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Prevention of N-methyl-D-aspartate (NMDA) Antagonist-induced Psychosis in Kids

This study has been completed.
Sponsor:
Collaborator:
National Alliance for Research on Schizophrenia and Depression
Information provided by (Responsible Party):
Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT00205712
First received: September 13, 2005
Last updated: March 18, 2014
Last verified: March 2014

September 13, 2005
March 18, 2014
February 2003
October 2007   (final data collection date for primary outcome measure)
Brief Psychiatric Ratings Scale (BPRS) Positive Symptom Subscale Score [ Time Frame: Before Ketamine, During Ketamine ] [ Designated as safety issue: No ]
Participant received behavioral ratings before medication and during medication for the primary analysis comparison. This is an observer-scale with a value range from 0-6 (0=no symptoms 6=worst symptoms)
Measure distress during sedation, fracture reduction, recovery
Complete list of historical versions of study NCT00205712 on ClinicalTrials.gov Archive Site
  • Visual Analog Scale (VAS) Pain Intensity [ Time Frame: Before Ketamine, During Ketamine, Post Ketamine and 1 Week Follow up ] [ Designated as safety issue: No ]
    Pain intensity was measured on a scale of 1-10 (1=lowest pain intensity, 10=highest pain intensity) in participants before medication, during medication, post medication and 1 week follow up.
  • Visual Analog Scale (VAS) Anxiety Rating [ Time Frame: Before Ketamine, During Ketamine, Post Ketamine, 1 week follow up ] [ Designated as safety issue: No ]
    Anxiety was measured on a scale of 1-10 (1=lowest pain intensity, 10=highest pain intensity) in participants before medication, during medication, post medication and 1 week follow up.
Evaluate behavioral & cognitive effects of subanesthetic doses of ketamine in healthy pre-/post-pubertal children
Not Provided
Not Provided
 
Prevention of N-methyl-D-aspartate (NMDA) Antagonist-induced Psychosis in Kids
Prevention of NMDA Antagonist-induced Psychosis and Memory Impairment in Children

Ketamine, an FDA approved anesthetic agent, is becoming the sedative/analgesic of choice for emergency sedation in children because it causes deep sedation with minimal respiratory depression in comparison to other available agents. However, emergence reactions are an important adverse effect of ketamine, characterized by transient changes in cognitive function, dissociation and mild schizophrenia-like symptoms. These cognitive and behavioral effects are dose-dependently induced by ketamine and other antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor. NMDA receptor hypofunction can disinhibit excitatory (cholinergic/glutamatergic) projections in key areas of the brain, and this has been proposed to explain key features of schizophrenia. Several treatments that block excessive excitatory transmitter release have also been shown to prevent cognitive and behavioral effects of ketamine-induced NMDA receptor hypofunction in humans. Alpha-2 adrenergic agonists, which can presynaptically inhibit acetylcholine release, can prevent mild ketamine-induced behavioral and cognitive symptoms in healthy human adults. However, this prevention strategy has not been evaluated in children. Children currently receive clinically-indicated treatment with the NMDA antagonist, ketamine, and this age group is an important target for pharmacological strategies aimed at the prevention of schizophrenia. This application proposes a double-blind, placebo-controlled, randomized trial to test the safety and effectiveness of dexmedetomidine, an FDA approved alpha-2 adrenergic agonist, in preventing ketamine-induced mental symptoms in children. Planned primary analyses will evaluate effects of the hypothesized prevention treatment on clinical and cognitive variables using analysis of variance (ANOVA). The proposed experiments are relevant to future prevention trials for individuals at risk for schizophrenia, and to preventing adverse effects of NMDA antagonist anesthetic agents (ketamine, nitrous oxide).

The proposed study will be conducted using existing dedicated clinical and research space in St. Louis Children's Hospital's Emergency Department, Pediatric Clinical Research Center (PCRC), and Orthopedic Clinic. This project has 3 major aims and 1 exploratory aim addressed by a prospective randomized blinded placebo controlled drug trial to test whether a pharmacological strategy can prevent NMDA receptor hypofunction-induced behavioral and cognitive dysfunction in pre- and post-pubertal children. Based on previous preclinical and clinical research on the effects and blockade of the effects of ketamine and similar compounds, the study investigators have carefully selected a dose of the alpha-2 adrenergic agonist dexmedetomidine that will permit this study to be conducted with low risk to enrolled subjects who are undergoing clinically-indicated ketamine sedation for forearm fracture reduction.

General Experimental Design: This project will test the safety and effectiveness of dexmedetomidine for preventing ketamine-induced behavioral and cognitive symptoms in healthy human children undergoing clinically indicated ketamine sedation for forearm fracture reduction.

Aims 1 and 2 will be addressed by randomized, blinded administration of dexmedetomidine or saline placebo to ketamine-sedated subjects to test the efficacy of dexmedetomidine in preventing ketamine-induced behavioral and cognitive changes during recovery from sedation.

Aim 3 will be addressed by comparing between the subjects randomized to receive dexmedetomidine or saline placebo measurements of distress and frequency of adverse cardiopulmonary effects during sedation, fracture-reduction, and recovery.

Interventional
Phase 4
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
Psychoses, Substance-Induced
  • Drug: Ketamine
    Ketamine without dexmedetomidine
    Other Names:
    • Ketanest
    • Ketaset
    • Ketalar
  • Drug: Dexmedetomidine
    Ketamine plus dexmedetomidine
    Other Name: Precedex
  • Placebo Comparator: Ketamine plue saline
    Ketamine without dexmedetomidine
    Intervention: Drug: Ketamine
  • Experimental: Ketamine plus dexmedetomidine
    Ketamine infusion plus dexmedetomidine
    Intervention: Drug: Dexmedetomidine
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
40
October 2007
October 2007   (final data collection date for primary outcome measure)

Inclusion Criteria:

Patients presenting to St. Louis Children's Hospital's Emergency Department who require reduction of an acute forearm fracture will be recruited for enrollment if they satisfy the following:

  1. Age 7-17 years, inclusive;
  2. Are psychiatrically healthy (i.e. have never been under the care of a psychiatrist or taken psychiatrically active medications);
  3. Meet American Society of Anesthesiologist (ASA) Class I and II criteria (I=healthy, II=chronic disease under good control);
  4. Have had no prior fracture reduction or ketamine administration;
  5. Present for care when research assistants are present (Monday-Friday, 09:00-23:00); and
  6. Have a home telephone or ready means of establishing telephone contact.

All subjects and their parent/guardian will give Washington University Human Studies Committee approved written informed assent and consent prior to participation.

Exclusion Criteria:

  1. Solid food intake 2 hours or less before procedure;
  2. Compromised cardiorespiratory function; central nervous system, hepatic, or renal abnormality;
  3. History of psychosis in patient or first degree relative;
  4. Currently taking medications that stimulate or depress mental function, e.g. methylphenidate for attention deficit hyperactivity disorder or drugs of abuse;
  5. History of allergy or adverse reaction to alpha-2 adrenoreceptor agonist drugs, e.g. clonidine.

These exclusion criteria relate to contraindications for use of the agents employed in the study. Criteria 1, 2, 3 and 4 are current routine practice for ketamine sedations.

Both
7 Years to 17 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00205712
NARSAD - Kids, 01-0886
No
Washington University School of Medicine
Washington University School of Medicine
National Alliance for Research on Schizophrenia and Depression
Principal Investigator: John W. Newcomer, M.D. Washington University School of Medicine and Florida Atlantic University
Washington University School of Medicine
March 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP