Dose-Finding Study of Intranasal Midazolam for Procedural Sedation in Children

Study Overview
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Brief Summary
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Dose-finding study to compare intranasal midazolam doses of 0.2, 0.3, 0.4 and 0.5 mg/kg in children undergoing laceration repair to achieve the following aims: Specific Aim #1: To determine the most effective dose of intranasal midazolam for producing adequate sedation state and time to onset of minimal sedation associated with each dose. Specific Aim #2: To determine the time to recovery and describe the adverse events associated with each dose.

Detailed Description
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Intranasal midazolam is a common and effective sedative whose use in children presenting to emergency departments has been described. However, the doses of intranasal midazolam used have varied greatly, with no identified optimal dose. Doses most commonly described in literature reviews, research studies, and clinical guidelines range from 0.2 to 0.5 mg/kg. There is only one study, retrospective, that compares doses and suggests that clinical efficacy is improved with higher doses, without any clear difference in safety. There is a need for a rigorously-conducted trial to determine the dose of intranasal midazolam that optimizes the adequacy of sedation state without leading to adverse events or compromising emergency department-centric outcomes such as time to onset of sedation and time to recovery. To fill this important and persistent gap in knowledge, the investigator will conduct a dose-finding study using an adaptive trial design to compare intranasal midazolam doses of 0.2, 0.3, 0.4, and 0.5 mg/kg in children undergoing laceration repairs, one of the most common types of minor trauma treated in emergency departments.

Official Title
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Dose-Finding Study of Intranasal Midazolam for Procedural Sedation in Children

Conditions
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Procedural Anxiety

Intervention / Treatment
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* Drug: Intranasal midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ages 6 months to 7 years old (i.e. before their 8th birthday) Simple laceration Attending physician has decided intranasal midazolam indicated to facilitate repair Exclusion Criteria: Repair using tissue adhesive (e.g. Dermabond) or staples Known or confirmed developmental delay Baseline motor neurological abnormality (e.g. motor deficit, cerebral palsy) Autism spectrum disorder Illness associated with chronic pain Known allergy to midazolam or any other benzodiazepine Eyelid laceration Tongue or intraoral lacerations Nasal obstruction that cannot be easily cleared Does not speak English or Spanish Foster children, wards of the state

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 7 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
Interventional Model Description: Sequential selection procedure
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 0.2 mg/kg<br>Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.2 mg/kg. | Drug: Intranasal midazolam<br>* 5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device.<br>* Other names: IN midazolam;|
| Experimental: 0.3 mg/kg<br>Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.3 mg/kg. | Drug: Intranasal midazolam<br>* 5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device.<br>* Other names: IN midazolam;|
| Experimental: 0.4 mg/kg<br>Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.4 mg/kg. | Drug: Intranasal midazolam<br>* 5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device.<br>* Other names: IN midazolam;|
| Experimental: 0.5 mg/kg<br>Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.5 mg/kg. | Drug: Intranasal midazolam<br>* 5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device.<br>* Other names: IN midazolam;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pediatric Sedation State Scale Score | The Pediatric Sedation State Scale (PSSS) is scored from 0 to 5, representing a continuum of sedation that spans from over-sedation associated with changes in vital signs (0) to inadequate sedation (5). | From study drug administration until procedure finished (approximately 60 minutes) | 
| Time to onset of minimal sedation | Time (in minutes) from administration of intranasal midazolam until a University of Michigan Sedation State (UMSS) score of 1 is achieved. The UMSS represents a spectrum of depth of sedation ranging from unarousable (4) to awake and alert (0). | From study drug administration until procedure finished (approximately 60 minutes) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to recovery | Time (in minutes) from procedure completion until a Simplified Aldrete Score (SAS) of at least 6 is achieved. The score ranges from 0 (lowest) to 8 (highest). If a patient already fulfills criteria for recovery at procedure start, then time to recovery is 0. | From study drug administration until patient discharge (approximately 120 minutes) | 
| Incidence of adverse events | Adverse events will be defined using the Pediatric Emergency Research Canada and Pediatric Emergency Care Applied Research Network Consensus-Based Recommendations. These adverse events include oxygen desaturation; apnea (central, obstructive, laryngospasm); clinically apparent pulmonary aspiration; retching/vomiting; bradycardia; hypotension; excitatory movements; paradoxical response to sedation; unpleasant recovery reactions; and permanent complications (including death). | From study drug administration until patient discharge (approximately 120 minutes) | 
| OSBD-R Scale Score | Procedural pain and distress will be measured using the Observational Scale of Behavioral Distress - Revised (OSBD-R). Each 15-second interval is scored from 0 (no pain or distress) to 23.5 (maximal pain and distress). | From study drug administration until procedure finished (approximately 60 minutes) | 
| UMSS Scale Score | Depth of sedation will be measured using the University of Michigan Sedation Scale (UMSS). This sedation scale ranges from zero to four with higher numbers indicating deeper sedation. | From study drug administration until procedure finished (approximately 60 minutes) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Intranasal, Midazolam, Pediatric, Laceration repair, Sedation, Anxiolysis, Adaptive trial design, Dose finding