PREMIX vs PREMED Intranasal Lidocaine and Midazolam

• Sponsor: Columbia University (Other)
• Overall Status: Completed
• CT.gov ID: NCT03054844
• Collaborator: (none)
• Enrollment: 55
• Location: 1
• Arms: 2
• Actual Duration (Months): 6.2
• Patients Per Site Per Month: 8.8

Study Details

Study Description

Brief Summary

Intranasal (IN) midazolam is an anxiolytic that is commonly used in the pediatric population for procedural anxiolysis in the emergency department (ED) setting to facilitate painful and distressing procedures, such as laceration repairs. Intranasal midazolam is both effective and safe in children. However, due to the acidic nature of midazolam, there is a burning sensation that is associated with the intranasal administration of midazolam. The use of IN lidocaine has been shown to decrease the pain associated with the administration of IN midazolam and other acidic solutions. The IN lidocaine can be given as a premedication (PREMED), where it is sprayed in the nares first to provide topical anesthesia, and then followed by the administration of the IN midazolam. Lidocaine can also be given concurrently with the IN midazolam (PREMIX), where it is mixed with the midazolam and then the combined mixture administered. Both methods have been shown to be effective in decreasing the pain associated with the intranasal administration of acidic solutions, such as midazolam, although the PREMIX method could have the advantage of requiring less number of sprays, and be tolerated better by children. Although both methods have been shown to work, it is not known if the PREMIX method is non-inferior to the PREMED method for decreasing pain and distress associated with administering IN midazolam. Therefore, the investigators aim to determine if the PREMIX method is non-inferior to the PREMED method of using lidocaine to decrease the pain and distress associated with the administration of IN midazolam in children.

Condition or Disease	Intervention/Treatment	Phase
Pain	Drug: Lidocaine; Drug: Lidocaine and midazolam (PREMIX); Drug: Midazolam	Phase 2

Detailed Description

We will enroll 50 children to determine whether the PREMED method is non-inferior to the PREMIX method. We based our sample size on the outcome of pain and distress associated with the administration of IN midazolam, which will be measured using our primary outcome measure of the Observational Scale of Behavioral Distress-Revised (OSBD-R). The OSBD-R is an observational measure of distress that has been well validated in the pediatric population for evaluating painful and distressing procedures, and has been used in children as young as 1 year of age [1,2]. The sample size of 50 patients was determined based on a prestated margin of non-inferiority (delta) of 1.8 (SD 2.25). This value was based on the minimum clinically significant differences used in prior studies of painful procedures in children in the emergency department [3,4,5]. To determine noninferiority using a delta of 1.80 (SD 2.25), with a 1-tailed alpha of 0.025 and power of 80%, we would require 25 patients in each arm, for a total of 50 patients. OSBD-R scores will be determined independently by two blinded trained assessors who will review the videotapes of the study procedures. Interrater reliability of the OSBD-R between the two assessors will evaluated by determining the intraclass correlation coefficient. The period of administration of the midazolam alone in the PREMED group and the period of administration of the midazolam/lidocaine mixture in the PREMIX group are the two phases which will be compared to each other to determine our primary outcome.

Secondary outcome measures of pain and distress associated with IN midazolam administration will include the Children's Hospital of Eastern Ontario Pain Scale (CHEOPS); the Faces-LegsActivity-Crying-Consolability (FLACC) scale; and cry duration. These are all continuous measures that will be analyzed using the independent samples t-test.We will also evaluate parental and provider satisfaction across various domains using a 5-point Likert scale (see attached document for questions to be asked). Responses will be dichotomized into "agree" (i.e. if respondent answers "agree" or "strongly agree") or "disagree" (i.e. if respondent responds "undecided", "disagree", or "strongly disagree") and analyzed using the chi square test.

Study Design

• Study Type: Interventional
• Actual Enrollment: 55 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Comparison of Two Methods Using Intranasal Lidocaine to Alleviate Discomfort Associated With Administration of Intranasal Midazolam in Children.
• Actual Study Start Date: Apr 3, 2017
• Actual Primary Completion Date: Oct 10, 2017
• Actual Study Completion Date: Oct 10, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PREMED Patients will receive 0.25 mL of IN 4% lidocaine (10 mg) in each naris (total of 0.5 mL/20 mg for both nares) preceding adminstration of IN midazolam.	Drug: Lidocaine; Lidocaine will be administered before administration of midazolam.; Other Names: PREMED ; Drug: Midazolam; Midazolam will be administered either after lidocaine, or as a mixture with lidocaine.
Experimental: PREMIX Patients will receive midazolam mixed with 0.5 mL of 4% lidocaine (20 mg).	Drug: Lidocaine and midazolam (PREMIX); Lidocaine will be administered as a mixture with midazolam.; Other Names: PREMIX

