Intranasal Dexmedetomidine Premedication in Children

• Sponsor: University of Mississippi Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT02250703
• Collaborator: (none)
• Enrollment: 75
• Location: 1
• Arms: 2
• Duration (Months): 24
• Patients Per Site Per Month: 3.1

Study Details

Study Description

Brief Summary

BACKGROUND INFORMATION AND RATIONALE

Pediatric patients scheduled for dental procedures under general anesthesia can have significant anxiety before the procedure. They are commonly pre medicated to minimize distress and to facilitate a smooth induction of anesthesia. Oral Midazolam at 0.5mg/kg dose is more widely used for this purpose . However the commonly used maximum dose is up to 15mg. It also has many limitations such as paradoxical reaction, increased incidence of emergence delirium and negative postoperative behavior changes . Intranasal dexmedetomidine has been used an effective and safe alternative premedication to oral midazolam in children. At a dose of 2micrograms/kg, intranasal dexmedetomidine as premedication resulted in excellent sedation in children aged 5-8yrs with no adverse hemodynamic effects. It has other advantages such as providing analgesia and facilitating smooth emergence from anesthesia.

The goal of this study is to find out if intranasal dexmedetomidine is a superior alternative as premedication to oral midazolam in children weighing more than 20kg undergoing general anesthesia for dental rehabilitation.

Condition or Disease	Intervention/Treatment	Phase
Preoperative Sedation	Drug: Midazolam; Drug: Dexmedetomidine	Phase 3

Detailed Description

After Institutional Review Board (IRB) approval and written informed consent from patients' parents or legally authorized representative, 80 children older than 5yrs and weighing more than 20kg, ASA physical status 1 or 2, scheduled for elective dental rehabilitation with general anesthesia will be enrolled in this prospective randomized double blinded study.

Exclusion criteria include known allergy or hypersensitivity to midazolam or dexmedetomidine, uncorrected congenital heart disease or history of cardiac arrhythmia, children at risk for airway obstruction (OSA or cranio facial syndrome) and pregnant minors Patients will be randomly assigned to one of two groups M (midazolam) or D (dexmedetomidine) using computer-generated numbers in sealed envelopes.

All the patients will be brought to their pre-op room and premedicated at least 30 min before induction of anesthesia.

In M group, patients will be given oral midazolam 0.5mg/kg upto maximum dose of 15mg (5mg/ml parenteral preparation) mixed with flavored syrup.

In D group, patients will be given intranasal dexmedetomidine 2mcg/kg upto maximum dose of 100mcg prepared from 100mcg/ml parenteral preparation (Hospira R). The drug will be administered using a intranasal mucosal administration device (LMA MAD NasalTM). Atomized nasal medications offer rapid absorption across mucosal membranes to the blood stream avoiding first-pass metabolism.

Parents will be present in the room during premedication. The Anesthesia personnel involved in the care of the patient (MD or CRNA) will prepare and administer all study drugs. All patients will be continuously monitored in the holding area with pulse oximetry and blood pressure monitor. HR, SPO2 and BP will be recorded every 15min after administration of premedication until transfer to the OR. Emergency medications including atropine and epinephrine will be immediately available in the pre-op holding area. Oral midazolam has been used with very little effect on hemodynamic parameters. Although intranasal dexmedetomidine can decrease HR and BP, it has been used at the dose of 2mcg/kg without any adverse hemodynamic effect . Any intervention needed to treat drop in HR (<50) and BP (sys BP <60) after the drug administration will be recorded.

Behavior of the children at the time of premedication will be documented ( easy or difficult). Any unwanted effects during administration such as spitting or vomiting of oral drug and pain or irritation from nasal administration will be documented.

The dental resident blinded to study drug administration will do the pre-operative sedation status and acceptance of mask induction.

Sedation status will be assessed using University of Michigan sedation scale (UMSS)on separation from parents and at induction after moving to the OR table. Acceptance of mask induction will be documented on a 4-point scale.

Standard ASA monitors will be applied before induction of anesthesia. All patients will undergo mask induction with O2/N2O/Sevo. An intravenous line will be inserted and secured. Both nostrils will be prepped nasal drops and tips of tracheal tubes covered with red rubber to minimize bleeding. Nasal intubation will be performed with direct laryngoscopy and McGill's forceps. Appropriate size cuffed tracheal tubes will be inserted and secured after additional IV medications with propofol 2-3mg/kg and fentanyl 1-2mcg/kg. Anesthesia will be maintained with O2/Sevo, IV morphine 0.05 to 0.1mg/kg and IV toradol 0.5mg/kg (if there is no allergy or contraindication to morphine or toradol) After the completion of procedure, patients will be extubated in the operating room and brought to recovery room and allowed to wake up slowly in the recovery position.

