Clinical trial NCT03054844
Conditions: Pain
Keywords: Intranasal Pain Lidocaine Midazolam Emergency department
Sponsor: Columbia University
Start date: 2017-04-03; Completion date: 2017-10-10
Enrollment: 55 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

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.

Arms: arm 1: 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. arm 2: Patients will receive midazolam mixed with 0.5 mL of 4% lidocaine (20 mg).
Interventions: intervention 1: Lidocaine intervention 2: Lidocaine and midazolam (PREMIX) intervention 3: Midazolam
Intervention descriptions: intervention 1: Lidocaine will be administered before administration of midazolam. intervention 2: Lidocaine will be administered as a mixture with midazolam. intervention 3: Midazolam will be administered either after lidocaine, or as a mixture with lidocaine.

Protocol documents:
Prot_SAP_000.pdf: 
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Comparison of Two Methods Using Lidocaine to Alleviate Discomfort 
Associated with Administration of Intranasal Midazolam in Children: 
Standalone Protocol 
 
Study Purpose and Rationale 
Intranasal (IN) midazolam is a common medication administered to children requiring anxiolysis to facilitate distressing 
medical procedures in the pediatric emergency department (Klein 2011, Yealy 1992, Theroux 1993) .  IN midazolam is 
safe and effective, but it causes a significant amount of nasal pain and burning when administered by the IN route (Lugo 
1993, Chiaretti 2011, Smith 2016).  One way of ameliorating the nasal pain associated with IN midazolam is to use IN 
lidocaine. 
Prior studies have described the successful use of IN lidocaine to decrease the pain associated with acidic IN 
medications, such as midazolam.  One method is to premedicate using IN lidocaine (PREMED), meaning that lidocaine is 
sprayed into the nares prior to a subsequent administration of IN midazolam (Chiaretti 2011, Lugo 1993, Smith 
2016).  The second method is to mix the lidocaine with the midazolam (PREMIX), and to administer both medications at 
the same time as a mixed solution (Antonio 2011). 
Both methods have been shown to effectively decrease the pain associated with acidic IN medications, such as 
midazolam (Chiaretti 2011, Smith 2016, Antonio 2011).  However, it is unclear whether one method is more effective than 
the other when used in children.  A method, such as PREMIX, which requires administering only one solution, rather than 
two as required by the PREMED method, would be more convenient and potentially less distressing to children if it 
worked as well as the PREMED method.  Therefore, we aim to determine whether using intranasal lidocaine via the 
PREMIX method is non-inferior to the PREMED method for reducing pain associated with IN midazolam. 
REFERENCES: 
Antonio, C., Zurek, J., Creighton, P., Johnson, K. & Heard, C. Reducing the pain of intranasal drug administration. Pediatr. Dent. 33, 415–419 (2011). 
Chiaretti, Antonio, Barone, Giuseppe, Rigante, Donato, Ruggiero, Antonio Pierri, Filmena, Barbi, Egidio, Barone, Giovanni, Riccardi, R. MATERIALS 
AND METHODS STATISTICAL ANALYSIS. Arch Dis Child 96, (2011). 
Klein, E. J., Brown, J. C., Kobayashi, A., Osincup, D. & Seidel, K. A randomized clinical trial comparing oral, aerosolized intranasal, and aerosolized 
buccal midazolam. Ann. Emerg. Med. (2011). doi:10.1016/j.annemergmed.2011.05.016 
Lugo, R. A., Fishbein, M., Nahata, M. C. & Lininger, B. Complication of Intranasal Midazolam. Pediatr.  92, 638 (1993). 
Smith, D, Cheek H, Pruitt, C. Lidocaine pretreatment reduces the discomfort of intranasal midazolam administration: A randomized, double-blind, 
placebo-controlled trial. Acad Emerg Med. 2016. Oct 14. doi: 10.1111/acen.13115. [Epub aheada of print]  
Theroux, M. C. et al. Efficacy of intranasal midazolam in facilitating suturing of lacerations in preschool children in the emergency 
department. Pediatrics 91, 624–7 (1993). 
Yealy, D. M., Ellis, J. H., Hobbs, G. D. & Moscati, R. M. Intranasal midazolam as a sedative for children during laceration repair. Am. J. Emerg. 
Med. (1992). doi:10.1016/0735-6757(92)90190-9    
 