Outcome Measures

Primary Outcome Measures

1. Procedural Distress, OSBD-R [10 minutes]

   The Observational Scale of Behavioral Distress-Revised (OSBD-R) is an observational measure of pain and distress shown to have strong validity in children. The scale is an 8-factor, weighted observational scale used to measure distress associated with medical procedures, which has been validated in children and adults aged 1 to 20 years. The total Observational Scale of Behavioral Distress-Revised score is the sum of the scale scores for each phase, with each phase assigned a score from 0 to 23.5 units on a scale (0=no distress, 23.5=maximum distress), based on the frequency and types of behaviors observed during a predetermined number of 15-second intervals during each phase. There were four phases so the range of scores for the total OSBD-R was 0 to 94 units on a scale, with a higher score indicated a greater degree of distress.

Secondary Outcome Measures

1. Procedural Pain [10 minutes]

   The Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) utilizes six observational factors (cry, facial, verbal, torso, touch, and legs) to evaluate pain in young children and can be used to monitor the effectiveness of interventions for reducing the pain and discomfort of an intervention. This scale rates each behavior numerically, with a score of 4-6 units on a scale representing no pain, and a maximum score of 13 units on a scale representing (most pain perceived).

2. Procedural Distress, FLACC [10 minutes]

   The Faces, Legs, Activity, Cry, Consolability (FLACC) scale is comprised of five criteria (face, legs, activity, cry, consolability), with a possible score of 0 to 2 units on a scale for each criteria and a possible total score of 0 to 10 units on a scale (0 meaning no pain, 10 meaning most pain).

3. Procedural Distress, Cry Duration [10 minutes]

   Cry duration was measured in seconds and defined as the time from onset of crying following administration of an IN medication until the cessation of crying sounds and/or tears. If a patient did not cry, the cry duration was zero

4. Parental Satisfaction [1 minute]

   If my child needed medications to stay calm for a procedure, I would like to use these same medications again.

5. Provider Satisfaction [1 minute]

   I would like to use this method of administering intranasal midazolam and lidocaine again in the future

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Months to 7 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Between the age of ≥ 6 months or ≤ 7 years old

2. Undergoing a laceration repair

3. Treating physician has determined that patient requires intranasal midazolam to facilitate the laceration repair

Exclusion Criteria:

1. Weight < 5 kg

2. Known allergy to Lidocaine or Midazolam

3. Does not speak English or Spanish

4. Nasal injury precluding IN medication delivery

5. Presence of intranasal obstruction (mucous/blood) not easily cleared with suction or nose blowing

6. Baseline motor neurological abnormality (e.g. motor deficit, cerebral palsy)

7. Developmental delay, autism, autism spectrum disorder

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Morgan Stanley Children's Hospital	New York	New York	United States	10032

Sponsors and Collaborators

• Columbia University

Investigators

• Principal Investigator: Daniel S Tsze, MD, MPH, Columbia University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 22, 2016

More Information

Publications

• Fenster DB, Dayan PS, Babineau J, Aponte-Patel L, Tsze DS. Randomized Trial of Intranasal Fentanyl Versus Intravenous Morphine for Abscess Incision and Drainage. Pediatr Emerg Care. 2018 Sep;34(9):607-612. doi: 10.1097/PEC.0000000000000810.
• Godambe SA, Elliot V, Matheny D, Pershad J. Comparison of propofol/fentanyl versus ketamine/midazolam for brief orthopedic procedural sedation in a pediatric emergency department. Pediatrics. 2003 Jul;112(1 Pt 1):116-23.
• Lee-Jayaram JJ, Green A, Siembieda J, Gracely EJ, Mull CC, Quintana E, Adirim T. Ketamine/midazolam versus etomidate/fentanyl: procedural sedation for pediatric orthopedic reductions. Pediatr Emerg Care. 2010 Jun;26(6):408-12. doi: 10.1097/PEC.0b013e3181e057cd.
• Tsze DS, Ieni M, Fenster DB, Babineau J, Kriger J, Levin B, Dayan PS. Optimal Volume of Administration of Intranasal Midazolam in Children: A Randomized Clinical Trial. Ann Emerg Med. 2017 May;69(5):600-609. doi: 10.1016/j.annemergmed.2016.08.450. Epub 2016 Nov 4.
• Tsze DS, Steele DW, Machan JT, Akhlaghi F, Linakis JG. Intranasal ketamine for procedural sedation in pediatric laceration repair: a preliminary report. Pediatr Emerg Care. 2012 Aug;28(8):767-70.