PACU nurses will evaluate Behavior at awakening using four-point wake up score (9,20). Patients will also be asked if they remember mask induction (yes or no) when they are ready for discharge. Incidence of nausea, vomiting, shivering will be documented in PACU. Time spent in phase 1 recovery room will also be recorded .

Study Design

• Study Type: Interventional
• Actual Enrollment: 75 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: Comparing Intranasal Dexmedetomidine With Oral Midazolam as Premedication for Older Children Undergoing General Anesthesia for Dental Rehabilitation
• Study Start Date: Sep 1, 2014
• Actual Primary Completion Date: Sep 1, 2016
• Actual Study Completion Date: Sep 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Midazolam In M group, patients will be given oral midazolam 0.5mg/kg upto maximum dose of 15mg (5mg/ml parenteral preparation) mixed with flavored syrup as premedication	Drug: Midazolam; oral midazolam 0.5mg/kg upto maximum dose of 15mg
Experimental: Dexmedetomidine In D group, patients will be given intranasal dexmedetomidine 2mcg/kg upto maximum dose of 100mcg prepared from 100mcg/ml parenteral preparation (Hospira R) . The drug will be administered using a intranasal mucosal administration device (LMA MAD NasalTM).	Drug: Dexmedetomidine; intranasal dexmedetomidine 2mcg/kg upto maximum dose of 100mcg

Outcome Measures

Primary Outcome Measures

1. University of Michigan Sedation Scale [Day 0:Just before the patient will be brought to the operating room]

   Level of sedation at separation from parents and at the time of mask induction will be measured on a scale of 0 to 4 (University of Michigan Sedation Scale) University of Michigan Sedation Scale: 0 -Awake/Alert 1 -Minimally Sedated: Tired/sleepy, appropriate response to verbal conversation and/or sounds. 2- Moderately Sedated: Somnolent/sleeping, easily aroused with light tactile stimulation. 3 - Deeply Sedated: Deep sleep, arousable only with significant physical stimulation. 4 - Unarousable Moderately and Deeply sedated: Satisfactory Awake, minimally sedate, unarousable: Unsatisfactory

Secondary Outcome Measures

1. Acceptance of Mask Induction [Day 0: At the time when anesthesia is induced]

   on a scale of 1 to 4 excellent( cooperative) good( slight fear, easily calmed) fair ( moderate fear, not calmed with reassurance) Poor( agitated, terrified) 1 and 2 are considered satisfactory 3 and 4 are considered unsatisfactory

2. Wake up Behavior [Day 0: At the end of surgery when the patient recovers from anesthesia]

   assessed in post anesthesia recovery unit after the procedure on a scale of 1o 4 calm not calm but easily calmed moderately agitated or restless combative/disoriented 1 and 2 are considered satisfactory 3 and 4 are considered unsatisfactory

3. Presence of Amnesia to Mask Induction [Day 0: at the time of discharge of the patient from the recovery room]

   Yes or No (if the patient remembers mask induction)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 5 Years to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Children older than 5yrs and weighing more than 20kg , who are scheduled for ambulatory dental rehabilitation at Batson operating rooms.

• ASA classification 1 or 2

Exclusion Criteria

• Known allergy to midazolam, dexmedetomidine,morphine, fentanyl, sevoflurane and propofol.

• uncorrected congenital heart disease or history of cardiac arrhythmia,

• children at risk for airway obstruction (OSA or cranio facial syndrome),

• pregnant minors

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's of Mississippi/University of Mississipi Medical Center	Jackson	Mississippi	United States	39216

Sponsors and Collaborators

• University of Mississippi Medical Center

Investigators

• Principal Investigator: Madhankumar Sathyamoorthy, MBBS, MS, University of Mississippi Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

• Kain ZN, Mayes LC, Bell C, Weisman S, Hofstadter MB, Rimar S. Premedication in the United States: a status report. Anesth Analg. 1997 Feb;84(2):427-32.
• Kanegaye JT, Favela JL, Acosta M, Bank DE. High-dose rectal midazolam for pediatric procedures: a randomized trial of sedative efficacy and agitation. Pediatr Emerg Care. 2003 Oct;19(5):329-36.
• Lönnqvist PA, Habre W. Midazolam as premedication: is the emperor naked or just half-dressed? Paediatr Anaesth. 2005 Apr;15(4):263-5.
• McGraw T, Kendrick A. Oral midazolam premedication and postoperative behaviour in children. Paediatr Anaesth. 1998;8(2):117-21.

