Epinephrine Bitartrate: Summary Report

Home , Dental anesthesia, Infiltration analgesia, Topical anesthetic

Epinephrine bitartrate: Summary Report

Item Type Report

Authors Yoon, SeJeong; Gianturco, Stephanie L.; Pavlech, Laura L.; Storm, Kathena D.; Yuen, Melissa V.; Mattingly, Ashlee N.

Publication Date 2021-03

Keywords Epinephrine; Adrenaline; Compounding; Food, Drug and Cosmetic Act; Food, Drug and Cosmetic Act, Section 503B; Food and Drug Administration; Outsourcing facility; Drug compounding; Legislation, Drug; United States Food and Drug Administration

Rights Attribution-NoDerivatives 4.0 International

Download date 30/09/2021 03:56:46

Item License http://creativecommons.org/licenses/by-nd/4.0/

Link to Item http://hdl.handle.net/10713/15462 Summary Report

Epinephrine bitartrate

Prepared for: Food and Drug Administration Clinical use of bulk drug substances nominated for inclusion on the 503B Bulks List Grant number: 5U01FD005946

Prepared by: University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI) University of Maryland School of Pharmacy

March 2021

This report was supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award (U01FD005946) totaling $2,342,364, with 100 percent funded by the FDA/HHS. The contents are those of the authors and do not necessarily represent the official views of, nor an endorsement by, the FDA/HHS or the U.S. Government.

Table of Contents

INTRODUCTION ...... 5 REVIEW OF NOMINATIONS ...... 5 METHODOLOGY ...... 6 Background information ...... 6 Systematic literature review ...... 6 Interviews ...... 7 Survey ...... 8 CURRENT AND HISTORIC USE ...... 9 Results of background information ...... 9 Results of literature review ...... 12 Results of interviews ...... 22 Results of survey ...... 23 CONCLUSION ...... 30 REFERENCES ...... 32 APPENDICES ...... 62 Appendix 1. Search strategies for bibliographic databases ...... 62 Appendix 2. Summary of included studies ...... 72 Appendix 3.1. Single-agent survey instrument for medical associations ...... 232 Appendix 3.2. Lidocaine / epinephrine / tetracaine survey instrument for medical associations ...... 236 Appendix 3.3. Survey instrument for Ambulatory Surgery Center Association ...... 239 Appendix 4. Survey distribution to professional associations ...... 242

Table of Tables

Table 1. Currently approved products – US ...... 9 Table 2. Currently approved products – select non-US countries and regions ...... 10 Table 3. Types of studies ...... 16 Table 4. Number of studies by country ...... 16 Table 5. Summary of included studies ...... 19 Table 6. Dosage by indication – US ...... 19 Table 7. Dosage by indication – non-US countries ...... 20 Table 8. Number of studies by combinations ...... 20 Table 9. Compounded products – US ...... 21 Table 10. Compounded products – non-US countries ...... 21 Table 11. Characteristics of survey respondents ...... 25 Table 12. Conditions for which single-agent or combination epinephrine prescribed or administered...... 25 Table 13. Reasons for using compounded single-agent or combination epinephrine ...... 26 Table 14. Use of non-patient-specific compounded single-agent or combination epinephrine ...... 26 Table 15. Ambulatory Surgery Center Association respondents’ familiarity with compounding terms .... 27 Table 16. Products obtained from a 503B outsourcing facility ...... 27 Table 17. Type of specialty procedures performed at ambulatory surgery facility ...... 29

Frequently Used Abbreviations

API Active Pharmaceutical Ingredient

EMA European Medicines Agency

EU European Union

FDA Food and Drug Administration

IRB Institutional Review Board

LET Lidocaine, epinephrine and tetracaine

OTC Over-the-counter

ROA Route of administration

UK United Kingdom

US United States

INTRODUCTION This report was created to assist the Food and Drug Administration (FDA) in their evaluation of the use of epinephrine bitartrate (UNII code: 30Q7KI53AK), which was nominated for use as a bulk drug substance in compounding by outsourcing facilities under section 503B of the Federal Food, Drug, and Cosmetic Act. The aim of this report was to describe how epinephrine bitartrate is used in clinical research and practice to diagnose, prevent, or treat disease. Due to the broad, exploratory nature of this aim, scoping review methodology was used. Following the scoping review framework, a systematic literature review was conducted and healthcare practitioners were consulted to identify how epinephrine bitartrate has been used historically and currently.1-3 Assessment of study quality and risk of bias were not performed because the aim of this report was not to make specific recommendations on the use of this substance in clinical practice.1,4,5 Rather, the aim was to summarize the available evidence on the use of epinephrine bitartrate and thereby assist the FDA to determine whether there is a need for the inclusion of this substance on the 503B Bulks List. REVIEW OF NOMINATIONS Epinephrine bitartrate was nominated for inclusion on the 503B Bulks List by Athenex Pharma Solutions, Cantrell Drug Company, Specialty Sterile Pharmaceutical Society, and US Compounding Pharmacy. Epinephrine bitartrate was nominated for use in combination with additional Active Pharmaceutical Ingredients (API) (refer to Table 8). Epinephrine bitartrate was nominated for use as a 0.05% and 0.18% topical gel in combination with 4% lidocaine and 0.5% tetracaine for use as a local anesthetic. Epinephrine was also nominated for use as a 0.4-1000 mcg/mL solution for infiltration, epidural, perineural, intracaudal, subcutaneous, intramuscular, and intravenous injection to treat the following conditions: acute bronchospasm, anaphylaxis, angioedema, asthma, blood coagulation disorder, bradycardia, bronchospasm prophylaxis, cardiac arrest, cardiopulmonary resuscitation, chloroquine overdose, congestion of mucosa, excessive uterine contraction, glaucoma, hypersensitivity reaction, hypotension, laryngotracheobronchitis (croup), mydriasis induction, nasal congestion, pulseless electrical activity, septic shock, status asthmaticus, surgical bleeding, syncope due to complete heart block or carotid sinus hypersensitivity, urticarial, ventricular asystole, ventricular fibrillation. Nominators provided references from published literature to describe the pharmacology, and support the clinical use, of epinephrine bitartrate.6-13 Reasons provided for nomination to the 503B Bulks List included: • Patient need for dosage form or strength, including greater concentration, that is not available commercially. • Patient sensitivities to dyes, fillers, preservatives, or other excipients in manufactured products. • Having a compounded ready-to-administer syringe or bag will reduce the risk of contamination when a pharmacy technician compounds the dose. • Hospital pharmacies are limited to production of black and white “stick on” labels that are hard to read. Compounded products can be produced with high-alert labels to reduce the risk of medication errors. • Compounding companies can formulate doses that have a longer expiration date than 48 hours. • There is no FDA-approved form of epinephrine bitartrate, lidocaine, and tetracaine combination and children are better responsive to the topical application versus an injection.

• Prescriber or hospital preference for various strengths, combinations with other drugs, volumes and/or final product containers for administration. • Unsafe to expose the direct compounding area to hundreds of vials or ampoules and hundreds of aseptic manipulations during the compounding of a typical size batch for outsourcing facilities; a single vessel compounded from bulk API is safer and more efficient than unmanageable amounts of small vials. • As required by Current Good Manufacturing Practices, bulk API powders can be formulated to 100 percent potency, but finished products cannot; commercially available finished products have an inherent variance in potency, creating an uncertain final concentration for the new product. • According to SSPS, in order to utilize the most advanced technology available to provide the greatest level of sterility assurance and quality, bulk starting material is required; it is not feasible financially, nor from a processing standpoint, to use finished pharmaceutical dosage forms with advanced isolated robotic equipment or other advanced aseptic processing equipment. • Practitioner or facility need for different strength or form, or ready-to-use packaging. • Manufacturer backorder. METHODOLOGY Background information The national medicine registers of 13 countries and regions were searched to establish the availability of epinephrine bitartrate products in the United States (US) and around the world. The World Health Organization, the European Medicines Agency (EMA), and globalEDGE were used to identify regulatory agencies in non-US countries. The medicine registers of non-US regulatory agencies were selected for inclusion if they met the following criteria: freely accessible; able to search and retrieve results in English language; and desired information, specifically, product trade name, active ingredient, strength, form, route of administration (ROA), and approval status, provided in a useable format. Based on these criteria, the medicine registers of 13 countries/regions were searched: US, Canada, European Union (EU), United Kingdom (UK), Ireland, Belgium, Latvia, Australia, New Zealand, Saudi Arabia, Abu Dhabi, Hong Kong, and Namibia. Both the EMA and the national registers of select EU countries (Ireland, UK, Belgium, and Latvia) were searched because some medicines were authorized for use in the EU and not available in a member country and vice versa. Each medicine register was searched for epinephrine bitartrate; name variations of epinephrine bitartrate were entered if the initial search retrieved no results. The following information from the search results of each register was recorded in a spreadsheet: product trade name; active ingredient; strength; form; ROA; status and/or schedule; approval date. Information was recorded only for products with strengths, forms, and/or ROA similar to those requested in the nominations. In addition to the aforementioned medicine registers, the DrugBank database (version 5.1.5) and the Natural Medicines database were searched for availability of over-the-counter (OTC) products containing epinephrine bitartrate. The availability of OTC products (yes/no) in the US and the ROA of these products were recorded in a spreadsheet. Individual product information was not recorded. Systematic literature review Search strategy A medical librarian constructed two separate search strategies for both Ovid MEDLINE and Embase. The first search strategy used a combination of controlled vocabulary terms and keywords to describe three concepts: epinephrine; epidural, intrathecal or perineural administration; and therapeutic use for

anesthesia or analgesia (refer to Appendix 1 for full search strategies). The second search strategy used a combination of controlled vocabulary terms and keywords to describe four concepts: epinephrine bitartrate; topical administration or gel form; lidocaine; and tetracaine. A literature review was not conducted for intramuscular, intravenous or subcutaneous administration due to the availability of FDA-approved epinephrine products for these ROA. Results were limited to human studies in English language. Searches were conducted on March 28, 2020. The reference lists of relevant systematic reviews and meta-analyses were reviewed to identify additional studies. In addition, the ECRI Guidelines Trust® repository was searched on March 28, 2020 for clinical practice guidelines that recommended the use of epinephrine bitartrate and provided sufficient information on dosing and administration. Results were exported to EndNote for Windows version X9.2 (Clarivate Analytics), and duplicates were removed. The de-duplicated results were uploaded to Covidence (Veritas Health Innovation) for screening. Study selection Studies in which epinephrine bitartrate or epinephrine (salt form not specified) was used in the nominated dosage form, ROA, and/or combination product to diagnose, prevent or treat the nominated disease or condition, or other conditions not specified in the nomination, were included. Studies were excluded if they were: written in a language other than English; reviews or meta- analyses; surveys or questionnaires (cross-sectional design); designed to evaluate cost-effectiveness, mechanism of action, pre-clinical use, safety, or toxicity; or any study design other than a randomized controlled trial conducted in a non-US country. Studies were also excluded if epinephrine bitartrate or epinephrine (salt form not specified) was used as: a brand or proprietary product; an FDA- approved product in the nominated dosage form, ROA, or combination; or a dosage form, ROA, or combination that was not nominated. Studies in which epinephrine bitartrate or epinephrine (salt form not specified) was used to diagnose, prevent, or treat autism were excluded due to a separate project examining the use of compounded substances in individuals with autism. Studies that did not meet the inclusion criteria but provided valuable information about the pharmacological or current or historical use of the substance were noted and put in a separate group in the EndNote library. Two reviewers independently screened titles and abstracts and reviewed full-text articles. A third reviewer reconciled all disagreements. Data extraction The following information was recorded in a standard data extraction form: author names; article title; journal; year of publication; country; study type; historical use of epinephrine bitartrate; setting; total number of patients; number of patients who received epinephrine bitartrate; patient population; indication for use of epinephrine bitartrate; dosage form and strength; dose; ROA; frequency and duration of therapy; use of epinephrine bitartrate in a combination product; use and formulation of epinephrine bitartrate in a compounded product; use of epinephrine bitartrate compared to FDA- approved drugs or other treatments; outcome measures; authors’ conclusions. One reviewer extracted data from the included studies; a second reviewer checked the data extraction. Interviews Semi-structured interviews with subject matter experts (SMEs) were conducted to understand how and in what circumstances epinephrine bitartrate was used in a clinical setting. The systematic literature review and indications from the nominations were reviewed to identify the following medical specialties that would potentially use epinephrine bitartrate: anesthesiology, dermatology, and pain management.

