Clinical trial NCT04688346
Conditions: Epinephrine Causing Adverse Effects in Therapeutic Use
Sponsor: University of Washington
Start date: 2019-06-10; Completion date: 2019-11-30
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

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.

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.

Arms: arm 1: Saline Pellet arm 2: Racemic Epinephrine Pellet
Interventions: intervention 1: HemeRX epinephrine pellets
Intervention descriptions: intervention 1: Racemic Epinephrine Pellet

Protocol documents:
Prot_SAP_000.pdf: 
 1
Cardiovascular Effects of Racemic Epinephrine Pellets Used in Pediatric Restorative Dentistry 
Under General Anesthesia 
12-23-2020 
 
 


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INTRODUCTION 
 
Dental caries is the most common chronic disease of childhood.1 According to the 
American Academy of Pediatric Dentistry, it is estimated that 5% of children under the age of 6 
experience severe early childhood caries, an additional 15% roughly 1.5 million US children 
experience lesser levels of ECC, a condition that may necessitate restorative dental treatment. 2,3,4 
Prefabricated crowns are the treatment of choice for children with rampant caries involving large 
or multiple surface lesions or developmental defects.5 In such situations, crowns reinforce the tooth 
and provide increased durability and longevity over intracoronal restorations such as fillings.  
Crowns also reduce the chance of recurrent caries. 5 
In routine clinical practice, preformed metal crowns, also known as stainless steel crowns 
(SSC) are frequently indicated due to their durability, relatively low cost, and minimal technique 
sensitivity.5 They are adapted to the prepared tooth and cemented with a biocompatible luting 
agent.6,7,8,9 According to American Academy of Pediatric Dentistry5, use of SSCs should be 
considered in patients at high risk for caries, whose cooperation is affected by age, behavior or 
medical history. Such patients frequently receive treatment under sedation or general anesthesia.  
Although SSCs are highly effective, esthetics can be a concern for parents.10 Prefabricated 
zirconia crowns provide an esthetic solution and are now available for both primary incisors and 
molars. Zirconium dioxide (zirconia) is a crystalline solid that has strength similar to metals while 
its color is similar to that of teeth. According to a recent randomized controlled trial, both stainless 
steel and zirconia crowns proved to be an excellent choice for posterior full coverage restoration 
of primary teeth.11 However, zirconia crowns have shown to have better performance with regards 
to esthetics, gingival response and plaque retention.4,11,12,13 


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The process of preparing the tooth for a prefabricated zirconia crown requires a 
circumferential subgingival preparation. Prefabricated zirconia crown preparations include 
occlusal reduction of 1-2 mm followed by supragingival reduction of 0.5-1.25 mm 
circumferentially. Once prepared, caries is removed, and the preparation is reduced 1-2 mm 
subgingivally to create a feather edge margin. Tissue irritation and bleeding is inherent in this 
process. If hemostasis is inadequate when the crown is cemented, blood contamination will affect 
the integrity of the tooth-cement-crown interface. Zirconia crowns are also translucent, and blood 
incorporated into the cement may cause visible discoloration, resulting in poor esthetics.   
Hemostasis can be achieved by allowing the tissues to clot naturally using direct pressure 
with gauze. However, in clinical settings, it is not always possible or desirable to wait for extended 
periods of time. Thus, clinicians have relied upon topical or injected vasoconstrictors such as 
epinephrine to facilitate rapid hemostasis. Epinephrine is a powerful stimulator of both alpha and 
beta-adrenergic receptors, eliciting different effects depending on the tissue involved. Alpha- 
adrenergic receptors predominate in tissues such as oral mucosa and periodontium where 
epinephrine causes vasoconstriction of blood vessels.14 Beta 1 receptors, predominantly located in 
the heart, can increase heart rate and contraction force. Beta 2 receptors are predominately located 
in the lungs and skeletal muscle. Activation can cause bronchodilation in lungs, vasodilation of 
skeletal muscle and increased cardiac output. In medical and dental surgical practice, dilute 
formulations of injectable epinephrine are used to provide local hemostasis; however, when 
injected, they may raise serum epinephrine levels and increase potential for cardiopulmonary side 
effects.12 In contrast, topical epinephrine causes local vasoconstriction of the contacted mucosa, 
resulting in decreased systemic absorption. Administration of topical epinephrine has been shown 


