Intranasal Midazolam for Treatment of Anxiety in Children Undergoing Suturing in the Pediatric Emergency Department

Atomized Intranasal Midazolam for Anxiolysis and Facilitation of Laceration Repair in the Pediatric Emergency Department: A Randomized Controlled Trial

Laceration repair can cause significant anxiety in children. As open wounds account for 21-25% of injuries in children presenting to the emergency department, the management of anxiety is of great importance. Anxiety can often lead to poor patient cooperation and the use of potentially excessive physical restraint. High rates of procedural anxiety have also been correlated with increased rates of negative behaviours after discharge.

The current standard of care for suture closure of lacerations throughout most of Canada is to provide local analgesia only. The literature has therefore focused on finding anxiolytic adjuncts to local analgesia.

Midazolam is an ideal adjunct due to its fast onset and short duration of action with an excellent safety profile. The advantages of the IN route are less pain on administration when compared to the IV and IM routes, and increased acceptability compared to the rectal route in older children. Oral midazolam also has poor palatability.

While the onset of INM at 5-10 minutes, and duration of 20-40 minutes make it an ideal candidate for anxiolysis in the ED its use has been limited by the common side effect of nasal irritation, burning and lacrimation when it is administered in its droplet form. The recent development of mucosal atomization devices (MAD) has resolved this issue by delivering 30-μ particles to the nasal mucosa.

Previous studies investigating the use of INM for laceration repair in the pediatric ED have demonstrated that INM is safe but most used non-validated measurement tools to assess anxiety and facilitation. Only one of these studies used atomized INM, retrospectively examining safety as the primary outcome. The authors reported an excellent safety profile for INM using the mucosal atomization device MAD-300 (Wolfe Tory Medical Inc.). The use of atomized INM for anxiolysis during pediatric laceration repair has not been evaluated prospectively.

Most studies have focused on preschool aged children (<6 years). While studies have demonstrated that the prevalence of procedural anxiety is higher in younger children, up to 51% of children age 7-12 years experience high levels of procedural distress. The effectiveness of INM in the pre-adolescent age group is, therefore, yet to be determined.

It is hypothesized that INM will reduce anxiety in children age 2-12 years undergoing laceration repair and will facilitate the successful completion of suturing by the physician.

Study Overview

• Status: Completed
• Conditions: Lacerations; Anxiety
• Intervention / Treatment: Drug: Saline; Drug: Midazolam

• Study Type: Interventional
• Enrollment (Actual): 79
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 12 years (Child)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• children 2-12 years requiring laceration repair using suturing and use of injected lidocaine

Exclusion Criteria:

• Administration in ER of analgesia or sedation other than acetaminophen or ibuprofen prior to enrolment
• ASA of III or greater
• Multi-system trauma
• Severe neurologic impairment or non-verbal autism, known allergy/hypersensitivity to lidocaine or midazolam
• Parent/guardian does not speak one of French or English
• No parent/guardian present during procedure

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Intranasal Saline; 0.08ml/kg of saline to a maximum of 2ml intranasally with an atomizer MAD-300	Drug: Saline; Intranasal administration of saline at a dose of 0.08ml/kg (max 2ml) one time prior to laceration repair as a placebo
Active Comparator: Intranasal Midazolam; 0.08ml/kg (0.4mg/kg of 5mg/ml IV solution) intranasal midazolam, to a maximum of 2ml (10mg), with an atomizer MAD-300	Drug: Midazolam; Intranasal administration of midazolam at dose of 0.4mg/kg (max 10 mg) one time 10 minutes prior to laceration repair