Potential SMEs within the relevant medical specialties were identified through recommendations and referrals from professional associations, colleagues’ professional networks, and authors of relevant literature. In addition, the American Society of Health-System Pharmacists (ASHP) and select outsourcing facilities were contacted for interviews and referrals to additional SMEs. SMEs provided oral informed consent to be interviewed and audio recorded. Interviews lasting up to 60 minutes were conducted via telephone, audio recorded, and professionally transcribed. The transcriptions and notes were entered into NVivo 12 (QSR International) for qualitative data analysis. Several members of the research team independently coded the transcriptions of two representative interviews for themes. The team members discussed the codes that emerged from their independent analysis, as well as those codes that were determined a priori. The code book was developed out of the integration of these coding schemes. Survey A survey was distributed to the members of professional medical associations to determine the use of epinephrine bitartrate in clinical practice. The online survey was created using Qualtrics® software (refer to Appendix 3 for complete surveys). A Google™ search was conducted to identify the professional associations in the US for the relevant medical specialties. An association’s website was searched to identify the email of the executive director, regulatory director, media director, association president, board members, or other key leaders within the organization to discuss survey participation. If no contact information was available, the “contact us” tab on the association website was used. An email describing the project and requesting distribution of the survey to the association’s members was sent to the identified person(s). Associations that declined, did not respond, or did not provide significant data in project Year 1 were not contacted to distribute the project Year 2 surveys. The survey was posted on the project website and the survey link was distributed to the associations that agreed to participate (refer to Appendix 4 for associations that participated and those that did not). Participation was anonymous and voluntary. The estimated time for completion was 15 minutes with a target of 50 responses per survey. The University of Maryland, Baltimore Institutional Review Board (IRB) and the FDA IRB reviewed the interview and survey methods and found both to be exempt. The Office of Management and Budget approved this project.

CURRENT AND HISTORIC USE Results of background information • Epinephrine is available as an FDA-approved product in the nominated dosage forms and ROA. The combinations of epinephrine and lidocaine as a 2% topical solution and epinephrine and prilocaine as a 1-2% injection were previously available but have been discontinued, not for safety or efficacy reasons. • There is a current United States Pharmacopeia (USP) monograph for epinephrine. • Epinephrine is available in the nominated dosage forms and ROA in Abu Dhabi, Australia, Belgium, Canada, Hong Kong, Ireland, Latvia, Namibia, New Zealand, Saudi Arabia, and UK. Table 1. Currently approved products – USa

Route of Active Ingredient Concentration Dosage Form Status Approval Dateb Administration

Intramuscular, Epinephrine 0.1-0.3 mg/delivery Injectable Prescription 12/22/1987 subcutaneous

Intramuscular, intraocular, Epinephrine 0.1-1 mg/mL Solution Prescription 12/7/2012 intravenous, subcutaneous

Epinephrine bitartrate / 0.005-0.01 mg/mL / Injectable Injection Prescription 4/3/2000 Articaine HCl 4%

Epinephrine bitartrate / 0.009 mg/mL / Injectable Injection Prescription 6/16/1988 Bupivacaine HCl 0.25-0.75%

Epinephrine bitartrate / 0.005-0.02 mg/mL / Approved prior to Injectable Injection Prescription Lidocaine HCl 2-4% 1/1/1982

Epinephrine bitartrate / 0.005 mg/mL / 4% Injectable Injection Prescription 8/30/2011 Prilocaine HCl Abbreviation: HCl, hydrochloride. aSource: US FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book). bIf multiple approval dates and/or multiple strengths, then earliest date provided.

Table 2. Currently approved products – select non-US countries and regionsa

Approved for Use Active Route of Concentration Dosage Form Ingredientb Administration Country Status Approval Datec

Abu Dhabi Active –

Pharmacist-only Australia 3/25/2014 medicine

Belgium Prescription 6/14/1998

Canada Ethical 8/23/2018 Injection, intramuscular, Ireland Prescription 4/1/1979 Epinephrine 0.1-2 mg/mL Solution intravenous, subcutaneous Latvia Prescription 10/19/2005

Namibia – 8/18/2004

New Zealand Restricted 2/7/1997

Saudi Arabia Prescription –

UK Prescription 3/28/1996

Abu Dhabi Active – Epinephrine / 0.0005% / 0.25- Solution Injection Bupivacaine 0.5% UK Prescription 3/15/1991

Abu Dhabi Active –

Infiltration, Australia Prescription 7/13/1994 Epinephrine / 5-20 mcg/mL / Solution injection, Lidocaine HCl 1-2% intravenous Hong Kong Prescription 11/11/1985

Ireland Prescription 2/16/1988

Namibia – 7/2/1982

New Zealand Prescription 8/14/1984

Saudi Arabia Prescription – Abbreviation: “– “, not mentioned. aMedicine registers of national regulatory agencies were searched if they met the following criteria: freely accessible; able to search and retrieve results in English language; and desired information (product trade name, active ingredient, strength, form, ROA, and approval status) provided in a useable format. Information was recorded only for products with strengths, forms, and/or ROA similar to those requested in the nominations. See Methodology for full explanation. bEpinephrine used as the standard for name variations, including epinephrinum, adrenaline and adrenalin. cIf multiple approval dates and/or multiple strengths, then earliest date provided.

