Cardiovascular Effects of Racemic Epinephrine Pellets

• Sponsor: University of Washington (Other)
• Overall Status: Completed
• CT.gov ID: NCT04688346
• Collaborator: (none)
• Enrollment: 13
• Location: 1
• Arms: 2
• Actual Duration (Months): 5.7
• Patients Per Site Per Month: 2.3

Study Details

Study Description

Brief Summary

The primary aim of this study was to determine if topical racemic epinephrine pellets affect heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) or mean arterial pressure (MAP) in children receiving dental care under general anesthesia (GA). Thirteen patients requiring prefabricated zirconia crowns on both primary maxillary first molars were recruited into a split-mouth randomized controlled pilot study. Patients received a continuous infusion of propofol and remifentanil with inhaled nitrous oxide/oxygen. After patient randomization and tooth preparation, either saline pellets (control) or racemic epinephrine pellets (treatment) were applied directly to gingival tissue. Vital sign measurements were recorded for 5 minutes. The procedure was repeated with either control or treatment on the contralateral side.

Condition or Disease	Intervention/Treatment	Phase
Epinephrine Causing Adverse Effects in Therapeutic Use	Drug: HemeRX epinephrine pellets	Phase 2/Phase 3

Detailed Description

Dental caries is the most common chronic disease of childhood. 3-6% of US children experience early childhood caries, a condition that may necessitate restorative dental treatment. Prefabricated crowns are the treatment of choice for children with rampant caries involving large or multiple surface lesions or developmental defects. In such situations, crowns reinforce the tooth and provide increased durability and longevity over intracoronal restorations such as fillings. They also reduce the chance that the tooth will experience recurrent decay.

In routine clinical practice, preformed metal crowns, also known as stainless steel crowns (SSC) are frequently indicated due to their extreme durability, relatively low cost, and minimal technique sensitivity. Stainless steel crowns (SSC) are no longer the only standard of care in restoring primary teeth. Although SSCs are highly effective, esthetics can be a concern for parents. Prefabricated zirconia crowns provide an esthetic solution. Zirconia is a crystalline dioxide of zirconium that has mechanical properties similar to those of metals while its color is similar to that of teeth. According to a recent randomized controlled trial, both SSC and zirconia crowns proved to be an excellent choice for molar teeth full coverage restorations. However, zirconia crowns performed better from the standpoint of esthetics, gum tissue response and plaque retention. (Abdulhadi Bashaer S, Abdullah Medhat M, et al. Clinical evaluation between zirconia crowns and stainless steel crowns in primary molars teeth. Journal of pediatric dentistry. 2017, Vol 5, issue 1; 21-27.)

Both Stainless steel crown and zirconia crown preparations include removing caries, followed by reducing the height of the tooth by 1.5 mm, reducing the sides of the tooth to make the pre-fabricated crown fit on the tooth. The SSC preparation requires subgingival reduction 1-2 mm below the gumline on anterior and posterior surfaces (not medial and lateral). The only additional preparation step that zirconia crown preparation involves is medial and lateral reduction of the tooth; therefore, there is little additional time that is needed for preparation of the crown since the only difference is the depth of the side reduction and preparing it circumferentially. In addition, the Primary Investigator (PI) is the provider who will be treating all patients. The PI is an experienced pediatric dentist and has been providing both types of crowns to patients under general anesthesia every week for many years.

The average time for a dental procedure under general anesthesia is between 1-3 hours. Factors that increase time include extent of disease, number of fillings/crowns placed, and pediatric dentist's experience.

The pediatric dentist that will be doing the surgery on all patients has been practicing for many years and has prepared thousands of SSC and zirconia crowns. Therefore, it is not anticipated that it will require additional time to prepare the zirconia crowns versus stainless steel crowns.

Vital signs (BP and HR) will be monitored for 4 minutes/tooth, 5-8 minutes total (See attached chart showing the difference). During this time the patient will be continuously anesthetized and under close observation by the attending anesthesiologist. This constitutes a minimal risk to a child's health.

According to studies, epinephrine half-life is about two minutes and once the epinephrine pellet is removed, concentrations will drop by 93.75% over 4 half-lives which is about 8 minutes. Therefore, if there is any effect on blood pressure it will show immediately and will go back to normal within the time frame that we are recording data. The procedure will be stopped if the blood pressure is at a harmful range to patient.

All children will have both of their maxillary primary first molars (#B, #I) prepared for prefabricated Zirconia crowns. Teeth that require pulpotomy or pulpectomy treatment will be excluded from the study.

In the control group, hemostasis will be achieved by using two pellets soaked with 0.9% sodium chloride (physiological saline). In the intervention group, hemostasis will be achieved by using two racemic epinephrine HCl pellets (HemeRX, Racellet #3, Sprig Oral Health Technologies, Inc. Loomis, CA). Racellet #3 contains an average of 0.55 mg (0.42 to 0.68 mg/pellet) of racemic epinephrine hydrochloride per pellet.

