Efficacy of Ketamine Infusion Compared With Traditional Anti-epileptic Agents in Refractory Status Epilepticus

Efficacy of Ketamine Infusion Compared With Traditional Anti-epileptic Agents in Refractory Status Epilepticus- a Pilot Study

The study will investigate the efficacy of the N-methyl-D-aspartate receptor antagonist ketamine as a first line agent in refractory status epilepticus versus traditional general anesthetic agents used for burst suppression that target the gamma-aminobutyric acid adrenergic receptors.

Study Overview

• Status: Withdrawn
• Conditions: Refractory Epilepsy
• Intervention / Treatment: Drug: Traditional Treatment (Group T); Drug: Ketamine Infusion (Group K)

Detailed Description

The traditional treatment for refractory status epilepticus includes diazepam, midazolam, valproic acid, thiopental and propofol. These medications fail to control seizure activity in 20-40% of patients. This is attributed to decrease in activity of gamma-aminobutyric acid receptors along with reciprocal up regulation of N-Methyl-D-aspartate receptors. Glutamate activation of N-methyl-D-aspartate receptors promotes calcium influx and excitotoxicity. Ketamine, an intravenous anesthetic agent which is a non-competitive antagonist of N-methyl-D-aspartate receptors can block the flow of Ca and Na and by combining with phencyclidine binding sites inside the ion channel of N-methyl-D-aspartate receptors, reduce the epileptiform burst discharges and after potential. Therefore, targeting the N-methyl-D-aspartate receptors with ketamine may provide a novel approach to control refractory seizures. Moreover, by blocking glutamate mediated N-methyl-D-aspartate receptor induced neurotoxicity, ketamine may render neuroprotection. Ketamine also provides additional advantage of hemodynamic stability. Currently, ketamine is used as a last resort drug in the treatment of refractory status epilepticus.

The specific aim is to determine whether continuous infusion of ketamine as a first line agent for refractory status epilepticus is effective in controlling seizures.

The central hypothesis of our proposal is that early treatment with ketamine will be much more efficacious in controlling refractory status compared to the traditional treatment.

• Study Type: Interventional
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • UAB Department of Anesthesiology and Perioperative Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 98 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients more than 18 years of age with a diagnosis of status epilepticus
• Considered for burst suppression therapy after failing 2 or 3 anti-epileptic medications

Exclusion Criteria:

• Post anoxic status epilepticus
• Pregnant women, as confirmed by urine, or blood human chorionic gonadotropin, ultrasound or physical exam
• Prisoners
• Age less than 18 years
• Allergy or sensitivity to the drug in question

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Traditional Treatment (Group T); Group T patients will be placed into burst suppression with the traditional drug infusions which include any single or combination of drugs; usually benzodiazepines, barbiturates and or propofol.	Drug: Traditional Treatment (Group T); Patients will receive traditional drug infusions; Other Names: benzodiazepines, barbiturates, propofol
Active Comparator: Ketamine Infusion (Group K); Patients in the group K arm will receive a loading dose of 2.5 mg/kg of ketamine followed by a continuous infusion with a starting dose of 3mg/kg/hr with titration in 1mg/kg/hr increments until burst suppression is achieved or a maximum dose of 10mg/kg/hr is reached. After 48 hours of burst suppression the ketamine dosage will be reduced by 2mg/kg/hr in a stepwise fashion to evaluated for EEG or clinical evidence of seizure recurrence.	Drug: Ketamine Infusion (Group K); Patients will receive loading dose of 2.5 mg/kg of ketamine followed by a continuous infusion with a starting dose of 3mg/kg/hr with titration in 1mg/kg/hr increments until burst suppression is achieved or a maximum dose of 10mg/kg/hr is reached; Other Names: Ketalar

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time taken for burst suppression	Average time for burst suppression	Baseline to 1 hr
Time taken for termination of seizures	Average time for seizures to terminate	Baseline to 24 hrs

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Use of vasopressors	The need of vasopressors	baseline to 72 hrs
Number of days on ventilator	Total number of days patient is on the ventilator	Baseline to 72 hrs
Length of stay in ICU	Total number of days in the ICU	Baseline to 72 hrs postoperatively
Use of parenteral or enteral nutrition	Nutrition provided through a feeding tube or catheter	Baseline to 72 hrs postoperatively
Medical imaging results	MRI scans 7 to 10 days after burst suppression	Post-op Day 2 to Post-op day 10
Mortality	death	baseline to post-op day 10

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Investigators: Principal Investigator: Vinodkumar Singh, MD, University of Alabama at Birmingham

Publications and helpful links

General Publications

• Rosati A, De Masi S, Guerrini R. Ketamine for Refractory Status Epilepticus: A Systematic Review. CNS Drugs. 2018 Nov;32(11):997-1009. doi: 10.1007/s40263-018-0569-6.

Study record dates

Study Major Dates

• Study Start (Actual): May 4, 2017
• Primary Completion (Actual): December 31, 2019
• Study Completion (Actual): May 18, 2021

Study Registration Dates

• First Submitted: April 10, 2017
• First Submitted That Met QC Criteria: April 10, 2017
• First Posted (Actual): April 14, 2017

Study Record Updates

• Last Update Posted (Actual): May 21, 2021
• Last Update Submitted That Met QC Criteria: May 18, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Ketamine; seizure; glutamate activation; N-Methyl D-Aspartate; gamma-aminobutyric acid receptor
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Epilepsy; Seizures; Drug Resistant Epilepsy; Status Epilepticus; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Hypnotics and Sedatives; Ketamine; Propofol
• Other Study ID Numbers: F151214004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes