Subcutaneous Injection of Large Volumes of Tumescent Lidocaine and Epinephrine by Laypersons

Study Overview
=================
Brief Summary
-----------------
This research is intended to show that it is safe and not difficult for nearly anyone to inject at least 125ml of a dilute solution of tumescent lidocaine and epinephrine (TLE), where a TLE solution consists of lidocaine (1gm/L) and epinephrine (1mg/L) in normal saline.

Detailed Description
-----------------
The primary aim of this research is to demonstrate that of subcutaneous injection of tumescent (dilute) lidocaine and epinephrine (TLE) is safe, well tolerated, and easily performed by nearly anyone who is at least 16 years old. The primary aim will be achieved by conducting an IRB-approved double-blind, non-inferiority, randomized clinical trial (RCT). The indications for TLE when injected into subcutaneous tissue are Pre-hospital treatment of a snakebite envenomation (SBE) Dermatologic surgical procedures totally by local anesthesia Pure sensory regional anesthesia for significant cutaneous and musculoskeletal pain. The present TLE-RCT has three research Arms, which are as follows: Injection of 125ml by a physician and self-injection of 125ml by a volunteer (Arm I): A volunteer layperson (research subject), at least 16 years of age, will first receive 125ml of TLE injected subcutaneously into the left anterior thigh by a physician. Then the subject will self-inject a second 125ml of TLE into his/her right anterior thigh. Injection of 125ml by a physician and 125ml by another volunteer (Arm II): A volunteer layperson (primary research subject), at least 16 years of age, will first receive 125ml of TLE injected subcutaneously into the left anterior thigh by a physician. The primary research subject will then receive a second 125ml of TLE injected into his/her right anterior thigh by a second adult volunteer who is at least 16 years old and not a medical professional. Injection of 250ml by a physician into a volunteer (Arm III) : A volunteer layperson (research subject), at least 16 years of age, will receive 250ml of TLE injected subcutaneously into the one anterior thigh by a physician. There will be two TLE formulations, F1 and F2. F1 contains epinephrine 1mg/L = 1:1,000,000, or 0.25mg/250ml. F2 contains epinephrine 2mg/L = 1:500,000, or 0.5mg/250ml. F1 and F2 will both contain lidocaine 1gm/L = 0.1gm/100ml = 0.1% The maximum dose of dilute tumescent epinephrine in F1 and F2 is 0.25mg and 0.5mg, respectively. An EpiPen® contains 0.3mg of epinephrine. The concentration of epinephrine in an EpiPen® is 1:1000, which is 1000 and 500 times greater than the concentration of epinephrine in F1 and F2, respectively. Individual subjects will be randomly assigned to receive either F1 or F2. The maximum dosage of tumescent lidocaine is 5mg/kg, which is clearly a safe dosage given that the risk of mild lidocaine toxicity at 28mg/kg of 0.1% TLE is 1 per 5,000,000

Official Title
-----------------
Subcutaneous Injection of Large Volumes of Tumescent Lidocaine and Epinephrine (TLE) by Laypersons: a Double-blind, Non-inferiority, Randomized Clinical Trial

Conditions
-----------------
Venomous Snakebites, Local Anesthesia, Painless Injection, Regional Anesthesia, Dermatologic Surgery, Cutaneous Pain, Musculoskeletal Pain

Intervention / Treatment
-----------------
* Drug: Tumescent Lidocaine and Epinephrine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: All volunteer subjects will be healthy, mature in behavior and temperament, without mental impairment and at least 16 years of age. A volunteer TLE research subject must be a non-medical-professional layperson and must have signed an IRB-approved informed consent form prior to participation. All subjects must weigh at least 40kg = 88lb Exclusion Criteria: Anyone who has a significant fear of needles or fear of injections A history of lidocaine allergy. A significant history of epinephrine hypersensitivity. History of an adverse reaction to percutaneous injections, such as fainting and lightheadedness (vasovagal reactions, near syncope). Significant needle phobia or anxiety. Vasovagal reaction associated with any medical procedures or the sight of blood. Uncontrolled or labile hypertension. Hyperthyroidism, thyroid medications. Recent phenylephrine (Actifed®) or pseudoephedrine use. Any significant cardiac arrhythmia including controlled atrial fibrillation tachycardia, mitral valve prolapse. Significant chronic renal impairment. Significant liver function abnormalities. History of having or having had a blood born infection with HIV, Hepatitis B, Hepatitis C. Evidence of active skin infection. Pregnant women are excluded. Subject has recently taken any drug(s) known to interfere with the metabolism of lidocaine such as erythromycin, clarithromycin, ketoconazole, fluconazole, sertraline (Zoloft), or ciprofloxacin. Subject has recently taken any drug known to interact adversely with epinephrine such as pseudoephedrine, ephedrine, or beta-blocker. History of radiation therapy or surgery involving the area near the proposed injection site. Pre-existing or concurrent infections (cutaneous, urinary, pneumonia are exclusionary).

