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

October 27, 2024 updated by: Esraa Abdelsamee Ahmed, Sohag University

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

144

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Egypt
      • Sohag, Egypt, 82524
        • Sohag University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

6 months to 16 years (Child)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Study group (Ket-Mid)
Children receiving ketamine + midazolam
Drug: Midazolam
Intravenous midazolam 0.2 mg/kg (maximum 10 mg) over 2 minutes
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
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cessation of seizures at 5 minutes
Time Frame: 5 minutes
Cessation of clinical seizures at 5 minutes study timepoint
5 minutes

Secondary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sohag University

Investigators

  • Study Chair: Abdelrahim A Sadek, MD, PhD, Faculty of Medicine, Sohag University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 21, 2023

Primary Completion (Actual)

August 26, 2024

Study Completion (Actual)

August 30, 2024

Study Registration Dates

First Submitted

March 9, 2023

First Submitted That Met QC Criteria

March 9, 2023

First Posted (Actual)

March 22, 2023

Study Record Updates

Last Update Posted (Actual)

October 29, 2024

Last Update Submitted That Met QC Criteria

October 27, 2024

Last Verified

October 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Soh-Med-23-03-12MS

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Unidentified individual patients' data will be available upon reasonable request after publication

IPD Sharing Time Frame

After publication and for 3 years

IPD Sharing Access Criteria

Contact the principal investigator

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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