A standard general anesthesia protocol will be used during the study. All monitoring equipment will be applied at this time for the measurement of vital signs throughout the anesthesia. Vital signs will include: respiratory rate, oxygen-saturated hemoglobin percentage, heart rate (HR) in beats per minute (bpm) and cardiac rhythm, which will be continuously recorded from a 3-lead electrocardiogram (ECG). The systolic blood pressures (SBP) and diastolic blood pressures (DBP) will be measured in millimeters of mercury (mmHg) via ankle artery cuff connected to monitors.

Investigators will use a randomization software before the enrollment of the first subject to randomly determine if the right or the left side of the mouth will be the intervention. Once consent is obtained, randomization software will be used again to determine whether the patient will be given control or intervention treatment first. Once patients are under anesthesia and after other dental treatments are completed, the maxillary first primary molars (#B, #I) will be prepared for Zirconia crowns. The crowns will be prepared independently. One tooth will be prepared first, the pre-fabricated crown will be tried on to make sure the fit is correct. Next either intervention or control pellets will be placed around the gumline of the tooth and removed after one minute. The vital signs will continue to be recorded for the next 4 minutes meanwhile he crown is being cemented on the tooth. Once that is done the operator will move to the other tooth and repeat the same steps.

The process of preparing the tooth for a Zirconia crown requires a circumferential subgingival preparation. Tissue irritation and bleeding is inherent in this process. Once the crown is ready to be permanently cemented hemostasis becomes very important. In both the control and intervention group of teeth, two pellets will be applied directly around the gingival tissue of the prepared tooth and held for one minute with direct pressure and then removed based on the manufacturer's recommendation. The time of application will be recorded. The adequacy of hemostasis will be determined subjectively by the attending dentist and recorded as "adequate" or "inadequate" at 1, 2, 3, 4, and 5 minutes after placement. Adequate hemostasis is defined as gingival tissue being dry and hemorrhage-free. Inadequate hemostasis is defined as inability to keep the gingival tissue dry and without hemorrhage. If hemostasis is not achieved after four minutes of managing a subject during the study intervention (saline or epinephrine pellets) to which a tooth has been randomized, we will revert to the standard of care in order to stop the bleeding. Lidocaine will not be administered as a primary local anesthetic nor would it be used during our study. Only epinephrine pellets and saline pellets will be used in the study for achieving hemostasis.

Cardiovascular outcomes of patient's systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) will be collected by the graduate researcher during the procedure. The researcher will record the blood pressure/HR before placement of pellets, immediately after placement and at 1, 2, 3, 4, 5 minutes after placement. The pellets will stay on the tissue for 1 minute only and then removed. The researcher will also record hemostasis efficacy as per dental surgeon as either "adequate" or "inadequate" during the procedure.

In addition to the above measurements, cardiac rhythms will be assessed continuously via ECG and recording any arrhythmias. Mean arterial pressure (MAP), the amount of time in surgery and anesthesia medications used for each patient will also be recorded. All patients will be discharged on the same day after adequate recovery observation time.

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: This is a, single-blinded, placebo-controlled, split-mouth randomized trial. A sample size of 20 pediatric patients will be used for this pilot study.This is a, single-blinded, placebo-controlled, split-mouth randomized trial. A sample size of 20 pediatric patients will be used for this pilot study.
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Cardiovascular Effects of Racemic Epinephrine Pellets Used in Pediatric Restorative Dentistry Under General Anesthesia
• Actual Study Start Date: Jun 10, 2019
• Actual Primary Completion Date: Nov 30, 2019
• Actual Study Completion Date: Nov 30, 2019

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Control Saline Pellet	Drug: HemeRX epinephrine pellets; Racemic Epinephrine Pellet
Experimental: Intervention Racemic Epinephrine Pellet	Drug: HemeRX epinephrine pellets; Racemic Epinephrine Pellet

Outcome Measures

Primary Outcome Measures

1. Cardiovascular Outcomes [5 minutes]

   To determine heart rate change of patients receiving treatment with topical racemic epinephrine compared to those receiving a placebo.

2. Cardiovascular Outcomes [5 minutes]

   To determine blood pressure change of patients receiving treatment with topical racemic epinephrine compared to those receiving a placebo.

Secondary Outcome Measures

1. Hemostasis Efficacy [5 minutes]

   To determine time to achieving hemostasis (based upon subjective assessment of surgeon) on patients receiving treatment with topical racemic epinephrine compared to those receiving a placebo.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years to 9 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Children ages 2-9 years undergoing general anesthesia for comprehensive dental treatment at the University of Washington Center of Pediatric Dentistry.

