabilization phase (0 - 5 minutes).
* Traumatic brain injury.
6 Months
16 Years
ALL
No
Sponsors
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Sohag University
OTHER
Responsible Party
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Esraa Abdelsamee Ahmed
Principal Investigator
Principal Investigators
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Abdelrahim A Sadek, MD, PhD
Role: STUDY_CHAIR
Faculty of Medicine, Sohag University
Locations
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Sohag University Hospital
Sohag, , Egypt
Countries
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References
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Trinka E, Cock H, Hesdorffer D, Rossetti AO, Scheffer IE, Shinnar S, Shorvon S, Lowenstein DH. A definition and classification of status epilepticus--Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia. 2015 Oct;56(10):1515-23. doi: 10.1111/epi.13121. Epub 2015 Sep 4.
Singh A, Stredny CM, Loddenkemper T. Pharmacotherapy for Pediatric Convulsive Status Epilepticus. CNS Drugs. 2020 Jan;34(1):47-63. doi: 10.1007/s40263-019-00690-8.
Glauser T, Shinnar S, Gloss D, Alldredge B, Arya R, Bainbridge J, Bare M, Bleck T, Dodson WE, Garrity L, Jagoda A, Lowenstein D, Pellock J, Riviello J, Sloan E, Treiman DM. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016 Jan-Feb;16(1):48-61. doi: 10.5698/1535-7597-16.1.48.
Naylor DE. Treating acute seizures with benzodiazepines: does seizure duration matter? Epileptic Disord. 2014 Oct;16 Spec No 1:S69-83. doi: 10.1684/epd.2014.0691.
Rosati A, L'Erario M, Ilvento L, Cecchi C, Pisano T, Mirabile L, Guerrini R. Efficacy and safety of ketamine in refractory status epilepticus in children. Neurology. 2012 Dec 11;79(24):2355-8. doi: 10.1212/WNL.0b013e318278b685. Epub 2012 Nov 28.
Gaspard N, Foreman B, Judd LM, Brenton JN, Nathan BR, McCoy BM, Al-Otaibi A, Kilbride R, Fernandez IS, Mendoza L, Samuel S, Zakaria A, Kalamangalam GP, Legros B, Szaflarski JP, Loddenkemper T, Hahn CD, Goodkin HP, Claassen J, Hirsch LJ, Laroche SM. Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study. Epilepsia. 2013 Aug;54(8):1498-503. doi: 10.1111/epi.12247. Epub 2013 Jun 12.
Niquet J, Baldwin R, Norman K, Suchomelova L, Lumley L, Wasterlain CG. Midazolam-ketamine dual therapy stops cholinergic status epilepticus and reduces Morris water maze deficits. Epilepsia. 2016 Sep;57(9):1406-15. doi: 10.1111/epi.13480. Epub 2016 Aug 8.
Martin BS, Kapur J. A combination of ketamine and diazepam synergistically controls refractory status epilepticus induced by cholinergic stimulation. Epilepsia. 2008 Feb;49(2):248-55. doi: 10.1111/j.1528-1167.2007.01384.x. Epub 2007 Oct 15.
Buratti S, Giacheri E, Palmieri A, Tibaldi J, Brisca G, Riva A, Striano P, Mancardi MM, Nobili L, Moscatelli A. Ketamine as advanced second-line treatment in benzodiazepine-refractory convulsive status epilepticus in children. Epilepsia. 2023 Apr;64(4):797-810. doi: 10.1111/epi.17550. Epub 2023 Mar 2.
Sidharth, Sharma S, Jain P, Mathur SB, Malhotra RK, Kumar V. Status Epilepticus in Pediatric patients Severity Score (STEPSS): A clinical score to predict the outcome of status epilepticus in children- a prospective cohort study. Seizure. 2019 Oct;71:328-332. doi: 10.1016/j.seizure.2019.09.005. Epub 2019 Sep 11.
Other Identifiers
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Soh-Med-23-03-12MS
Identifier Type: -
Identifier Source: org_study_id
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