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intention to Treat (ITT): Modified Yale Preoperative Anxiety Score (mYPAS)	Measurement of patient anxiety used to test effect of anxiolytic pre-medication.The mYPAS consists of 5 items (activity, vocalizations, emotional expressivity, state of apparent arousal, and use of parents). Each item has Likert scale whereby participant's behavior is rated from 1 to 4 (Note: Vocalizations is the only item rated from 1 to 6), with higher numbers indicating the highest severity within that item. Each participant was given a mYPAS score for the "suturing" by two independent raters. These raters watched a digital recording of the participant undergoing suturing and from this digital recording used the mYPAS scale to assign a measurement of the participant's anxiety. The mYPAS scale is rated as follows: Final scores = (Activity/4 + Vocal/6 + Emotional/4 + Arousal/4 + Parents/4) X 20. Scores range from 23 to 100 where a lower score is indicative of a lower level of anxiety and a higher is indicative of a higher level of anxiety.	Day 1: During suturing
Per-Protocol: Modified Yale Preoperative Anxiety Score (mYPAS)	Measurement of patient anxiety used to test effect of anxiolytic pre-medication.The mYPAS consists of 5 items (activity, vocalizations, emotional expressivity, state of apparent arousal, and use of parents). Each item has Likert scale whereby participant's behavior is rated from 1 to 4 (Note: Vocalizations is the only item rated from 1 to 6), with higher numbers indicating the highest severity within that item. Each participant was given a mYPAS score for the "suturing" by two independent raters. These raters watched a digital recording of the participant undergoing suturing and from this digital recording used the mYPAS scale to assign a measurement of the participant's anxiety. The mYPAS scale is rated as follows: Final scores = (Activity/4 + Vocal/6 + Emotional/4 + Arousal/4 + Parents/4) X 20. Scores range from 23 to 100 where a lower score is indicative of a lower level of anxiety and a higher is indicative of a higher level of anxiety.	Day 1: During suturing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intention to Treat (ITT): Modified Yale Preoperative Anxiety Score (mYPAS)	Measurement of patient anxiety used to test effect of anxiolytic pre-medication.The mYPAS consists of 5 items (activity, vocalizations, emotional expressivity, state of apparent arousal, and use of parents). Each item has Likert scale whereby participant's behavior is rated from 1 to 4 (Note: Vocalizations is the only item rated from 1 to 6), with higher numbers indicating the highest severity within that item. Each participant was given a mYPAS score for the "suturing" by two independent raters. These raters watched a digital recording of the participant undergoing suturing and from this digital recording used the mYPAS scale to assign a measurement of the participant's anxiety. The mYPAS scale is rated as follows: Final scores = (Activity/4 + Vocal/6 + Emotional/4 + Arousal/4 + Parents/4) X 20. Scores range from 23 to 100 where a lower score is indicative of a lower level of anxiety and a higher is indicative of a higher level of anxiety.	Day 1: During Baseline, Intervention & Lidocaine
Per-Protocol: Modified Yale Preoperative Anxiety Score (mYPAS)	Measurement of patient anxiety used to test effect of anxiolytic pre-medication.The mYPAS consists of 5 items (activity, vocalizations, emotional expressivity, state of apparent arousal, and use of parents). Each item has Likert scale whereby participant's behavior is rated from 1 to 4 (Note: Vocalizations is the only item rated from 1 to 6), with higher numbers indicating the highest severity within that item. Each participant was given a mYPAS score for the "suturing" by two independent raters. These raters watched a digital recording of the participant undergoing suturing and from this digital recording used the mYPAS scale to assign a measurement of the participant's anxiety. The mYPAS scale is rated as follows: Final scores = (Activity/4 + Vocal/6 + Emotional/4 + Arousal/4 + Parents/4) X 20. Scores range from 23 to 100 where a lower score is indicative of a lower level of anxiety and a higher is indicative of a higher level of anxiety.	Day 1: Baseline, Intervention & Lidocaine
Intention to Treat (ITT): State Trait Anxiety Inventory (STAI)	Validated measurement of anxiety, to be used to test parental/guardian anxiety at two time points. These time points are before intervention and immediately after suturing (prior to patient discharge from the ER, i.e. same day). The STAI contains 10 items for assessing trait anxiety and 10 for state anxiety. All items are rated on a standard scale ("Not at all", "Somewhat", "Moderately so", "Very much so") with a range of 20 to 80 where higher scores indicate greater anxiety and lower scores indicate lower levels of anxiety.	Day 1: Before intervention and immediately after suturing (prior to patient discharge from the ER, i.e. same day)
Per-Protocol: State Trait Anxiety Inventory (STAI)	Validated measurement of anxiety, to be used to test parental/guardian anxiety at two time points. These time points are before intervention and immediately after suturing (prior to patient discharge from the ER, i.e. same day). The STAI contains 10 items for assessing trait anxiety and 10 for state anxiety. All items are rated on a standard scale ("Not at all", "Somewhat", "Moderately so", "Very much so") with a range of 20 to 80 where higher scores indicate greater anxiety and lower scores indicate lower levels of anxiety.	Before intervention and immediately after suturing (prior to patient discharge from the ER, i.e. same day)
Intention to Treat (ITT): Dartmouth Operative Conditions Scale	A tool to measure the effectiveness and safety of pediatric sedation, regardless of technique used for decreasing anxiety or pain during a procedure. The scale asks the physician to rate patient states (pain/stress, movement, consciousness & sedation side effects) based on observed behaviors (each observed behavior is given a score). The scores are then added together to give a score where -3 to 5 where the lower number is indicative of less anxiety/pain.	Day 1: Immediately after suturing (prior to patient discharge from the ER, i.e. same day)
Per-Protocol: Dartmouth Operative Conditions Scale	A tool to measure the effectiveness and safety of pediatric sedation, regardless of technique used for decreasing anxiety or pain during a procedure. The scale asks the physician to rate patient states (pain/stress, movement, consciousness & sedation side effects) based on observed behaviors (each observed behavior is given a score). The scores are then added together to give a score where -3 to 5 where the lower number is indicative of less anxiety/pain.	Day 1: Immediately after suturing (prior to patient discharge from the ER, i.e. same day)
Intention to Treat (ITT): Faces Pain Scale-Revised/ FLACC Scale	Faces Pain Scale: Validated self-report tool of pain for participants less than 5 years old. It is a scale that allows one to score the sensation of pain from zero to ten. The scale shows a visuals (faces) for each levels 0, 2, 4, 6, 8 and 10 of the scale. For example, 0 is represented by a "face" visual that expresses no hurt. FLACC Scale: Tool to assess pain in children unable to use Faces Pain Scale-revised. The Face, Legs, Activity, Cry, Consolability scale or FLACC scale is a measurement used to assess individuals that are unable to communicate their pain. The scale is scored in a range of 0-10 (0 represents no pain).	Day 1: immediately after intervention
Per-Protocol: Faces Pain Scale-Revised/ FLACC Scale	Faces Pain Scale: Validated self-report tool of pain for participants less than 5 years old. It is a scale that allows one to score the sensation of pain from zero to ten. The scale shows a visuals (faces) for each levels 0, 2, 4, 6, 8 and 10 of the scale. For example, 0 is represented by a "face" visual that expresses no hurt. FLACC Scale: Tool to assess pain in children unable to use Faces Pain Scale-revised. The Face, Legs, Activity, Cry, Consolability scale or FLACC scale is a measurement used to assess individuals that are unable to communicate their pain. The scale is scored in a range of 0-10 (0 represents no pain).	Day 1: immediately after intervention