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to result in elevation of serum concentrations 140-times less than injections of even dilute 
epinephrine preparations.15,16   
Topical epinephrine has been used widely in medicine and dentistry to achieve rapid 
hemostasis. Studies by Korkmaz et al and Gunaratane et al showed no significant hypertensive 
episodes and no hemodynamic parameter changes associated with placement of 1:1000 topical 
epinephrine.17,18 However, others have reported topical epinephrine sensitivity on only small 
portion of patients. These studies showed that topical epinephrine may induce significant 
hemodynamic changes in only a subset of patients which included the ones with preexisting 
cardiovascular diseases.19,20 
A literature review of prior studies investigating the effects of topical racemic epinephrine 
showed its effectiveness to decrease intraoperative bleeding. Degerliyurt K. et al. showed practical 
use of topical epinephrine without safety concerns for sinus surgery.15,21,22 Vickers et al. studied 
the cardiovascular effects of topical epinephrine pellets and 20% ferric sulfate in endodontic 
surgery. They found that neither agent had any statistically significant cardiovascular effects. 
However, subjectively, epinephrine pellets showed better hemostasis outcome than 20% ferric 
sulfate.23  
Complications associated with use of topical epinephrine are extremely rare, and changes 
in cardiovascular outcomes have not been shown to be statistically significant.15,23,24 To the best 
of our knowledge, no well-designed clinical trials have been conducted to assess the cardiovascular 
effects of topical epinephrine on gingival tissue in a pediatric population.  
The overarching purpose of this split-mouth randomized pilot study was to determine the 
efficacy and safety of receiving treatment with topical racemic epinephrine compared to placebo, 
measured by cardiovascular and hemostasis outcomes. Specifically, the primary objective of this 


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study was to determine if the use of racemic epinephrine has any effect on heart rate, blood 
pressure, or cardiac rhythm in children receiving dental care under general anesthesia. We 
hypothesized that the use of topical racemic epinephrine would be associated with no significant 
change on heart rate, blood pressure, or mean arterial pressure in children receiving dental care 
under general anesthesia compared to patients receiving a placebo.  
The secondary objective of this study was to determine if the use of racemic epinephrine 
has any effect on hemostasis, as measured subjectively by the dentist performing the procedure. 
We hypothesized that the use of topical racemic epinephrine would reduce clotting time around 
the gingival tissue, resulting in more rapid hemostasis. 
 
METHODS 
 
The study was approved by the Institutional Review Board at the University of Washington 
(STUDY00006670). Participants and their parents/legal guardian were recruited from a pool of 
patients who were scheduled to receive comprehensive dental care under general anesthesia (GA) 
at the University of Washington Center for Pediatric Dentistry. Families were approached 
regarding study participation the day of the initial dental surgery consultation or were contacted 
by phone at least 2 days prior to their scheduled dental surgery appointment. Consent was obtained 
the day of the surgery. Inclusion criteria included American Academy of Anesthesiologists 
physical status classification (ASA) I or II, English speaking, and having caries lesions requiring 
prefabricated crowns on both primary maxillary first molars, teeth #B and I.  
Subjects were excluded from the study if the parents or guardians were not able to 
communicate with the study coordinator in English or the patient had severe systemic illness (ASA 
III or greater), cardiac arrhythmia, cardiovascular disease, diabetes, thyroid disease and/or 
prescribed anti-arrhythmic, antihypertensive, or ionotropic medications. Subjects were also 


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excluded if they required pulpotomy or pulpectomy treatment on the primary maxillary first 
molars.  
This was a single blinded, split-mouth randomized controlled pilot study. We recruited 
patients from June 2019 until November 2019. Sixteen children met inclusion criteria and were 
approached for participation. Three patients were excluded from the study: One patient did not 
meet the inclusion criteria after new radiographs were taken under GA and two caregivers declined 
to participate in the study on the day of surgery (Figure 1).  
Randomization was performed in two stages. Using Stata 14.2 (StataCorp, College Station, 
TX) statistical software we first randomized whether the control treatment would be applied to the 
primary right or left maxillary first molar. The first randomization resulted in assignment of the 
right side of the mouth for the control treatment. This assignment was maintained for all 
participants.  The second randomization step determined the treatment sequence; whether control 
or intervention treatment was done first. A randomization list was created and placed into a 
password protected Excel file prior to the start of the study.  The order in which the patient received 
the intervention (either first or second) was randomly assigned to each patient using the 
randomization list. 
The main objective of this method was to have each patient serve as their own control and 
ensure randomization of the timing (first or second) of the experimental condition. Parents were 
not present during the procedure, and patients were unconscious and therefore blinded to the 
intervention. The treating dentist and study personnel were not blinded.  
Each patient’s weight and medical history was updated on the day of surgery. All patients 
fasted for at least eight hours prior to the procedure. They were transferred to the operating room 
and received mask inhalation induction (8% sevoflurane and 50-70% N2O/O2). Monitoring 