• Responsible Party: Madhankumar Sathyamoorthy, Assistant Professor, University of Mississippi Medical Center
• ClinicalTrials.gov Identifier: NCT02250703
• Other Study ID Numbers: 2014-0131
• First Posted: Sep 26, 2014
• Last Update Posted: Jul 7, 2017
• Last Verified: Jun 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Madhankumar Sathyamoorthy, Assistant Professor, University of Mississippi Medical Center: Premedication
• Additional relevant MeSH terms: Midazolam; Dexmedetomidine

Study Results

Participant Flow

Arm/Group Title	Midazolam	Dexmedetomidine
Arm/Group Description	In M group, patients will be given oral midazolam 0.5mg/kg upto maximum dose of 15mg (5mg/ml parenteral preparation) mixed with flavored syrup as premedication Midazolam: oral midazolam 0.5mg/kg upto maximum dose of 15mg	In D group, patients will be given intranasal dexmedetomidine 2mcg/kg upto maximum dose of 100mcg prepared from 100mcg/ml parenteral preparation (Hospira R) . The drug will be administered using a intranasal mucosal administration device (LMA MAD NasalTM). Dexmedetomidine: intranasal dexmedetomidine 2mcg/kg upto maximum dose of 100mcg
Period Title: Overall Study
STARTED	38	37
COMPLETED	37	36
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Midazolam	Dexmedetomidine	Total
Arm/Group Description	In M group, patients will be given oral midazolam 0.5mg/kg upto maximum dose of 15mg (5mg/ml parenteral preparation) mixed with flavored syrup as premedication Midazolam: oral midazolam 0.5mg/kg upto maximum dose of 15mg	In D group, patients will be given intranasal dexmedetomidine 2mcg/kg upto maximum dose of 100mcg prepared from 100mcg/ml parenteral preparation (Hospira R) . The drug will be administered using a intranasal mucosal administration device (LMA MAD NasalTM). Dexmedetomidine: intranasal dexmedetomidine 2mcg/kg upto maximum dose of 100mcg	Total of all reporting groups
Overall Participants	37	36	73
Age (Count of Participants)
<=18 years	37 100%	36 100%	73 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	7.62 (2.3)	8.0 (3.37)	7.9 (3.1)
Sex: Female, Male (Count of Participants)
Female	11 29.7%	12 33.3%	23 31.5%
Male	26 70.3%	24 66.7%	50 68.5%
Region of Enrollment (Count of Participants)
United States	37 100%	36 100%	73 100%

Outcome Measures

1. Primary Outcome

Title	University of Michigan Sedation Scale
Description	Level of sedation at separation from parents and at the time of mask induction will be measured on a scale of 0 to 4 (University of Michigan Sedation Scale) University of Michigan Sedation Scale: 0 -Awake/Alert 1 -Minimally Sedated: Tired/sleepy, appropriate response to verbal conversation and/or sounds. 2- Moderately Sedated: Somnolent/sleeping, easily aroused with light tactile stimulation. 3 - Deeply Sedated: Deep sleep, arousable only with significant physical stimulation. 4 - Unarousable Moderately and Deeply sedated: Satisfactory Awake, minimally sedate, unarousable: Unsatisfactory
Time Frame	Day 0:Just before the patient will be brought to the operating room

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Midazolam	Dexmedetomidine
Arm/Group Description	In M group, patients will be given oral midazolam 0.5mg/kg upto maximum dose of 15mg (5mg/ml parenteral preparation) mixed with flavored syrup as premedication Midazolam: oral midazolam 0.5mg/kg upto maximum dose of 15mg	In D group, patients will be given intranasal dexmedetomidine 2mcg/kg upto maximum dose of 100mcg prepared from 100mcg/ml parenteral preparation (Hospira R) . The drug will be administered using a intranasal mucosal administration device (LMA MAD NasalTM). Dexmedetomidine: intranasal dexmedetomidine 2mcg/kg upto maximum dose of 100mcg
Measure Participants	37	36
Satisfactory sedation on separation from parents	15 40.5%	25 69.4%
Unsatisfactory sedation on separation from parents	22 59.5%	11 30.6%
Satisfactory sedation on transfer to OR table	12 32.4%	22 61.1%
Unsatisfactory sedation on transfer to OR table	25 67.6%	14 38.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Midazolam, Dexmedetomidine
	Comments	A sample size of at least 33 patients in each group would detect at least 30% difference in proportion of children who achieve satisfactory sedation between the M and D groups at 0.05 level of significance and 80% power
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.025
	Comments	Difference in proportions in satisfactory sedation on separation from parents and on induction between M and D groups (Primary Outcome variables)
	Method	Chi-squared
	Comments

2. Secondary Outcome

Title	Acceptance of Mask Induction
Description	on a scale of 1 to 4 excellent( cooperative) good( slight fear, easily calmed) fair ( moderate fear, not calmed with reassurance) Poor( agitated, terrified) 1 and 2 are considered satisfactory 3 and 4 are considered unsatisfactory
Time Frame	Day 0: At the time when anesthesia is induced

