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

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.

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:

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

• Solid food intake 2 hours or less before procedure;
• Compromised cardiorespiratory function; central nervous system, hepatic, or renal abnormality;
• History of psychosis in patient or first degree relative;
• Currently taking medications that stimulate or depress mental function, e.g. methylphenidate for attention deficit hyperactivity disorder or drugs of abuse;
• 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.