• Responsible Party: Daniel S Tsze, MD, MPH, Assistant Professor of Pediatrics at CUMC, Columbia University
• ClinicalTrials.gov Identifier: NCT03054844
• Other Study ID Numbers: AAAQ6408
• First Posted: Feb 16, 2017
• Last Update Posted: Sep 11, 2019
• Last Verified: Aug 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Daniel S Tsze, MD, MPH, Assistant Professor of Pediatrics at CUMC, Columbia University: Intranasal; Pain; Lidocaine; Midazolam; Emergency department
• Additional relevant MeSH terms: Lidocaine; Midazolam

Study Results

Participant Flow

Arm/Group Title	PREMED	PREMIX
Arm/Group Description	Patients will receive 0.25 mL of IN 4% lidocaine (10 mg) in each naris (total of 0.5 mL/20 mg for both nares) preceding adminstration of IN midazolam. Lidocaine: Lidocaine will be administered before administration of midazolam. Midazolam: Midazolam will be administered either after lidocaine, or as a mixture with lidocaine.	Patients will receive midazolam mixed with 0.5 mL of 4% lidocaine (20 mg). Lidocaine and midazolam (PREMIX): Lidocaine will be administered as a mixture with midazolam.
Period Title: Overall Study
STARTED	28	27
COMPLETED	25	26
NOT COMPLETED	3	1

Baseline Characteristics

Arm/Group Title	PREMED	PREMIX	Total
Arm/Group Description	Patients will receive 0.25 mL of IN 4% lidocaine (10 mg) in each naris (total of 0.5 mL/20 mg for both nares) preceding adminstration of IN midazolam. Lidocaine: Lidocaine will be administered before administration of midazolam. Midazolam: Midazolam will be administered either after lidocaine, or as a mixture with lidocaine.	Patients will receive midazolam mixed with 0.5 mL of 4% lidocaine (20 mg). Lidocaine and midazolam (PREMIX): Lidocaine will be administered as a mixture with midazolam.	Total of all reporting groups
Overall Participants	25	26	51
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	2	2	2
Sex: Female, Male (Count of Participants)
Female	12 48%	10 38.5%	22 43.1%
Male	13 52%	16 61.5%	29 56.9%
Race/Ethnicity, Customized (Count of Participants)
Hispanic	16 64%	21 80.8%	37 72.5%
White	3 12%	1 3.8%	4 7.8%
Black	2 8%	2 7.7%	4 7.8%
More than one	4 16%	2 7.7%	6 11.8%

Outcome Measures

1. Primary Outcome

Title	Procedural Distress, OSBD-R
Description	The Observational Scale of Behavioral Distress-Revised (OSBD-R) is an observational measure of pain and distress shown to have strong validity in children. The scale is an 8-factor, weighted observational scale used to measure distress associated with medical procedures, which has been validated in children and adults aged 1 to 20 years. The total Observational Scale of Behavioral Distress-Revised score is the sum of the scale scores for each phase, with each phase assigned a score from 0 to 23.5 units on a scale (0=no distress, 23.5=maximum distress), based on the frequency and types of behaviors observed during a predetermined number of 15-second intervals during each phase. There were four phases so the range of scores for the total OSBD-R was 0 to 94 units on a scale, with a higher score indicated a greater degree of distress.
Time Frame	10 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PREMED	PREMIX
Arm/Group Description	Patients will receive 0.25 mL of IN 4% lidocaine (10 mg) in each naris (total of 0.5 mL/20 mg for both nares) preceding adminstration of IN midazolam. Lidocaine: Lidocaine will be administered before administration of midazolam. Midazolam: Midazolam will be administered either after lidocaine, or as a mixture with lidocaine.	Patients will receive midazolam mixed with 0.5 mL of 4% lidocaine (20 mg). Lidocaine and midazolam (PREMIX): Lidocaine will be administered as a mixture with midazolam.
Measure Participants	25	26
Mean (95% Confidence Interval) [Units on a scale]	6.4	7

2. Secondary Outcome

Title	Procedural Pain
Description	The Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) utilizes six observational factors (cry, facial, verbal, torso, touch, and legs) to evaluate pain in young children and can be used to monitor the effectiveness of interventions for reducing the pain and discomfort of an intervention. This scale rates each behavior numerically, with a score of 4-6 units on a scale representing no pain, and a maximum score of 13 units on a scale representing (most pain perceived).
Time Frame	10 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PREMED	PREMIX
Arm/Group Description	Patients will receive 0.25 mL of IN 4% lidocaine (10 mg) in each naris (total of 0.5 mL/20 mg for both nares) preceding adminstration of IN midazolam. Lidocaine: Lidocaine will be administered before administration of midazolam. Midazolam: Midazolam will be administered either after lidocaine, or as a mixture with lidocaine.	Patients will receive midazolam mixed with 0.5 mL of 4% lidocaine (20 mg). Lidocaine and midazolam (PREMIX): Lidocaine will be administered as a mixture with midazolam.
Measure Participants	25	26
Mean (95% Confidence Interval) [Units on a scale]	10.6	10.5