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Midazolam	Dexmedetomidine
Arm/Group Description	In M group, patients will be given oral midazolam 0.5mg/kg upto maximum dose of 15mg (5mg/ml parenteral preparation) mixed with flavored syrup as premedication Midazolam: oral midazolam 0.5mg/kg upto maximum dose of 15mg	In D group, patients will be given intranasal dexmedetomidine 2mcg/kg upto maximum dose of 100mcg prepared from 100mcg/ml parenteral preparation (Hospira R) . The drug will be administered using a intranasal mucosal administration device (LMA MAD NasalTM). Dexmedetomidine: intranasal dexmedetomidine 2mcg/kg upto maximum dose of 100mcg
Measure Participants	37	36
Satisfactory mask induction	35 94.6%	29 80.6%
unsatisfactory mask induction	2 5.4%	7 19.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Midazolam, Dexmedetomidine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Chi-squared
	Comments

3. Secondary Outcome

Title	Wake up Behavior
Description	assessed in post anesthesia recovery unit after the procedure on a scale of 1o 4 calm not calm but easily calmed moderately agitated or restless combative/disoriented 1 and 2 are considered satisfactory 3 and 4 are considered unsatisfactory
Time Frame	Day 0: At the end of surgery when the patient recovers from anesthesia

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Midazolam	Dexmedetomidine
Arm/Group Description	In M group, patients will be given oral midazolam 0.5mg/kg upto maximum dose of 15mg (5mg/ml parenteral preparation) mixed with flavored syrup as premedication Midazolam: oral midazolam 0.5mg/kg upto maximum dose of 15mg	In D group, patients will be given intranasal dexmedetomidine 2mcg/kg upto maximum dose of 100mcg prepared from 100mcg/ml parenteral preparation (Hospira R) . The drug will be administered using a intranasal mucosal administration device (LMA MAD NasalTM). Dexmedetomidine: intranasal dexmedetomidine 2mcg/kg upto maximum dose of 100mcg
Measure Participants	37	36
satisfactory wake up behavior	37 100%	35 97.2%
unsatisfactory wake up behavior	0 0%	1 2.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Midazolam, Dexmedetomidine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Chi-squared
	Comments

4. Secondary Outcome

Title	Presence of Amnesia to Mask Induction
Description	Yes or No (if the patient remembers mask induction)
Time Frame	Day 0: at the time of discharge of the patient from the recovery room

Outcome Measure Data

Analysis Population Description

7 patients in the M group and 5 patients in D group had significant developmental delay and could not answer the question regarding memory of mask induction. Thus, only 61 were analyzed for this part

Arm/Group Title	Midazolam	Dexmedetomidine
Arm/Group Description	In M group, patients will be given oral midazolam 0.5mg/kg upto maximum dose of 15mg (5mg/ml parenteral preparation) mixed with flavored syrup as premedication Midazolam: oral midazolam 0.5mg/kg upto maximum dose of 15mg	In D group, patients will be given intranasal dexmedetomidine 2mcg/kg upto maximum dose of 100mcg prepared from 100mcg/ml parenteral preparation (Hospira R) . The drug will be administered using a intranasal mucosal administration device (LMA MAD NasalTM). Dexmedetomidine: intranasal dexmedetomidine 2mcg/kg upto maximum dose of 100mcg
Measure Participants	30	31
memory of mask induction-yes	6 16.2%	5 13.9%
memory of mask induction-no	24 64.9%	26 72.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Midazolam, Dexmedetomidine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Chi-squared
	Comments

Adverse Events

Time Frame	After premedication, patients will be continuously monitored including HR, BP, RR and SPO2 and documented every 15 min
Arm/Group Title	Midazolam		Dexmedetomidine
Arm/Group Description	In M group, patients will be given oral midazolam 0.5mg/kg upto maximum dose of 15mg (5mg/ml parenteral preparation) mixed with flavored syrup as premedication Midazolam: oral midazolam 0.5mg/kg upto maximum dose of 15mg		In D group, patients will be given intranasal dexmedetomidine 2mcg/kg upto maximum dose of 100mcg prepared from 100mcg/ml parenteral preparation (Hospira R) . The drug will be administered using a intranasal mucosal administration device (LMA MAD NasalTM). Dexmedetomidine: intranasal dexmedetomidine 2mcg/kg upto maximum dose of 100mcg
All Cause Mortality
	Midazolam		Dexmedetomidine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Midazolam		Dexmedetomidine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/37 (0%)		0/36 (0%)
Other (Not Including Serious) Adverse Events
	Midazolam		Dexmedetomidine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/37 (0%)		0/36 (0%)

Limitations/Caveats

All the consecutive patients were screened for eligibility. Patients were not selected on the basis of need for premedication.

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.