Cardiovascular Effects of Racemic Epinephrine Pellets Used in Pediatric Restorative Dentistry Under General Anesthesia
Phase: PHASE2
Conditions: Epinephrine Causing Adverse Effects in Therapeutic Use
Sponsor: University of Washington

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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.