Ket-Mid: Combined Ketamine and Midazolam for Generalized Convulsive Status Epilepticus
Study Details
Study Description
Brief Summary
Generalized convulsive status epilepticus (GCSE) is a common neurological emergency in children. Benzodiazepines are the recommended first line antiseizure medication (ASMs), but they fail to control seizures in a third of cases. Combination of benzodiazepines with another ASM that has a different mechanism of action may be a promising option for faster control of 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.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 2/Phase 3 |
Detailed Description
Generalized convulsive status epilepticus (GCSE) is a common neurological emergency in children, which is associated with significant morbidity and mortality. This condition is defined as > 5 minutes of continuous or recurrent generalized tonic-clonic seizure activity without regaining consciousness. GCSE requires immediate evaluation and management in order to control ongoing seizures.
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Study group (Ket-Mid) Children receiving ketamine + midazolam |
Drug: Ketamine
Intravenous ketamine 2 mg/kg (max 60 mg) over 2 minutes (diluted with isotonic saline to 5 mg/ml concentration)
Other Names:
Drug: Midazolam
Intravenous midazolam 0.2 mg/kg (maximum 10 mg) over 2 minutes
|
Placebo Comparator: Control group (Pla-Mid) Children receiving placebo + midazolam |
Drug: Midazolam
Intravenous midazolam 0.2 mg/kg (maximum 10 mg) over 2 minutes
Drug: Placebo
Intravenous isotonic saline 0.4 ml/kg (max 12 ml) over 5 minutes
|
Outcome Measures
Primary Outcome Measures
- Cessation of seizures at 5 minutes [5 minutes]
Cessation of clinical seizures at 5 minutes study timepoint
Secondary Outcome Measures
- Need for repeating midazolam [15 minutes]
Need for repeating midazolam during the first therapy phase
- Cessation of seizures at 15 minutes [15 minutes]
Cessation of clinical seizures at 15 minutes study timepoint
- Cessation of seizures at 35 minutes [35 minutes]
Cessation of clinical seizures at 35 minutes study timepoint
- Cessation of seizures at 55 minutes [55 minutes]
Cessation of clinical seizures at 55 minutes study timepoint
- Seizure recurrence [24 hours]
Recurrence of clinical seizures after initial cessation in the first 24 hours
- Hypotension [24 hours]
Occurrence of hypotension
- Hypertension [24 hours]
Occurrence of hypertension
- Intubation [24 hours]
Need for endotracheal intubation
- Arrhythmia [24 hours]
Occurrence of Arrhythmia
- Emergence phenomenon [24 hours]
Occurrence of emergence phenomenon, as one or more of the following: hallucination, delirium, vivid dreams, blurred/double vision, nausea/vomiting, hypersalivation.
- Skin rash [24 hours]
Occurrence of skin rash
- Mortality [24 hours]
Occurrence of death
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Age from 6 month to 16 years.
-
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:
-
Failure to obtain informed consent.
-
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.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Sohag University Hospital | Sohag | Egypt | 82524 |
Sponsors and Collaborators
- Sohag University
Investigators
- Study Chair: Abdelrahim A Sadek, MD, PhD, Faculty of Medicine, Sohag University
Study Documents (Full-Text)
None provided.More Information
Publications
- 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 Feb 15. doi: 10.1111/epi.17550. Online ahead of print.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Soh-Med-23-03-12MS