Cardiovascular Effects of Racemic Epinephrine Pellets
Condition: Epinephrine Causing Adverse Effects in Therapeutic Use
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

Intervention name(s): HemeRX epinephrine pellets
Intervention type(s): Drug
Intervention description(s): Racemic Epinephrine Pellet
Intervention MeSH terms: Epinephrine
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.
Masking: None (Open Label)
Primary purpose: Other