Results of literature review Study selection Database searches yielded 7244 references; 2 additional references were identified from searching ECRI Guidelines Trust® and the references of relevant systematic reviews. After duplicates were removed, 4869 titles and abstracts were screened. After screening, the full text of 2859 articles were reviewed. Four hundred forty-four studies were included; after multiple reports of the same study were merged, there were 429 included studies. Two thousand four hundred fifteen studies were excluded for the following reasons: wrong study design (1136 studies); used in FDA approved form (849); used in non-nominated form (237); used as test dose only (70); no clinical use (33); used in unspecified form (23); not in English (20); unable to obtain (17); mentioned briefly (9); wrong substance/salt form (7); used harmful excipient (6); duplicate (4); not used in humans (3); retracted (1). Refer to Figure 1 for the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram. Characteristics of included studies The 429 included studies were published between 1949 and 2020. There were 350 experimental studies, 37 observational studies, 42 descriptive studies, and 0 clinical practice guidelines. The 429 studies were conducted in the following countries: Australia, Belgium, Brazil, Cambodia, Canada, Chile, China, Columbia, Croatia, Denmark, Egypt, Finland, Germany, Greece, Hong Kong, India, Ireland, Italy, Japan, Macedonia, Mexico, New Zealand, Norway, Russia, Saudi Arabia, Serbia, Singapore, Slovenia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, The Netherlands, Turkey, UK, US, and Zimbabwe. A total of 70,627 patients participated in the 429 included studies. The number of patients in each study ranged from 1 to 19,672. Outcome measures differed among the included studies and included: pain on Visual Analog Scale (VAS), Verbal Numeric Rating Scale (VNRS), or other scale; patient and/or clinician-reported overall satisfaction with anesthesia and/or analgesia; Neonatal Neurologic and Adaptive Capacity Scores (NNACS), Apgar score and other measures of neonatal condition; onset, duration and quality of motor and sensory block level; postoperative use of opioids or other pain medications; plasma concentration of local anesthetics. Refer to Table 5 for summary of study country, design, patient population, intervention and comparator, and outcome measures. Use of epinephrine bitartrate Forty-three thousand three hundred sixty-nine patients received epinephrine for analgesia/anesthesia. Epinephrine was administered as a caudal injection in doses ranging from 20 to 30 mL or 0.5 to 1.25 mL/kg, once. Epinephrine was administered caudally with bupivacaine, clonidine, etidocaine, fentanyl, lidocaine, meperidine, mepivacaine, midazolam, neostigmine, ropivacaine and sufentanil. Epinephrine was administered epidurally in doses ranging from 3 to 30 mL. The duration of treatment ranged from once to 40 hours, or as needed until delivery. Epinephrine was administered for patient-controlled epidural analgesia in doses ranging from 4 to 16 mL/hour for a duration of 24 to 72 hours, or until delivery. Epinephrine was administered epidurally with bupivacaine,

buprenorphine, 2-chloroprocaine, clonidine, dexamethasone, diamorphine, etidocaine, fentanyl, hydromorphone, lidocaine, levobupivacaine, meperidine, mepivacaine, morphine, prilocaine, propitocaine, ropivacaine, and sufentanil. Epinephrine was administered perineurally in doses ranging from 0.2 to 80 mL or 0.3 to 1 mL/kg, administered once. Epinephrine was administered perineurally with articaine, bupivacaine, butorphanol, 2-chloroprocaine, clonidine, dexamethasone, dexmedetomidine, diphenhydramine, etidocaine, fentanyl, hyaluronidase, levobupivacaine, lidocaine, mepivacaine, piperocaine, pontocaine, prilocaine, procaine, ropivacaine, tetracaine, and tramadol. One patient received ropivacaine and epinephrine via bilateral paravertebral catheters as a constant infusion at 9 mL/hour for 6 days.14 Epinephrine was given as a local infiltration in doses ranging from 10 to 150 mL, administered for 1 to 3 doses. Sites of local infiltration included: intra- or peri-articular; nephrostomy tract; quadratus lumborum; area of planned incision for orthognathic surgery; and area of sternotomy and chest tube placement. Epinephrine was administered as a local infiltration with bupivacaine, clonidine, dexamethasone, dexmedetomidine, ketorolac, levobupivacaine, morphine and ropivacaine. Epinephrine was administered topically as a gel or solution, in combination with lidocaine and tetracaine, in doses ranging from 1 to 5 mL, once for a duration of 10 to 45 minutes. Refer to Tables 6 and 7 for summaries of dosage by indication. Epinephrine was used as a compounded product and was used as a combination product (refer to Tables 8-10). In 60 studies, the authors’ concluding statement recommended the use of epinephrine for analgesia/anesthesia. In 17 studies, the authors concluded that the use of epinephrine was not recommended for analgesia/anesthesia, or further studies were necessary. In 25 studies, the authors concluded that epinephrine has similar efficacy to the comparators. In 327 studies, the authors’ conclusions did not address the use of epinephrine. Refer to Table 5 for summary of authors’ conclusions. Pharmacology and historical use There were several studies identified that provided valuable information about the pharmacology and historical use of epinephrine. As a sympathomimetic drug, epinephrine interacts with the alpha, beta-1, and beta-2 adrenergic receptors.15 The stimulation of the receptors depends on the epinephrine plasma concentration.15 At lower concentrations, the beta adrenergic receptors are mainly stimulated, causing increased heart rate via beta-1 and peripheral vasodilation via beta-2 receptors.15 At higher concentrations, alpha adrenergic activity begins to appear with increased blood pressure and vascular tone.15 Epinephrine has been shown to help with pain relief when added to epidural medications.16 In the combination of bupivacaine, fentanyl, and epinephrine for labor analgesia, bupivacaine has a slow onset for pain relief and “its brief duration necessitates repeated injections or continuous infusion for labor analgesia.”17 Epinephrine helps enhance the analgesia provided by bupivacaine while fentanyl also helps speed up the onset and prolongs the duration of analgesia.17 The mechanism in which epinephrine improves pain relief is not completely understand but “one possibility is that epinephrine acts primarily via alpha-1 adrenergic activity, resulting in vasoconstriction of the epidural blood vessels.”18 Vasoconstriction allows more of the active substances, such as the local anesthetics and opioids, to remain in the epidural space.16 The other possibility is “epinephrine produces pain relief

