Procedural Anxiety
Conditions
Keywords
Intranasal, Midazolam, Pediatric, Laceration repair, Sedation, Anxiolysis, Adaptive trial design, Dose finding
Brief summary
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 associated with each dose. Specific Aim #2: To determine the time to recovery and describe the adverse events associated with each dose.
Detailed description
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.
Interventions
5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device.
Sponsors
Emergency Medicine Foundation
Mailman School of Public Health
Columbia University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Sequential selection procedure
Eligibility
Sex/Gender
ALL
Age
6 Months to 7 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Children Who Achieved PSSS Score 2, 3, or 4 for 95% or Greater of the Scored Procedure | From study drug administration until procedure finished (approximately 60 minutes) | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Recovery | From study drug administration until patient discharge (approximately 120 minutes) | 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. |
| Number of Adverse Events | From study drug administration until patient discharge (approximately 120 minutes) | 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). |
| Time to Onset of Minimal Sedation | From study drug administration until procedure finished (approximately 60 minutes) | 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). Note: This outcome was initially listed as a primary outcome, but was changed to a secondary outcome in the IRB-approved protocol and prior to enrollment of the first patient. |
| UMSS Scale Score | From study drug administration until procedure finished (approximately 60 minutes) | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 0.2 mg/kg Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.2 mg/kg.
Intranasal midazolam: 5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device. | 19 |
| 0.3 mg/kg Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.3 mg/kg.
Intranasal midazolam: 5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device. | 24 |
| 0.4 mg/kg Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.4 mg/kg.
Intranasal midazolam: 5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device. | 29 |
| 0.5 mg/kg Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.5 mg/kg.
Intranasal midazolam: 5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device. | 29 |
| Total | 101 |
Baseline characteristics
| Characteristic | 0.2 mg/kg | 0.3 mg/kg | 0.4 mg/kg | 0.5 mg/kg | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 19 Participants | 24 Participants | 29 Participants | 29 Participants | 101 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 2 years | 3 years | 4 years | 3 years | 3 years |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Black | 2 Participants | 0 Participants | 2 Participants | 4 Participants | 8 Participants |
| Race/Ethnicity, Customized Hispanic | 13 Participants | 17 Participants | 24 Participants | 21 Participants | 75 Participants |
| Race/Ethnicity, Customized More than one race | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 2 Participants | 7 Participants | 1 Participants | 3 Participants | 13 Participants |
| Region of Enrollment United States | 19 participants | 24 participants | 29 participants | 29 participants | 101 participants |
| Sex: Female, Male Female | 6 Participants | 11 Participants | 10 Participants | 11 Participants | 38 Participants |
| Sex: Female, Male Male | 13 Participants | 13 Participants | 19 Participants | 18 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 24 | 0 / 29 | 0 / 29 |
| other Total, other adverse events | 0 / 19 | 0 / 24 | 2 / 29 | 0 / 29 |
| serious Total, serious adverse events | 0 / 19 | 0 / 24 | 0 / 29 | 0 / 29 |
Outcome results
Primary
Number of Children Who Achieved PSSS Score 2, 3, or 4 for 95% or Greater of the Scored Procedure
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).
Time frame: From study drug administration until procedure finished (approximately 60 minutes)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 0.2 mg/kg | Number of Children Who Achieved PSSS Score 2, 3, or 4 for 95% or Greater of the Scored Procedure | 9 Participants |
| 0.3 mg/kg | Number of Children Who Achieved PSSS Score 2, 3, or 4 for 95% or Greater of the Scored Procedure | 12 Participants |
| 0.4 mg/kg | Number of Children Who Achieved PSSS Score 2, 3, or 4 for 95% or Greater of the Scored Procedure | 20 Participants |
| 0.5 mg/kg | Number of Children Who Achieved PSSS Score 2, 3, or 4 for 95% or Greater of the Scored Procedure | 19 Participants |
Secondary
Number 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).
Time frame: From study drug administration until patient discharge (approximately 120 minutes)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 0.2 mg/kg | Number of Adverse Events | 0 adverse events |
| 0.3 mg/kg | Number of Adverse Events | 0 adverse events |
| 0.4 mg/kg | Number of Adverse Events | 2 adverse events |
| 0.5 mg/kg | Number of Adverse Events | 0 adverse events |
Secondary
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). Note: This outcome was initially listed as a primary outcome, but was changed to a secondary outcome in the IRB-approved protocol and prior to enrollment of the first patient.
Time frame: From study drug administration until procedure finished (approximately 60 minutes)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 0.2 mg/kg | Time to Onset of Minimal Sedation | 4.2 minutes |
| 0.3 mg/kg | Time to Onset of Minimal Sedation | 3.7 minutes |
| 0.4 mg/kg | Time to Onset of Minimal Sedation | 3.9 minutes |
| 0.5 mg/kg | Time to Onset of Minimal Sedation | 3.9 minutes |
Secondary
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.
Time frame: From study drug administration until patient discharge (approximately 120 minutes)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 0.2 mg/kg | Time to Recovery | 0 minutes |
| 0.3 mg/kg | Time to Recovery | 0 minutes |
| 0.4 mg/kg | Time to Recovery | 0 minutes |
| 0.5 mg/kg | Time to Recovery | 0 minutes |
Secondary
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.
Time frame: From study drug administration until procedure finished (approximately 60 minutes)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 0.2 mg/kg | UMSS Scale Score | UMSS = 0 | 3 Participants |
| 0.2 mg/kg | UMSS Scale Score | UMSS = 2, 3 or 4 | 0 Participants |
| 0.2 mg/kg | UMSS Scale Score | UMSS = 1 | 16 Participants |
| 0.3 mg/kg | UMSS Scale Score | UMSS = 0 | 2 Participants |
| 0.3 mg/kg | UMSS Scale Score | UMSS = 2, 3 or 4 | 0 Participants |
| 0.3 mg/kg | UMSS Scale Score | UMSS = 1 | 22 Participants |
| 0.4 mg/kg | UMSS Scale Score | UMSS = 1 | 28 Participants |
| 0.4 mg/kg | UMSS Scale Score | UMSS = 0 | 1 Participants |
| 0.4 mg/kg | UMSS Scale Score | UMSS = 2, 3 or 4 | 0 Participants |
| 0.5 mg/kg | UMSS Scale Score | UMSS = 0 | 2 Participants |
| 0.5 mg/kg | UMSS Scale Score | UMSS = 2, 3 or 4 | 0 Participants |
| 0.5 mg/kg | UMSS Scale Score | UMSS = 1 | 27 Participants |