Combined Ketamine and Midazolam for Generalized Convulsive Status Epilepticus

Generalized Convulsive Status Epilepticus Clinical Trial

— Ket-Mid  

Official title:

Efficacy of Combined Ketamine and Midazolam for Treatment of Generalized Convulsive Status Epilepticus in Children .

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05779657
• Other study ID #: Soh-Med-23-03-12MS
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: March 21, 2023
• Est. completion date: April 2, 2024

Study information

• Verified date: March 2023
• Source: Sohag University
• Contact: Esraa Abdelsamea Ahmed, MB.B.CH
• Phone: 01211740367
• Email: esraaabdelsamea[@]med.sohag.edu.eg
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 144
• Est. completion date: April 2, 2024
• Est. primary completion date: April 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 16 Years

Eligibility

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.

Related Conditions & MeSH terms

• Generalized Convulsive Status Epilepticus
• Status Epilepticus

Intervention

Drug:
• 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

Locations

Country	Name	City	State
Egypt	Sohag University Hospital	Sohag

Sponsors (1)

Lead Sponsor	Collaborator
Sohag University

Country where clinical trial is conducted

Egypt, 

References & Publications (10)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cessation of seizures at 5 minutes	Cessation of clinical seizures at 5 minutes study timepoint	5 minutes
Secondary	Need for repeating midazolam	Need for repeating midazolam during the first therapy phase	15 minutes
Secondary	Cessation of seizures at 15 minutes	Cessation of clinical seizures at 15 minutes study timepoint	15 minutes
Secondary	Cessation of seizures at 35 minutes	Cessation of clinical seizures at 35 minutes study timepoint	35 minutes
Secondary	Cessation of seizures at 55 minutes	Cessation of clinical seizures at 55 minutes study timepoint	55 minutes
Secondary	Seizure recurrence	Recurrence of clinical seizures after initial cessation in the first 24 hours	24 hours
Secondary	Hypotension	Occurrence of hypotension	24 hours
Secondary	Hypertension	Occurrence of hypertension	24 hours
Secondary	Intubation	Need for endotracheal intubation	24 hours
Secondary	Arrhythmia	Occurrence of Arrhythmia	24 hours
Secondary	Emergence phenomenon	Occurrence of emergence phenomenon, as one or more of the following: hallucination, delirium, vivid dreams, blurred/double vision, nausea/vomiting, hypersalivation.	24 hours
Secondary	Skin rash	Occurrence of skin rash	24 hours
Secondary	Mortality	Occurrence of death	24 hours