13 via a spinal cord mechanism – alpha-2 adrenergic receptors have been shown to produce analgesia.”18 In a study by Li et al, they concluded that adding epinephrine to epidural bupivacaine reduced the bupivacaine concentration needed for labor pain relief.19 The authors believe this is due to epinephrine’s effect on alpha-2 adrenergic receptors since “the alpha-1 adrenergic mediated vasoconstriction would not affect the initiation of labor analgesia.”18 Epinephrine was nominated topically for use in combination with other APIs. When Pryor et al reported on the use of tetracaine, adrenaline and cocaine (TAC) in 1980, they challenged the use of “traditional methods of anesthesia with lidocaine infiltration.”9 Although lidocaine infiltration was a “safe, established method of achieving local anesthesia for laceration repair, its use in children [was] often painful and frightening.20 Since then, use of topical anesthetics for non-mucous-membrane injuries has become more prevalent.21,22 Topical anesthetics have the advantage of being less invasive than lidocaine infiltration, improving patient cooperation.20,23 A disadvantage of topical anesthetics is they have a slow rate of onset, some may require up to an hour.11 TAC is a combination shown to have 80 to 95% efficacy when used alone as a topical anesthetic for facial lacerations; however for use in extremity lacerations, its efficacy ranges from 43-55%.24 The rationale for this combination is that tetracaine and cocaine would provide local anesthesia while epinephrine and cocaine cause vasoconstriction, which “minimizes bleeding from the wound, decreases the amount of local anesthetic absorbed through the skin, and limits toxicity.”23 A 1985 study by Schaffer found TAC to be superior to a tetracaine with adrenaline solution while a 1986 study by White et al found TAC superior to tetracaine alone.25-28 Cocaine is a controlled substance, which requires special storage procedures and documentation.29,30 In addition, improper use of TAC has led to hypertension, seizures, and death.29,31,32 Because of these concerns with TAC, an alternative topical combination of lidocaine, epinephrine, and tetracaine (LET) gel was tested by Schilling et al in a 1995 study.9,23 Schilling et al found LET to be an effective alternative to TAC for anesthesia during suturing of uncomplicated lacerations of the face and scalp in children.9,23 In a 2004 study by White et al, they mentioned that use of epinephrine containing topical anesthetic agents is “theoretically contraindicated in areas of the body with end artery blood supply, such as the finger.” However, there have been surgeons who have safely used lidocaine and epinephrine during digital blocks and a review of the literature did not identify any cases with finger necrosis caused by these digital blocks.33 A 2016 guideline by the American Academy of Dermatology (AAD) for the use of local anesthesia (defined for the guideline as topical, infiltrative, nerve blocks, and infiltrative tumescent) in office- based dermatologic surgery also found no reported cases of necrosis.34 The guideline stated that “the addition of epinephrine to local infiltration anesthesia is safe and recommended for use on the ear, nose, hand, feet, and digits.”34 LET is less costly, easier to prepare, and “[compares] favorably with TAC without the risks and administrative hassles associated with cocaine.”9,29 However, there have been toxicity reports involving lidocaine and tetracaine related to “mucous membrane application with large concentrations applied or ingested.”35 In the 2016 AAD guideline, they conducted a systematic review and found “no significant difference in efficacy among topical [TAC] and 6 different cocaine-free formulations, but the addition of cocaine was associated with a higher cost and potential for adverse effects.”34 The guideline suggested that “non-cocaine anesthetics are preferred over those containing cocaine.”34 A 2019 study by Konigs et al stated that most pediatric emergency departments use the topical combination LET gel or EMLA with infiltration of local anesthetic, such as lidocaine or mepivacaine, for pain control during skin repair.36

Figure 1. PRISMA flow diagram showing literature screening and selection.

