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

• ClinicalTrials.gov Identifier: NCT03115489
• Recruitment Status: Recruiting
• First Posted: April 14, 2017
• Last Update Posted: August 14, 2019
• Sponsor: University of Alabama at Birmingham
• Information provided by (Responsible Party): Vinodkumar Singh, University of Alabama at Birmingham

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Refractory Epilepsy	Drug: Traditional Treatment (Group T); Drug: Ketamine Infusion (Group K)	Phase 2; Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Prevention
• Official Title: Efficacy of Ketamine Infusion Compared With Traditional Anti-epileptic Agents in Refractory Status Epilepticus- a Pilot Study
• Actual Study Start Date: May 4, 2017
• Estimated Primary Completion Date: December 2019
• Estimated Study Completion Date: December 2020

Arms and Interventions

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 Name: 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 Name: Ketalar

Outcome Measures

Primary Outcome Measures :

1. Time taken for burst suppression [ Time Frame: Baseline to 1 hr ]
   Average time for burst suppression
2. Time taken for termination of seizures [ Time Frame: Baseline to 24 hrs ]
   Average time for seizures to terminate

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 100 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Contacts

Contact: Adam Sturdivant, MPH; 205-934-4042; Adamsturdivant@uabmc.edu

Contact: Ayesha Bryant, MD; 205-996-7383; asbryant@uabmc.edu

Locations

United States, Alabama

UAB Department of Anesthesiology and Perioperative Medicine; Recruiting

Birmingham, Alabama, United States, 35249

Contact: Adam Sturdivant, MPH 205-934-4042 adamsturdivant@uabmc.edu

Contact: Ayesha Bryant, MSPH, MD 205-996-7383 asbryant@uabmc.edu

Principal Investigator: Vinodkumar Singh, MD

Sub-Investigator: Angela Douglas, MD

Sub-Investigator: Casey May, PharmD

Sponsors and Collaborators

University of Alabama at Birmingham

Investigators

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Vinodkumar Singh, Assistant Professor, University of Alabama at Birmingham
• ClinicalTrials.gov Identifier: NCT03115489
• Other Study ID Numbers: F151214004
• First Posted: April 14, 2017
• Last Update Posted: August 14, 2019
• Last Verified: August 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by Vinodkumar Singh, University of Alabama at Birmingham:

seizure; glutamate activation; N-Methyl D-Aspartate; gamma-aminobutyric acid receptor; Ketamine

Additional relevant MeSH terms:

Status Epilepticus; Drug Resistant Epilepsy; Epilepsy; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Seizures; Neurologic Manifestations; Signs and Symptoms; Ketamine; Propofol; Anticonvulsants; Hypnotics and Sedatives; Central Nervous System Depressants; Physiological Effects of Drugs; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Anesthetics, Dissociative; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action