 
 
 
 
 
 
 
 
 
 


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Study Design 
 
We will conduct a prospective, randomized, investigator blinded, non-inferiority clinical trial of 55 children comparing the 
PREMED (premedicating with IN lidocaine before IN midazolam administration) versus the PREMIX (mixing lidocaine with 
midazolam and administering the combined mixture) methods of administering IN lidocaine to decrease the pain 
associated with IN midazolam.  Eligible patients will be block randomized to receive IN midazolam and lidocaine by either 
the PREMED or PREMIX method. Both techniques are currently considered standard of care at NYPH (please see 
attached hospital protocol).  
 
Statistical Procedures 
We will enroll 55 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 (Tsze 2013, Tsze 
2016).   
The sample size of 50 patients was determined based on a pre-stated 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 (Fenster 2016, Godambe 2003, Lee-Jayaram 2010). To determine non-inferiority 
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 (See Figure 2; phases to be compared highlighted by red 
boxes).  
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-Legs-Activity-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. 
Procedures 
 
Patients between the ages of 6 months to 7 years who require a laceration repair will be screened for possible enrolment. 
If the patient requires IN midazolam to facilitate the laceration repair, as determined by their treating physician, and the 
patient fulfills inclusion criteria (age of ≥ 6 months  or ≤ 7 years old, undergoing a laceration repair, and identified by 
physician as as needing IN Midazolam) and exclusion criteria (weight < 5 kg , known allergy to Lidocaine or Midazolam, 
inability to speak English or Spanish, nasal injury precluding IN medication delivery, presence of intranasal obstruction 
(mucous/blood) not easily cleared with suction or nose blowing, baseline motor neurological abnormality (e.g. motor 
deficit, cerebral palsy), developmental delay, autism, or autism spectrum disorder).  The treating physician will ask the 
family if they would be interested in hearing about the study. If the family agrees, the study will be introduced and 
discussed with the family, and written informed consent obtained, by a member of the study team. 
 
Enrolled patients will be block randomized using an online randomization program to either the PREMED or PREMIX 
study arm.  Study arm assignment will be concealed until the patient is enrolled and the online randomization program is 
accessed. 
 
 


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We will collect patient demographics and relevant historical information. These data elements include the patient's age 
(years); sex (female/male); weight (kilograms); race (Black/African American, White, Asian, Native American/Other Pacific 
Islander, American Indian/Alaskan Native, more than one race, non-specific ) and ethnicity (Hispanic or Latino, Non-
Hispanic or Latino, or non-specific); whether the patient has ever received IN midazolam before (yes/no); and whether the 
patient has received any type of intranasal medication before (yes/no). The dose of IN midazolam administered 
(milligrams) will be recorded. 
 
All IN medications will be administered in a standardized fashion using a mucosal atomization device (MAD), as per 
NYPH Medication Use Manual Policy "Intranasal Administration of Analgesics and Sedatives Using a Mucosal 
Atomization Device (see attached documents). All patients will receive the standard dose of IN midazolam (0.05 mg/kg, 
maximum total dose 20 mg), and the standard dose of IN lidocaine (4% lidocaine, 20 mg = 0.5 mL total; 0.25 mL per 
nare), as per NYPH policy. 
 
All patients will have a baseline assessment of pain and distress prior to administration of any medications.  A study team 
member will videotape the child for 1 minute. 
 
*For patients randomized to the PREMED study arm: 
1. Patients will receive 0.25 mL of IN lidocaine in each nare (0.5 mL total) 
2. IN lidocaine administration will be videotaped, starting from time of administration of the first aliquot of lidocaine. 
3. Wait at least 5 minutes after time of IN lidocaine administration (patient will still be videotaped during this time). 
4. Patients will receive 0.5 mg/kg of IN midazolam. The total volume will be divided into aliquots of 0.5 mL, and 
administered into alternating nares until the total volume is dispensed.  There will be at least a 10-second pause before 
re-administering to the same nare a subsequent time. 
5. The administration of IN midazolam administration will also be videotaped, continuing from the prior steps; it will 
continue until at least 1 minute after completion of administration of IN midazolam, or until at least 30 seconds after 
cessation of crying (if crying occurs). 
6. The administration of all medications must be completed by a pediatric emergency medicine attending or pediatric 
emergency medicine fellow.  
 