Table 3. Types of studies

Types of Studies Number of Studies

Descriptive37-76 42

Experimental6,9,11,19,23,29,35,36,77-431 350

Observational14,33,432-466 37

Clinical practice guideline 0

Table 4. Number of studies by country

Country Number of Studies

Australia99,140,365 3

Belgium112,129,130,204,223,253,279,342,343,352,353,392,393,396,397,399,400,402,403,467 19

Brazil92,106,198,251,270,313,320,339 8

Canada6,80,81,87-90,92,98,102,108,109,118,126,127,183,186,193,210,212,213,258,280,281,284,285,324,361,363 24

Chile252 1

China155,171,317,412,413,426,431 7

Columbia282 1

Croatia276,286 2

Denmark93-96,111,117,141,177,195,241-247,309,328,336,384,404-407 24

Egypt287,294,304 3

Finland174,175,236,239,299,310,314 7

France142,143,179,394,395,401 6

Germany36 1

Greece271 1

Hong Kong222,254,296,297 4

India150,226,248,293,308,334,344-346,374,380,381,390,411 13

Ireland259 1

Italy120,306,327,430 4

Japan302,305,385,423,424 4

Macedonia373 1

Mexico300 1

New Zealand146 1

Norway144,145,196,267,295,319,335,364 8

Russia162-167 6

Saudi Arabia303 1

Serbia318 1

Singapore256,340,341,358 4

Slovenia122 1

South Africa157 1

South Korea128,202,203,215-219,230-232,255,307,330,362,427 15

Spain86,101,139,148,152 5

Sweden84,85,121,151,159,169,189,192,233,234,249,265,301,323,355,398 14

Switzerland369,415,421 3

Taiwan124,125,206,369,415,421 3

Thailand110 1

The Netherlands100,147,227,228,337,359,360 7

Turkey104,153,331,332,425 4

UK82,83,97,156,197,205,224,225,311,326,338,350,351,356,370,414,416,468 17

US9,11,14,19,23,29,33,35,37-79,103,105,107,113-116,119,123,131- 138,149,154,158,160,161,168,170,172,173,176,178,180-182,184,185,187,188,190,191,194,199-201,207- 209,211,214,220,221,229,235,237,238,250,257,262-264,266,268,269,272-275,277,278,283,288- 198 292,298,312,315,316,321,322,325,329,333,344,347-349,357,367,368,371,372,375-379,382,386-389,391,408-410,417- 420,422,428,429,432-466,469-471

Zimbabwe383 1

Multiple Countries • Canada, Thailand260,261 2 • Finland, US240 1

Total USa: 199 Total Non-US Countriesa: 230 aStudy 240 counted in both US and non-US total.

Table 5. Summary of included studies Refer to Appendix 2

Table 6. Dosage by indication – US

Route of Duration of Indication Dose Concentration Dosage Form Administration Treatment

20-30 mL 5 mcg/mL Solution Caudal Once Anesthesia/analgesia19,37,49,53,57,58,74,77-79,105,114- 116,132,149,170,172,184,188,194,220,237,238,257,262,268,269,272,274,288,289,315,321,322,32 Once – 40 hours 5,349,367,386,408,418,428,429,437,438,450,452,458,465,466,469 3-30 mL 1.67-8 mcg/mL Solution Epidural Until delivery

Patient-controlled analgesia67,71,103,113,133- 24-72 hours 137,180,185,200,263,273,333,441,446,447 6-16 mL/hour 0.5-5 mcg/mL Solution Epidural Until delivery

0.2-70 mL 2.5 mcg/mL – 1 mg/mL Solution Perineural Once 0.4-1 mL/kg Local anesthesia/analgesia9,11,14,23,29,33,35,38-48,50-52,54-57,59- 70,72,73,75,76,107,114,115,119,123,131,138,154,158,160,161,168,173,176,178,181,182,187,190, 9 mL/hour – Solution Perineural 6 days 191,199,201,207-209,211,214,221,229,235,250,264,266,269,275,277,278,283,290- 292,298,312,316,329,344,347-349,357,368,371,372,375-379,382,387- 30-150 mL 2.5-5 mcg/mL Solution Infiltration Once 389,391,409,410,417,419,420,422,432-436,439,440,442-445,448,451,453-457,459-464,470,471 1-3 mL 0.01-1 mg/mL Gel Once, for 10-45 Topical minutes 3-5 mL 0.5-1 mg/mL Solution Abbreviations: “–“, not provided.

Table 7. Dosage by indication – non-US countries

Route of Duration of Indication Dose Concentration Dosage Form Administration Treatment

Anesthesia/analgesia82,83,86,96,98,102,106,117,118,120,121,124,129,130,141,144,150, 0.5-1.25 mL/kg 5 mcg/mL Solution Caudal Once 156,171,203,205,206,223,225,227,228,239,248,251,253,254,258,265,270,279,281,284,293,297,301, 302,314,320,323,324,326,327,331,332,338,340,341,350,351,355,356,358-360,370,392-394,396- 1-3 doses 403,413,414,416,425-427,467,468,472,473 3-26 mL 1.25-100 mcg/mL Solution Epidural Until delivery

Patient-controlled 48-72 hours 145,169,174,175,189,196,233,234,236,267,296,302,364,421 4-15 mL/hour 1-5 mcg/mL Solution Epidural analgesia Until delivery

0.2-80 mL Local anesthesia/analgesia6,36,80,81,84,85,87-93,97,99-101,104,108-112,125- 2.5 mcg/mL – 1 mg/mL Solution Perineural Once 127,139,140,142,143,146-148,151- 0.3-75 mL/kg 153,155,159,177,179,183,186,192,193,195,197,198,204,210,212,213,215-219,222,224,226,230- 232,241-247,249,252,255,256,271,276,280,285-287,295,299,300,304-311,313,317,319,328,330- 10-150 mL 5 mcg/mL – 1 mg/mL Solution Infiltration 1-3 doses 332,334-337,339,342,343,345,346,352,353,361-363,365,369,374,380,381,383-385,390,395,404- 407,411,412,415,423,424,430,431,474 Once, for 45 3-5 mL 0.5 mg/mL Gel Topical minutes