Ages Eligible for Study
-----------------
Minimum Age: 16 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: double-blind, non-inferiority, randomized clinical trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Subcutaneous injection of 125ml by a physician and self-injection of 125ml by a volunteer (Arm I):<br>A volunteer layperson (research subject), at least 16 years of age, will first receive 125ml of TLE injected subcutaneously into the left anterior thigh by a physician. Then the subject will self-inject a second 125ml of TLE into his/her right anterior thigh. | Drug: Tumescent Lidocaine and Epinephrine<br>* Subcutaneous injection of a relatively large volume (125ml to 250ml) of a relatively dilute solution of lidocaine (1gm/L) and epinephrine (1mg/L or 2mg/L).<br>* Other names: Tumescent Local Anesthesia;|
| Active Comparator: Subcutaneous injection of 125ml by a physician and 125ml by another volunteer (Arm II):<br>A volunteer layperson (primary research subject), at least 16 years of age, will first receive 125ml of TLE injected subcutaneously into the left anterior thigh by a physician. The primary research subject will then receive a second 125ml of TLE injected into his/her right anterior thigh by a second adult volunteer who is at least 16 years old and not a medical professional. | Drug: Tumescent Lidocaine and Epinephrine<br>* Subcutaneous injection of a relatively large volume (125ml to 250ml) of a relatively dilute solution of lidocaine (1gm/L) and epinephrine (1mg/L or 2mg/L).<br>* Other names: Tumescent Local Anesthesia;|
| Active Comparator: Subcutaneous injection of 250ml by a physician into a volunteer (Arm III)<br>A volunteer layperson (research subject), at least 16 years old, will receive 250ml of TLE injected subcutaneously into the one anterior thigh by a physician. | Drug: Tumescent Lidocaine and Epinephrine<br>* Subcutaneous injection of a relatively large volume (125ml to 250ml) of a relatively dilute solution of lidocaine (1gm/L) and epinephrine (1mg/L or 2mg/L).<br>* Other names: Tumescent Local Anesthesia;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | the incidence of any clinically significant adverse event associated with TLE injection, such as pain at injection site, vasovagal event, tachycardia, infection | up to 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Numerical Pain Scale (NPS) | Numerical Pain Scale (NPS) score following each injection, where the range of he scale is 0 to 10, and where 0= no pain and 10=worst imaginable pain | immediately after intervention | 
| Pulse Rate | Measure difference between pulse rates before and after subcutaneous injection of 250ml of TLE. | up to 30 minutes after intervention | 
| Blood Pressure Changes | Measure the differences between systolic and diastolic blood pressures before and after subcutaneous injection of 250ml of TLE. | up to 30 minutes after intervention | 
| EKG rhythm changes | EKG rhythm strips will be recorded before and after 250ml of TLE and any significant changes will be documented. Prior to the initial subcutaneous injection of the TLE solution, the EKG rhythm will be noted and recorded. For example, if the pre-TLE rhythm is Normal Sinus Rhythm (NSR) this observation will be recorded. After the subcutaneous TLE injection, a second EKG rhythm will be recorded. The analysis of the these two EKG rhythm strips will provide a dichotomous outcome variable: no clinically significant EKG change or potentially significant EKG change. If there is a significant EKG rhythm strip change, then any relevant clinical details or observations will be recorded. | up to 30 minutes after intervention | 
| Human-Factors Associated with subcutaneous injection of a largfe volume of a TLE solution. | Human-factor, or user interface difficulties encountered during the TLE injection process will be observed and a narrative of the observations will be recorded. The TLE-RCT is intended to demonstrate that any layperson can give a 125ml subcutaneous injection of a TLE in a manner that is safe and effective and essentially non-inferior to a similar injection administered by a physician. We will observe and record an apparent difficulties experience by the layperson when giving the injection. We will ask questions of the layperson to determine if the instructions for use are sufficient, and if not, we will record their suggestions for improvement. | during the intervention |