Quetiapine Treatment for Pediatric Delirium

Study Overview
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Brief Summary
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This is a prospective, double-blind, randomized controlled trial to begin determining the efficacy of quetiapine as a treatment for pediatric delirium in patients admitted to the pediatric intensive care unit (PICU)

Detailed Description
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Delirium is an acute syndrome with fluctuation in mental status with altered cognition and consciousness. It is a common occurrence (17% to 38%) in critically ill children with serious short-term consequences. Its pathophysiology is complex and incompletely understood. Dopaminergic, serotoninergic, glutaminergic, and cholinergic pathways in the cerebral cortex, striatum, substantia nigra, and thalamus have been implicated. Imbalance in the synthesis, release, and inactivation of neurotransmitters can result in altered cognitive function, behavior, and mood. The Society of Critical Care Medicine set the adult practice guidelines including widespread delirium screening as well as treatment to decrease duration of delirium and ameliorate its long-term effects (12). The cornerstone of pharmacologic therapy for delirium in adults is antipsychotics, both first and second-generation (13-20). The current foundation of treatment for pediatric delirium is identifying and addressing the underlying etiology. Iatrogenic factors should be minimized, such as avoiding benzodiazepines and restraints, optimizing pain control, minimizing sedation, and treating withdrawal. The ICU environment should also be optimized to create a quiet, well-lit space with clustered care to allow for uninterrupted sleep. When non-pharmacologic treatment measures prove insufficient to manage the symptoms of delirium, we believe the second-generation antipsychotic (SGA) quetiapine may have a role in the treatment of delirium. However, there are currently no FDA-approved medications to treat delirium in this population. The European Society of Paediatric and Neonatal Intensive Care (ESPNIC) has recently recommended that all children in the ICU be monitored for delirium but provided no guidance on recommended treatments (21), likely due to the lack of evidence of proven delirium treatment in children. An adult systematic review and meta-analysis by Kishi et al concluded that antipsychotics are superior to placebo in decreasing severity of delirium and time to response with there was no significant difference in the side effects between the two groups. Additionally, SGAs are associated with a shorter time to response and lower side effect profile than haloperidol (a first-generation antipsychotic). A growing body of pediatric literature suggests that delirium is a serious and under recognized problem in critically ill children as well, however little research has been focused on treatment . A recent retrospective series looking at the use of quetiapine in suggested that quetiapine use for delirium treatment is a safe option in this population. With proven efficacy in adults with delirium, an established track record in children for indications other than delirium, a favorable safety profile, and a wide therapeutic window, quetiapine is a logical choice for the next phase of research into pediatric delirium treatment. In this study are looking prospectively at the effectiveness of quetiapine as a treatment for pediatric delirium.

Official Title
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Prospective, Double-Blind, Randomized Controlled Trial of Quetiapine as a Treatment for Delirium in Critically Ill Children

Conditions
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Delirium

Intervention / Treatment
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* Drug: Quetiapine
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 0 - 21 years old PICU admission Positive CAPD scoring For developmentally normal children a CAPD score of ≥ 9 For developmentally delayed a CAPD score of ≥ 9 and a Richmond Agitation Sedation Scale (RASS) fluctuation of at least 2 points in the last 24 hours Exclusion Criteria: Patients under neuromuscular blockade and/or therapeutic hypothermia. Patients undergoing treatment of alcohol withdrawal. Patients unable to tolerate enteral medications Patients on antipsychotics Patients with a history of: hepatic encephalopathy, hepatitis elevated liver enzymes defined ALT or AST above normal range for age since hospitalization baseline QTc prolongation (defined as greater than 97th percentile for age or greater than 20% increase from baseline or previous QTc) major depressive disorder or bipolar disorder, and movement disorder. Patients who are pregnant Non-English and non-Spanish speaking subjects and/or parent/guardian

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Quetiapine (0.5 mg/kg TID x 10 days)<br>This study group will receive treatment with quetiapine after diagnosis of pediatric delirium. Group assignment will be blinded. | Drug: Quetiapine<br>* Patients randomized to the study treatment group will received quetiapine at 0.5 mg/kg, three times a day for 10 days. Doses can be increased up to a maximum of 6 mg/kg/day, in increments of 0.5 mg/kg, based on the subject's clinical delirium symptoms. PRN doses of 0.5 mg/kg can be given up to three times a day based on the clinical judgement of the subject's ICU care team.<br>|
| Placebo Comparator: Placebo<br>This study group will receive a placebo treatment after diagnosis of pediatric delirium. Group assignment will be blinded. | Other: Placebo<br>* Patients randomized to the placebo group will be given an equivalent volume of sterile liquid or sugar pill, based on the individual subjects dosing preference or ability. Dosing will be done on the same schedule as the quetiapine group<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to resolution of delirium | Delirium symptoms will be monitored using CAPD (Cornell Assessment for Pediatric Delirium) score, collected twice a day. Time to resolution of delirium will be measured from the time of randomization to the time scores are within normal range (0-8). Number of days with abnormal CAPD scores will be compared between study groups | Screening through Study Day 14/Hospital Discharge |