2. Healthy patients according to the American Society of Anesthesiologists (ASA) classification I or II.

3. Patients who have caries lesions requiring prefabricated crowns on primary maxillary first molars #B and #I.

Exclusion Criteria:

1. Pediatric patients with any severe systemic illness (ASA Classification III or greater).

2. Pediatric patients with known cardiac arrhythmia, cardiovascular disease, diabetes and thyroid disease.

3. Patients who are taking anti-arrhythmic, antihypertensive, or ionotropic medications.

4. Patients who would need pulpotomy or pulpectomy treatment on primary maxillary first molars #B and I.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UW Center for Pediatric Dentistry	Seattle	Washington	United States	98115

Sponsors and Collaborators

• University of Washington

Investigators

• Principal Investigator: Travis M Nelson, DDS, University of Washington

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 23, 2020

More Information

Publications

None provided.

• Responsible Party: Travis Nelson, Clinical Associate Professor, School of Dentistry, University of Washington
• ClinicalTrials.gov Identifier: NCT04688346
• Other Study ID Numbers: STUDY00006670
• First Posted: Dec 30, 2020
• Last Update Posted: May 13, 2021
• Last Verified: May 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• 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
• Additional relevant MeSH terms: Epinephrine

Study Results

Participant Flow

Pre-assignment Detail	13 participants were enrolled. Each served as their own control. Left side primary maxillary molar received Saline, right side received Epinephrine pellets.

Arm/Group Title	Saline First, Then Epinephrine	First Epinephrine, Then Saline
Arm/Group Description	Saline Pellet HemeRX epinephrine pellets: Racemic Epinephrine Pellet	Racemic Epinephrine Pellet HemeRX epinephrine pellets: Racemic Epinephrine Pellet
Period Title: Overall Study
STARTED	6	7
First Intervention	6	7
Second Intervention	6	7
COMPLETED	6	7
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Saline First, Then Epinephrine	First Epinephrine, Then Saline	Total
Arm/Group Description	Saline Pellet HemeRX epinephrine pellets: Racemic Epinephrine Pellet	Racemic Epinephrine Pellet HemeRX epinephrine pellets: Racemic Epinephrine Pellet	Total of all reporting groups
Overall Participants	6	7	13
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	4.9 (1.5)	4.5 (1.7)	4.7 (1.6)
Sex: Female, Male (Count of Participants)
Female	3 50%	3 42.9%	6 46.2%
Male	3 50%	4 57.1%	7 53.8%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
United States	6 100%	7 100%	13 100%

Outcome Measures

1. Primary Outcome

Title	Cardiovascular Outcomes
Description	To determine heart rate change of patients receiving treatment with topical racemic epinephrine compared to those receiving a placebo.
Time Frame	5 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Intervention
Arm/Group Description	Saline Pellet HemeRX epinephrine pellets: Racemic Epinephrine Pellet	Racemic Epinephrine Pellet HemeRX epinephrine pellets: Racemic Epinephrine Pellet
Measure Participants	13	13
Mean (Standard Deviation) [Beats Per Minute]	91.5 (18.2)	93.4 (15.1)

2. Primary Outcome

Title	Cardiovascular Outcomes
Description	To determine blood pressure change of patients receiving treatment with topical racemic epinephrine compared to those receiving a placebo.
Time Frame	5 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Intervention
Arm/Group Description	Saline Pellet HemeRX epinephrine pellets: Racemic Epinephrine Pellet	Racemic Epinephrine Pellet HemeRX epinephrine pellets: Racemic Epinephrine Pellet
Measure Participants	13	13
Mean (Standard Deviation) [mmhg]	-3.1 (5.1)	-2.7 (3.6)

3. Secondary Outcome

Title	Hemostasis Efficacy
Description	To determine time to achieving hemostasis (based upon subjective assessment of surgeon) on patients receiving treatment with topical racemic epinephrine compared to those receiving a placebo.
Time Frame	5 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Intervention
Arm/Group Description	Saline Pellet HemeRX epinephrine pellets: Racemic Epinephrine Pellet	Racemic Epinephrine Pellet HemeRX epinephrine pellets: Racemic Epinephrine Pellet
Measure Participants	13	13
Mean (Standard Deviation) [Minutes]	4.2 (2)	2.2 (2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Intervention
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	t-test
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Participants were assessed for adverse outcomes during the period of their general anesthesia visit (1 day).
Adverse Event Reporting Description	cardiac and hematological adverse outcomes
Arm/Group Title	Control		Intervention
Arm/Group Description	Saline Pellet HemeRX epinephrine pellets: Racemic Epinephrine Pellet		Racemic Epinephrine Pellet HemeRX epinephrine pellets: Racemic Epinephrine Pellet
All Cause Mortality
	Control		Intervention
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)
Serious Adverse Events
	Control		Intervention
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Control		Intervention
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (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.