Psychoses, Substance-Induced
Conditions
Keywords
NMDA antagonist-induced psychosis, Children, Memory Impairment, Decreased cognitive function, Increased memory impairment
Brief summary
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).
Detailed description
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.
Interventions
DRUGKetamine
Ketamine without dexmedetomidine
DRUGDexmedetomidine
Ketamine plus dexmedetomidine
Sponsors
National Alliance for Research on Schizophrenia and Depression
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
7 Years to 17 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brief Psychiatric Ratings Scale (BPRS) Positive Symptom Subscale Score | Before Ketamine, During Ketamine | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Visual Analog Scale (VAS) Pain Intensity | Before Ketamine, During Ketamine, Post Ketamine and 1 Week Follow up | 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 | Before Ketamine, During Ketamine, Post Ketamine, 1 week follow up | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ketamine Alone ketamine without dexmedetomidine | 20 |
| Ketamine Plus Dexmedetomidine ketamine infusion plus dexmedetomidine | 20 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
Baseline characteristics
| Characteristic | Ketamine Plus Dexmedetomidine | Ketamine Alone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 20 Participants | 20 Participants | 40 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 10.9 years STANDARD_DEVIATION 2.4 | 11.2 years STANDARD_DEVIATION 2.2 | 11 years STANDARD_DEVIATION 2.3 |
| Region of Enrollment United States | 20 participants | 20 participants | 40 participants |
| Sex: Female, Male Female | 5 Participants | 7 Participants | 12 Participants |
| Sex: Female, Male Male | 15 Participants | 13 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 19 / 20 | 19 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
Primary
Brief Psychiatric Ratings Scale (BPRS) Positive Symptom Subscale Score
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)
Time frame: Before Ketamine, During Ketamine
Population: Completers analysis per protocol. Two participants were missing some data at either the before ketamine or during ketamine time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketamine Alone | Brief Psychiatric Ratings Scale (BPRS) Positive Symptom Subscale Score | BPRS Positive symptom subscale-before medication | 0.00 Scale of 0-6 | Standard Deviation 0 |
| Ketamine Alone | Brief Psychiatric Ratings Scale (BPRS) Positive Symptom Subscale Score | BPRS Positive symptom subscale-during medication | 1.40 Scale of 0-6 | Standard Deviation 2.37 |
| Ketamine Plus Dexmedetomidine | Brief Psychiatric Ratings Scale (BPRS) Positive Symptom Subscale Score | BPRS Positive symptom subscale-before medication | 0.00 Scale of 0-6 | Standard Deviation 0 |
| Ketamine Plus Dexmedetomidine | Brief Psychiatric Ratings Scale (BPRS) Positive Symptom Subscale Score | BPRS Positive symptom subscale-during medication | 1.00 Scale of 0-6 | Standard Deviation 1.41 |
Secondary
Visual Analog Scale (VAS) Anxiety Rating
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.
Time frame: Before Ketamine, During Ketamine, Post Ketamine, 1 week follow up
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketamine Alone | Visual Analog Scale (VAS) Anxiety Rating | VAS Anxiety-Before Medication | 5.0 Scale of 1-10 | Standard Deviation 2.43 |
| Ketamine Alone | Visual Analog Scale (VAS) Anxiety Rating | VAS Anxiety-Before Cogntive Testing | 1.67 Scale of 1-10 | Standard Deviation 0.97 |
| Ketamine Alone | Visual Analog Scale (VAS) Anxiety Rating | VAS Anxiety-After Cognitive Testing | 1.71 Scale of 1-10 | Standard Deviation 1.14 |
| Ketamine Alone | Visual Analog Scale (VAS) Anxiety Rating | VAS Anxiety-1 Week Follow Up | 1.56 Scale of 1-10 | Standard Deviation 1.2 |
| Ketamine Plus Dexmedetomidine | Visual Analog Scale (VAS) Anxiety Rating | VAS Anxiety-1 Week Follow Up | 2.06 Scale of 1-10 | Standard Deviation 1.82 |
| Ketamine Plus Dexmedetomidine | Visual Analog Scale (VAS) Anxiety Rating | VAS Anxiety-Before Medication | 5.0 Scale of 1-10 | Standard Deviation 2.35 |
| Ketamine Plus Dexmedetomidine | Visual Analog Scale (VAS) Anxiety Rating | VAS Anxiety-After Cognitive Testing | 3.00 Scale of 1-10 | Standard Deviation 2.04 |
| Ketamine Plus Dexmedetomidine | Visual Analog Scale (VAS) Anxiety Rating | VAS Anxiety-Before Cogntive Testing | 2.53 Scale of 1-10 | Standard Deviation 1.58 |
Secondary
Visual Analog Scale (VAS) Pain Intensity
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.
Time frame: Before Ketamine, During Ketamine, Post Ketamine and 1 Week Follow up
Population: Completers analysis per protocol. Two participants were missing some data at either the before ketamine or during ketamine time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketamine Alone | Visual Analog Scale (VAS) Pain Intensity | VAS Pain-Before Medication | 4.72 Scale of 1-10 | Standard Deviation 1.93 |
| Ketamine Alone | Visual Analog Scale (VAS) Pain Intensity | VAS Pain-Before Cognitive Testing | 2.75 Scale of 1-10 | Standard Deviation 1.65 |
| Ketamine Alone | Visual Analog Scale (VAS) Pain Intensity | VAS Pain-After Cognitive Testing | 2.61 Scale of 1-10 | Standard Deviation 1.33 |
| Ketamine Alone | Visual Analog Scale (VAS) Pain Intensity | VAS Pain-1 Week F/U | 1.33 Scale of 1-10 | Standard Deviation 0.59 |
| Ketamine Plus Dexmedetomidine | Visual Analog Scale (VAS) Pain Intensity | VAS Pain-1 Week F/U | 1.76 Scale of 1-10 | Standard Deviation 1.64 |
| Ketamine Plus Dexmedetomidine | Visual Analog Scale (VAS) Pain Intensity | VAS Pain-Before Medication | 4.03 Scale of 1-10 | Standard Deviation 2.38 |
| Ketamine Plus Dexmedetomidine | Visual Analog Scale (VAS) Pain Intensity | VAS Pain-After Cognitive Testing | 4.08 Scale of 1-10 | Standard Deviation 1.85 |
| Ketamine Plus Dexmedetomidine | Visual Analog Scale (VAS) Pain Intensity | VAS Pain-Before Cognitive Testing | 2.89 Scale of 1-10 | Standard Deviation 1.78 |