3. Secondary Outcome

Title	Procedural Distress, FLACC
Description	The Faces, Legs, Activity, Cry, Consolability (FLACC) scale is comprised of five criteria (face, legs, activity, cry, consolability), with a possible score of 0 to 2 units on a scale for each criteria and a possible total score of 0 to 10 units on a scale (0 meaning no pain, 10 meaning most pain).
Time Frame	10 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PREMED	PREMIX
Arm/Group Description	Patients will receive 0.25 mL of IN 4% lidocaine (10 mg) in each naris (total of 0.5 mL/20 mg for both nares) preceding adminstration of IN midazolam. Lidocaine: Lidocaine will be administered before administration of midazolam. Midazolam: Midazolam will be administered either after lidocaine, or as a mixture with lidocaine.	Patients will receive midazolam mixed with 0.5 mL of 4% lidocaine (20 mg). Lidocaine and midazolam (PREMIX): Lidocaine will be administered as a mixture with midazolam.
Measure Participants	25	26
Mean (95% Confidence Interval) [Units on a scale]	6.7	7

4. Secondary Outcome

Title	Procedural Distress, Cry Duration
Description	Cry duration was measured in seconds and defined as the time from onset of crying following administration of an IN medication until the cessation of crying sounds and/or tears. If a patient did not cry, the cry duration was zero
Time Frame	10 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PREMED	PREMIX
Arm/Group Description	Patients will receive 0.25 mL of IN 4% lidocaine (10 mg) in each naris (total of 0.5 mL/20 mg for both nares) preceding adminstration of IN midazolam. Lidocaine: Lidocaine will be administered before administration of midazolam. Midazolam: Midazolam will be administered either after lidocaine, or as a mixture with lidocaine.	Patients will receive midazolam mixed with 0.5 mL of 4% lidocaine (20 mg). Lidocaine and midazolam (PREMIX): Lidocaine will be administered as a mixture with midazolam.
Measure Participants	25	26
Mean (95% Confidence Interval) [seconds]	84	73

5. Secondary Outcome

Title	Parental Satisfaction
Description	If my child needed medications to stay calm for a procedure, I would like to use these same medications again.
Time Frame	1 minute

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PREMED	PREMIX
Arm/Group Description	Patients will receive 0.25 mL of IN 4% lidocaine (10 mg) in each naris (total of 0.5 mL/20 mg for both nares) preceding adminstration of IN midazolam. Lidocaine: Lidocaine will be administered before administration of midazolam. Midazolam: Midazolam will be administered either after lidocaine, or as a mixture with lidocaine.	Patients will receive midazolam mixed with 0.5 mL of 4% lidocaine (20 mg). Lidocaine and midazolam (PREMIX): Lidocaine will be administered as a mixture with midazolam.
Measure Participants	25	26
Count of Participants [Participants]	10 40%	12 46.2%

6. Secondary Outcome

Title	Provider Satisfaction
Description	I would like to use this method of administering intranasal midazolam and lidocaine again in the future
Time Frame	1 minute

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PREMED	PREMIX
Arm/Group Description	Patients will receive 0.25 mL of IN 4% lidocaine (10 mg) in each naris (total of 0.5 mL/20 mg for both nares) preceding adminstration of IN midazolam. Lidocaine: Lidocaine will be administered before administration of midazolam. Midazolam: Midazolam will be administered either after lidocaine, or as a mixture with lidocaine.	Patients will receive midazolam mixed with 0.5 mL of 4% lidocaine (20 mg). Lidocaine and midazolam (PREMIX): Lidocaine will be administered as a mixture with midazolam.
Measure Participants	25	26
Count of Participants [Participants]	8 32%	24 92.3%

Adverse Events

Time Frame	Course of ED visit, typically between 1-2 hours
Arm/Group Title	PREMED		PREMIX
Arm/Group Description	Patients will receive 0.25 mL of IN 4% lidocaine (10 mg) in each naris (total of 0.5 mL/20 mg for both nares) preceding adminstration of IN midazolam. Lidocaine: Lidocaine will be administered before administration of midazolam. Midazolam: Midazolam will be administered either after lidocaine, or as a mixture with lidocaine.		Patients will receive midazolam mixed with 0.5 mL of 4% lidocaine (20 mg). Lidocaine and midazolam (PREMIX): Lidocaine will be administered as a mixture with midazolam.
All Cause Mortality
	PREMED		PREMIX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/26 (0%)
Serious Adverse Events
	PREMED		PREMIX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/26 (0%)
Other (Not Including Serious) Adverse Events
	PREMED		PREMIX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/25 (16%)		0/26 (0%)
Gastrointestinal disorders
Vomiting	3/25 (12%)		0/26 (0%)
General disorders
Epistaxis	1/25 (4%)		0/26 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.