Hemodynamic and Electrocardiographic Effects of Hyaluronidase Associated With Local Anaesthetics

Study Overview
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Brief Summary
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Among the adjuvants to local anaesthetics (LA), the enzyme hyaluronidase is most often used as a diffuser agent of the LA in ophthalmic anaesthesia. It serves to improve clinical efficacy and prolong anaesthesia as an alternative to long-lasting and potentially more dangerous LA, especially in patients with increased cardiovascular risk. There is scarce clinical data about the safety of the use of hyaluronidase in dental procedures. This study aimed to compare hemodynamic and electrocardiographic variables during a dental surgical procedure using a local anaesthetic associated with hyaluronidase or placebo in healthy subjects.

Detailed Description
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This double-blind crossover split-mouth trial evaluated the cardiovascular effects induced by 3.6 mL of the LA 2% HCl mepivacaine with 1:100,000 epinephrine, concomitantly with 75 TRU/mL hyaluronidase or placebo in inferior alveolar nerve block, for the performance of bilateral and symmetrical third molar surgery in 20 outpatients. Cardiovascular parameters, including systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR), were monitored using oscillometric and photoplethysmographic methods in 10 clinical stages. Electrocardiographic records (ECG) of 12 leads were obtained in four steps. Hyaluronidase injected concomitantly with LA did not induce changes in SBP, DBP and HR compared to placebo. There were no instances of ST segment depression, ST segment elevation, wide QRS complex extrasystoles, or narrow QRS complex extrasystoles. To date, few studies in dentistry have investigated the effects of local anaesthetic efficacy in hyaluronidase, and even fewer have studied the relation to systemic effects induced by this interaction. The use of LA injected concomitantly with 75 TRU/mL of hyaluronidase is safe when using this dose and route of administration. Clinical Relevance: In dentistry, few studies have investigated the effects of hyaluronidase on local anaesthetic efficacy, and even fewer have examined the possible systemic effects induced by this interaction.

Official Title
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Hemodynamic and Electrocardiographic Effects of Hyaluronidase Associated With Local Anaesthetics: a Double-blind Split-mouth Controlled Trial.

Conditions
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Cardiac Arrhythmias

Intervention / Treatment
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* Drug: 3.6mL 2% Mepivacaine with 1:100,000 epinephrine
* Procedure: Lower Third Molar Extraction
* Drug: Hyaluronidase
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients should present bilateral lower third molars (teeth 38 and 48) for extraction and identical anatomical arrangement; Absence of significant clinical morbidities, ASA I (American Society of Anesthesiologists, 1963); Aged over 18 years. Exclusion Criteria: Women during pregnancy or lactation; Smokers; History of sensitivity to any drug used in the research; Presence or history of cancer or an infectious lesion; Individuals who used any medication in the last 15 days (except oral contraceptives); Presence of abscess or pericoronitis in the region to be operated; Patients who required supplemental anaesthesia upon anaesthetic block of the inferior alveolar nerve (post-randomisation exclusion).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Hyaluronidase<br>Lower Third Molar Extraction -- 3.6mL 2% Mepivacaine with 1:100,000 epinephrine + Hyaluronidase | Drug: 3.6mL 2% Mepivacaine with 1:100,000 epinephrine<br>* Local anesthetic with vasoconstrictor<br>* Other names: Mepivacaine with epinephrine;Procedure: Lower Third Molar Extraction<br>* Lower Third Molar Extraction with LA + hyaluronidase (or placebo)<br>* Other names: Molar surgery;Drug: Hyaluronidase<br>* 75RTU Hyaluronidase administration concomitant to the local anesthetic<br>|
| Placebo Comparator: Placebo<br>Lower Third Molar Extraction -- Anesthetic: 3.6 mL of the LA 2% HCl mepivacaine with 1:100,000 epinephrine + Placebo (0.9% saline) | Drug: 3.6mL 2% Mepivacaine with 1:100,000 epinephrine<br>* Local anesthetic with vasoconstrictor<br>* Other names: Mepivacaine with epinephrine;Procedure: Lower Third Molar Extraction<br>* Lower Third Molar Extraction with LA + hyaluronidase (or placebo)<br>* Other names: Molar surgery;Drug: Placebo<br>* 1mL 0.9% saline administration concomitant to the local anesthetic<br>* Other names: 0.9% NaCl;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Arrhythmia | Atrial or ventricular arrhythmias: isolated, paired or clustered extrasystoles, tachycardia, bradycardia and fibrillation. | 5min before anaesthesia | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PR segment | • Duration of the PR segment, in milliseconds. | 5min before anaesthesia; During anaesthetic injection; 5min after anaesthesia; Incision; Syndesmotomy; Luxation; Avulsion; Curetage; Suture; 1 hour after the end of surgery (At Patient discharge) and in the 7th postoperative day | 
| QRS complex | • Duration of the QRS complex, in milliseconds. | 5min before anaesthesia; During anaesthetic injection; 5min after anaesthesia; Incision; Syndesmotomy; Luxation; Avulsion; Curetage; Suture; 1 hour after the end of surgery (At Patient discharge) and in the 7th postoperative day | 
| Change from baseline Heart rate | • Change from baseline Heart rate (evaluated period - baseline), in beats per minute. Values will be expressed as the absolute difference and the percentage of change. | 5min before anaesthesia; During anaesthetic injection; 5min after anaesthesia; Incision; Syndesmotomy; Luxation; Avulsion; Curetage; Suture; 1 hour after the end of surgery (At Patient discharge) and in the 7th postoperative day | 
| Corrected QT | • Duration of the calculated corrected QT segment (QTc) in milliseconds. | 5min before anaesthesia; During anaesthetic injection; 5min after anaesthesia; Incision; Syndesmotomy; Luxation; Avulsion; Curetage; Suture; 1 hour after the end of surgery (At Patient discharge) and in the 7th postoperative day | 
| Heart rate (absolute values) | • Heart rate, (absolute values) in beats per minute. | 5min before anaesthesia; During anaesthetic injection; 5min after anaesthesia; Incision; Syndesmotomy; Luxation; Avulsion; Curetage; Suture; 1 hour after the end of surgery (At Patient discharge) and in the 7th postoperative day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Local Anaesthetics, Mepivacaine, hyaluronoglucosaminidase, Hemodynamic, Electrocardiography and Dentistry.