Hemodynamic and Electrocardiographic Effects of Hyaluronidase Associated With Local Anaesthetics

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

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.

Study Overview

• Status: Completed
• Conditions: Cardiac Arrhythmias
• Intervention / Treatment: Drug: 3.6mL 2% Mepivacaine with 1:100,000 epinephrine; Procedure: Lower Third Molar Extraction; Drug: Hyaluronidase; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 4

Contacts and Locations

Study Locations

• Brazil
  • Sao Paulo, Brazil, 05508-000
    • Stomatology Department, FOUSP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Systolic Pressure (absolute values)	Systolic Blood Pressure (absolute values), in mmHg.	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
Diastolic Pressure (absolute values)	Diastolic Blood Pressure, in mmHg.	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
Mean Blood Pressure (absolute values)	Mean Blood Pressure, in mmHg.	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 Diastolic Pressure	• Change from baseline Diastolic Blood Pressure (evaluated period - baseline), in mmHg. 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
Change from baseline Systolic Pressure	• Change from baseline Systolic Blood Pressure (evaluated period - baseline), in mmHg. 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
Change from baseline Mean Arterial Blood Pressure	• Change from baseline Mean Arterial Blood Pressure (evaluated period - baseline), in mmHg. 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

Collaborators and Investigators

• Sponsor: Mauricio Jose Tornelli
• Collaborators: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior.
• Investigators: Study Chair: Gustavo F Prado, PhD, FMUSP; Study Director: Maria A Borsatti, PhD, FOUSP; Study Director: Rodney G Rocha, PhD, FOUSP; Study Chair: Helena R Tornelli, MD, S, FOUSP; Study Chair: Renata MS Prado, MS, S, FOUSP

Study record dates

Study Major Dates

• Study Start: October 1, 2007
• Primary Completion (Actual): October 1, 2007
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: October 3, 2012
• First Submitted That Met QC Criteria: October 30, 2012
• First Posted (Estimate): November 1, 2012

Study Record Updates

• Last Update Posted (Estimate): November 2, 2012
• Last Update Submitted That Met QC Criteria: October 31, 2012
• Last Verified: October 1, 2012

More Information

Terms related to this study

• Keywords: Hemodynamic; Mepivacaine; hyaluronoglucosaminidase; Local Anaesthetics; Electrocardiography and Dentistry.
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Sensory System Agents; Anesthetics; Adrenergic alpha-Agonists; Adrenergic Agonists; Anesthetics, Local; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Adrenergic beta-Agonists; Sympathomimetics; Vasoconstrictor Agents; Mydriatics; Epinephrine; Racepinephrine; Epinephryl borate; Mepivacaine
• Other Study ID Numbers: MTornelli