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time That the Participant Remained in Hospital After Procedure (Mins)	Length of stay in the emergency department, measured from the end of the procedure to the time of discharge.	Day 1: at discharge from emergency department (i.e. same day)
Length of Procedure (Mins)	This is a measure of the length of the procedure (suturing) in minutes.	Day 1
Physician's Prediction is Respect to Intervention Drug	This is a measure how how many times the physician was correct in predicting whether the patient received intranasal saline or intranasal midazolam as the intervention drug.	Day 1: physician asked immediately after procedure finished
Guardian/Parent's Prediction is Respect to Intervention Drug	This is a measure how how many times the parent/guardian was correct in predicting whether the patient received intranasal saline or intranasal midazolam as the intervention drug.	Day 1: parent asked immediately after procedure complete

Collaborators and Investigators

• Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre

Study record dates

Study Major Dates

• Study Start: January 1, 2010
• Primary Completion (Actual): March 1, 2015
• Study Completion (Actual): November 1, 2015

Study Registration Dates

• First Submitted: November 23, 2015
• First Submitted That Met QC Criteria: November 28, 2015
• First Posted (Estimate): December 1, 2015

Study Record Updates

• Last Update Posted (Estimate): October 7, 2016
• Last Update Submitted That Met QC Criteria: September 5, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: Anxiety; Pediatrics; Anti-Anxiety Agents; Laceration
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Wounds and Injuries; Disease Attributes; Emergencies; Anxiety Disorders; Lacerations; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam
• Other Study ID Numbers: PED-08-053