*For patients randomized to the PREMIX study arm: 
1. 0.5 mg/kg of midazolam will be mixed with 20 mg (0.5 mL) of 4% lidocaine.  
2. The total volume will be administered to the patient in aliquots of 0.5 mL, and administered into alternating nares until 
the total volume is dispensed.  There will be at least a 10-second pause before re-administering to the same nare a 
subsequent time. 
3. Administration of the midazolam/lidocaine mixture will be videotaped, starting from the time of administration of the first 
aliquot of the mixture, until at least 1 minute later, or until at least 30 seconds after cessation of crying (if crying occurs). 
 
A flowchart illustrating the study procedure has been attached (see Figure 1 in attached documents). 
 
After the videotaping has been completed, all caregivers providers who administered the IN medications will be asked to 
complete a brief questionnaire regarding their satisfaction with the administration of IN medications (see attached 
documents for questions).  A study team member will monitor the patient during the remainder of their procedure, until 
procedure completion, to document any adverse events (see attached documents for adverse events collected).   
 
The administration of the midazolam alone in the PREMED group (Step #4 in the PREMED study arm description) and 
the administration of the midazolam/lidocaine mixture in the PREMIX group (Step #3 in the PREMIX study arm 
description) are the two phases which will be compared to each other to determine our primary outcome (See Figure 2).  
 
 
 
 
 
 
 
 
 


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MISSED ELIGIBLE POPULATION 
 
We will be doing a retrospective medical record review to identify a missed eligible population (i.e. patients who are 
eligible, but are not screened or enrolled).  As patients come to the emergency department 24/7, it is inevitable that some 
eligible patients will be missed.  We will collect information on these patients from the medical records to ensure scientific 
credibility by showing that we are not enrolling a biased sample of children with lacerations.  This population will not be 
subjected to study procedures or interventions. The data points collected for these patients will be retrieved from existing 
medical records and are limited and specific.  They include: 
- Age (years, months - NO date of birth will be documented) 
- Sex (female, male) 
- Chief complaint 
- Attending physician 
 
Potential Risks 
 
There are no risks greater than that to be expected as part of the usual medical care that we provide for children with the 
same condition who would receive the same medications.  All of the treatments you could receive in this study are 
considered usual practice as described in the NewYork Presbyterian Hospital Policy for intranasal medications. 
 
Potential Benefits 
 
There are no potential direct benefits to participating in this study, but there may be benefits for children in the future who 
will receive intranasal midazolam.      
 
Alternatives 
 
The parent/guardian can choose for their child not to participate in the study.  
 
Data and Safety Monitoring 
Data will be reviewed on an ongoing basis by the PI with each patient enrolled. On an ongoing basis, the investigators will 
monitor accrual of study subjects, assess adherence to study protocol, assess data quality, and collect and review 
adverse events and other subject safety matters. We will submit to the IRB protocol deviations and any requested protocol 
modifications.  
All data will be maintained on password protected computers and in locked file cabinets in a locked room to which only 
authorized study personnel will have access. Only approved research staff will view the clinical information of children 
enrolled in this study. We will retain study records, documentation and videotapes for 3 years after the last enrolled patient 
has completed all study procedures.  
We will convene a Data Safety Monitoring Board (DSMB) comprised of two physicians unrelated to the study (members 
TBD).  The DSMB will evaluate adherence to the protocol every 6 months and report any protocol violations to the IRB. 
Adverse Event Reporting: An adverse event is any untoward medical occurrence by a subject. For each patient, the 
investigators will evaluate adverse events after completion of enrollment. All unanticipated problems (i.e. unexpected 
events, outcomes, or occurrences, at least possibly related to the research, and suggest an increase in risk of harm to 
subjects or others) will be reported to the IRB. This reporting will be done promptly, but no later than one week after the 
occurrence or after the PI acquiring knowledge of the unanticipated problem, and will also be reported at time of 
continuing review. All serious adverse events (i.e. airway obstruction requiring airway repositioning or adjunct airway; 
positive pressure ventilation; apnea) will be reviewed by the investigators and reported to the IRB within 96 hours 
 
 
END OF STANDALONE PROTOCOL