Table 8. Number of studies by combinations

Combination Formula Number of Studies

Epinephrine bitartrate 0.001-1% / Lidocaine 1-4% / Tetracaine 0.5-4% (LET) – topical gel, Nominated 14 solution6,9,11,23,29,33,35,36,123,158,160,161,193,256

Table 9. Compounded products – US

Indication Publication Year Compounding Methoda Dosage Form Final Strength

Prepared by pharmacist from dry ingredients mixed with water and added to hydroxyethyl 1995 Gel 0.05% cellulose gel, with preservatives35,160,161

3 mL of stock LET solution (lidocaine 4%, epinephrine 0.1%, tetracaine 0.5%) was added Anesthesia/analgesia 1998 Gel 0.1% to methylcellulose and stirred for 2 minutes immediately prior to application9

Prepared by pharmacy as mixture of lidocaine 4%, epinephrine 1:2000, tetracaine 0.5% 2004 Gel 0.05% with methylcellulose and preservatives33 aMost studies did not specify the salt form, so bitartrate is not included unless the study specified use of this salt form.

Table 10. Compounded products – non-US countries

Indication Compounding Method Dosage Form Final Strength

"Our pharmacy prepares 3mL syringes of lidocaine-epinephrine-tetracaine from raw materials in-house at a Anesthesia/analgesia Gel Not provided cost of CAD $1.58 per dose (including the cost of the actual syringe)."6

Results of interviews Two hundred eighty-five SMEs were contacted for interviews; 96 agreed to be interviewed, and 189 declined or failed to respond to the interview request. Seventeen SMEs discussed epinephrine. Amongst these 17 SMEs, there were 8 medical doctors, 2 dentists, 4 pharmacists, 2 nurse practitioners, and 1 physician assistant. The SMEs specialized and/or were board-certified in anesthesiology, critical care, dermatology, neonatal/perinatal medicine, oncology/hematology, oral and maxillofacial surgery, orthopedics, pain medicine, palliative care, pediatrics, and pharmacotherapy, working in academia, academic medical centers, consulting, hospital/health systems, and retired. The SMEs had been in practice for 6 to 40 years. In the past, epinephrine has been combined with local anesthetics to prolong blocks. This is not done anymore because blood flow is limited to the nerves, which increases the risk of neurological injury post- operation. Nowadays, Precedex® (dexmedetomidine) and Decadron® (dexamethasone) are added to blocks instead. Several SMEs stated that epinephrine is used mainly in resuscitation; one SME specified that IV epinephrine is used for blood pressure support or refractory bradycardia and sometimes as a local infiltration to cause vasoconstriction. Epinephrine can also be used with lidocaine epidurally for cesarean sections. One SME mentioned using epinephrine if someone is having an allergic reaction, with another SME specifying that IM or sublingual epinephrine could be used for anaphylaxis. Another SME mentioned using epinephrine as a test dose before certain injections because it helps them determine whether the needle is positioned properly. If the heart rate increases with the test dose, then that means the needle position needs to be adjusted. One SME also mentioned a compounded injection combination of morphine, bupivacaine, and epinephrine made in the hospital pharmacy for pain control in knee patients. This combination is injected around the incision site because there is a lot of soft tissue trauma with total knee procedures. A SME expressed a need to get epinephrine prefilled if possible (varies due to shifts with shortages and supplies) and stated that mistakes such as mislabeling of epinephrine concentrations can be harmful. Several SMEs commented on epinephrine as a topical/local anesthetic product. One SME, who is a maxillofacial surgeon, used a commercially available combination local anesthetic product (epinephrine and lidocaine) daily and did not see a need for this to be compounded. This SME has had patients with allergies to the preservative in the product, but it is very rare. For those cases, the SME sends the patient to the primary care doctor to find out what the available options are and/or switches to other medications, such as Carbocaine® (mepivacaine), that do not have epinephrine. One SME specializing in palliative care would like a topical formulation to limit local bleeding for “tacky” wounds but stated this would not be a commonly used product. Another SME stated that at the beginning of a surgery they would inject epinephrine around the incision site to prevent bleeding. Epinephrine is not used at the end of surgery due to the risk of increasing the heart rate or blood pressure. A SME specializing in dermatology mentioned using lidocaine with a low dose of epinephrine when performing skin biopsies. Lidocaine has a low pH, so it is buffered with sodium bicarbonate to lessen the stinging and burning. The combination LET is also used in a lot of cosmeceutical procedures as a topical anesthetic. Epinephrine is for vasoconstriction so that there will be less bleeding. This SME stated that there is a potential for LET to be stocked in the office. Another SME also mentioned they have used compounded LET cream and mentioned that their trauma pain service unit has been interested in compounding drugs for pain management. As for the TAC combination, a SME mentioned that cocaine is a scheduled drug and that they were not sure if “you can dispense that relatively easily out of bulk compounding.” The only place they have seen cocaine used was for people getting rhinoplasty. Some other general SME comments include a SME who could see epinephrine used as a dental solution mixed with other substances.