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equipment was applied after the patient was anesthetized, and it was maintained in place 
throughout the course of the procedure. Vital sign measurements included capnography, oxygen-
saturated hemoglobin percentage (SpO2), heart rate (HR) in beats per minute (bpm), and cardiac 
rhythm-which was continuously recorded from a 5-lead electrocardiogram (ECG). The systolic 
blood pressures (SBP) and diastolic blood pressures (DBP) were measured in millimeters of 
mercury (mmHg) via standard automatic noninvasive arterial cuff on the ankle or upper arm.  
All baseline vitals were recorded and peripheral intravenous (IV) access was obtained. 
Patients then received 1to 2mg/kg of propofol, Decadron 4 to 6mg total and 0.5 mg/kg of ketorolac 
via IV, followed by direct laryngoscopy and nasotracheal intubation. Anesthesia was maintained 
throughout the procedure with a continuous IV infusion of propofol (50-100 mcg/kg/min), 
Remifentanil infusion (0.05-0.1 mcg/kg/min), and inhaled nitrous oxide/oxygen (30-70%).  
After successful intubation, necessary radiographs were taken, a throat pack was placed, 
followed by cleaning, dental examination and treatment planning. Next, the maxillary first primary 
molar that was randomized to be completed first was prepared to receive a zirconia crown. To 
reduce pressure stimulation, no dental isolation (e.g. rubber dam) was used during any of the study 
procedures. After preparation, an appropriately sized zirconia crown was fit, and baseline heart 
rate and blood pressure were recorded. Next, two saline or intervention pellets were stretched and 
applied directly around the gingival tissue of the prepared tooth covering the tooth circumference. 
Control pellets were prepared by soaking in 0.9% sodium chloride (physiological saline) whereas 
intervention pellets were obtained directly from the manufacturer, containing an average of 0.55 
mg (0.42 to 0.68 mg/pellet) of racemic epinephrine hydrochloride per pellet (HemeRx, Racellet#3, 
Sprig Oral Health Technologies, Inc. Loomis, CA).  Pellets were maintained in position for one 


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minute with gauze pressure based on manufacturer’s recommendation. After pellet removal, any 
residual coagulum was removed using suction or moistened gauze.  
Cardiovascular outcomes including patient’s systolic blood pressure (SBP), diastolic blood 
pressure (DBP) and heart rate (HR) and mean arterial pressure (MAP) were recorded via standard 
automatic noninvasive arterial cuff immediately before pellet placement (baseline) and again at 1, 
2, 3, 4 and 5 minutes after placement.  
The adequacy of hemostasis was determined subjectively by the operating dentist/principal 
investigator (TMN), as “adequate” or “inadequate” at baseline and again at 1, 2, 3, 4 and 5 minutes 
after placement. Adequate hemostasis was defined as cessation of blood flow from gingival tissue. 
Inadequate hemostasis was defined as continued blow flow from gingival tissue, with blood 
contamination of the prepared tooth. Figures 2 and 3 demonstrate examples of adequate vs. 
inadequate hemostasis. Figure 4 demonstrates pre and post-op intraoral photos of maxillary arch 
of one of the patients.  
Following study procedures, the remainder of each patient’s dental care was completed, 
including application of rubber dam isolation, sealants, composite restorations, pulpotomies, 
stainless-steel crowns and extractions. All patients were discharged on the same day after adequate 
recovery and observation time.  
Data was analyzed using Stata SE version 14.2 (College Station, TX) software. Descriptive 
statistics are reported as mean and standard deviation.  Paired t-test and one-way repeated analysis 
of variance (ANOVA) were used for comparison of cardiovascular outcomes within controls 
(Table 1) and within interventions (Table 2). A paired t-test with equal variance was used for 
comparing control and intervention cardiovascular values as well as time to hemostasis adequacy 
(Table 3). McNemar’s Exact test was used to compare whether a patient reached adequate 


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hemostasis in the intervention and control sides. A p-value < 0.05 was considered to be statistically 
significant.