Ket-Mid: Combined Ketamine and Midazolam for Generalized Convulsive Status Epilepticus

Sponsor

Sohag University (Other)

Overall Status

Recruiting

CT.gov ID

NCT05779657

Collaborator

(none)

144

Enrollment

Location

Arms

12.4

Anticipated Duration (Months)

11.6

Patients Per Site Per Month

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
Generalized Convulsive Status Epilepticus	Drug: Ketamine Drug: Midazolam Drug: Placebo	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

Study Type:

Interventional

Anticipated Enrollment :

144 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Two groups of children with continuing seizures after stabilization phase (5 minutes) 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.Two groups of children with continuing seizures after stabilization phase (5 minutes) 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.

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Enrolled children will be equally randomized into study and control group using computer generated numbers, which will be sealed into sequentially numbered opaque envelopes by a person not belonging to the research team. For each enrolled participant, the envelope in order will be opened, and the assigned study drug will be used. A pharmacist will fill the active and placebo preparations in similar containers with sealed code for identification. Participants' families, treating clinicians, and investigators will be unaware of group assignment and drug/placebo therapy.

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Mar 21, 2023

Anticipated Primary Completion Date :

Apr 1, 2024

Anticipated Study Completion Date :

Apr 2, 2024

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: Ketalar 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

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:

Ketalar

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

Ages Eligible for Study:

6 Months to 16 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.