Another SME expressed that the nominated combinations made sense to them and stated they see the potential benefits because “people like [epinephrine since] it reduces any bleeding.” This SME also mentioned being careful before using epinephrine in the patients with glaucoma. A SME expressed that using outsourcing facilities to compound epinephrine helps with efficiency and stated it is nice that drugs from outsourcing facilities have “extended stability dating.” While a hospital representative commented that they compound or outsource approximately half of their high-volume products, including epinephrine. Epinephrine “drips” and syringes for use in the operating room are compounded in-house. Results of survey Fourteen people responded to the single agent and lidocaine/epinephrine/tetracaine (LET) combination surveys distributed via professional medical associations and available on the project website (refer to Appendices 3.1-3.2 for survey instruments). Refer to Table 11 for respondent characteristics. Twelve respondents (86%) reported using epinephrine either alone or in the LET combination. Among respondents, 4 (33%) used epinephrine as a single-agent product, and 8 (67%) used epinephrine in combination with lidocaine and tetracaine. Of the 4 respondents who used epinephrine as a single-agent product the following salt forms were utilized: hydrochloride (1, 25%), bitartrate (0, 0%), unsure (1, 25%), other (1, 25%) with respondent entering “lidocaine with epinephrine (purchased as such) then buffered with 8.4% sodium bicarbonate,” or did not respond to this question (1, 25%). Respondents used single-agent epinephrine as an epidural, intracaudal, or perineural injectable solution (2, 50% of 4 respondents who used epinephrine), topical cream (1, 25%), inhaled nasal spray (0, 0%), and ‘none of the above’ (1, 25%), and did not respond to the question (1, 25%). Respondents used epinephrine as a single-agent product for anaphylaxis/hypersensitivity reactions (1, 25% of 4 respondents who used epinephrine), surgical bleeding (1, 25%), and others did not respond to the question (2, 50%). Of the 8 respondents who used epinephrine in combination with lidocaine and tetracaine the following dosage forms were utilized: topical gel (6, 75%), via an unspecified route (1, 13%), and others did not respond to the question (1, 13%). Respondents used epinephrine in combination with lidocaine and tetracaine to provide local anesthesia (6, 75%) and others did not respond to the question (2, 25%). Refer to Table 12 for conditions for which single-agent or combination epinephrine was used. The 12 respondents used compounded epinephrine either alone or in combination due to lack of commercial products in an appropriate dosage form, strength, or combination (5, 42% of respondents, where respondents were allowed to select multiple reasons), patient allergies (3, 25%), other patient conditions preventing use of commercial products (1, 8%), no commercially available products with epinephrine alone or in combination (5, 42%), or other (1, 8%) with respondent using compounded epinephrine in combination with lidocaine and tetracaine due to “cost, efficacy, access.” Refer to Table 13 for reasons for using compounded single-agent or combination epinephrine. Five respondents (42%) stocked non-patient-specific compounded epinephrine either alone or in combination with other substances at their practice. Respondents that did stock non-patient-specific epinephrine compounded the product at their practice (2, 40% of respondents that stocked non-patient- specific compounded epinephrine, where respondents were allowed to select more than one option), had the product compounded by an in-house pharmacy (1, 20%), purchased, or had the patient purchase, the product from a compounding pharmacy (3, 60%), or outsourcing facility (0, 0%). Refer to Table 14 for how respondents obtained compounded epinephrine.

A separate survey was distributed by the Ambulatory Surgery Center Association (ASCA); 230 people responded to this survey (refer to Appendix 3.3 for survey instrument). One hundred ten survey respondents (54% of 203 people who responded to this question) utilized a 503B outsourcing facility to acquire compounded drugs; 93 survey respondents (46%) did not utilize a 503B outsourcing facility. Two respondents (0.7% of 290 responses, where respondents were allowed to select multiple drug products) obtained budesonide from a 503B outsourcing facility (refer to Table 16). The most common types of procedures performed at the facilities where the ASCA survey respondents worked were: ophthalmology (115, 17% of responses, where respondents were allowed to select multiple procedure types); orthopedics (89, 13%); pain (80, 12%); podiatry (74, 11%); and plastics (72, 10%) (refer to Table 17).

Table 11. Characteristics of survey respondents

Terminal Clinical Degree Responses, n (N=12)

Doctor of Medicine (MD) 12

Doctor of Osteopathic Medicine (DO) 0

Doctor of Medicine in Dentistry (DMD/DDS) 0

Doctor of Pharmacy (PharmD) or Bachelor of Science in Pharmacy (BS Pharm) 0

Naturopathic Doctor (ND) 0

Nurse Practitioner (NP) 0

Physician Assistant (PA) 0

Practice Setting Responses, n (N=15)a

Physician office or private practice 11

Outpatient clinic 1

Hospital or health system 1

Academic medical center 2

Emergency room 0

Operating room 0

Compounding pharmacy 0 aSome respondents reported more than one practice setting.

Table 12. Conditions for which single-agent or combination epinephrine prescribed or administered

Condition Responses, n (N=8)a,b

Anaphylaxis/hypersensitivity reaction 1

Local anesthesia 6

Mydriasis for intraocular surgery 0

Open-angle glaucoma 0

Surgical bleeding 1 aOut of 14 respondents, 12 reported prescribing or using single-agent or combination epinephrine. bSurvey respondents allowed to select multiple conditions.

Table 13. Reasons for using compounded single-agent or combination epinephrine

Reason Responses, n (N=15)a,b

Commercial product not available in desired dosage form, strength, or combination 5

Patient allergies prevent use of commercial products 3

Patient conditions prevent use of commercial products 1

No commercial products 5

Otherc 1 aOut of 14 respondents, 12 reported prescribing or using single-agent or combination epinephrine. bSurvey respondents allowed to select multiple reasons. c”Cost, efficacy, access.”

Table 14. Use of non-patient-specific compounded single-agent or combination epinephrine

Do you stock non-patient-specific compounded single-agent or combination Responses, n (N=8)a epinephrine at your practice?

Yes 5

No 3

Not sure 0

How do you obtain your stock of non-patient-specific compounded single-agent or Responses, n (N=6)a combination epinephrine?

Compound yourself at practice 2

Product compounded by in-house pharmacy 1

Purchase from compounding pharmacy 3

Purchase from outsourcing facility 0 aOut of 14 respondents, 12 reported prescribing or using single-agent or combination epinephrine.

Table 15. Ambulatory Surgery Center Association respondents’ familiarity with compounding terms

Compounded drugs (medications prepared to meet a patient-specific need) Responses, n (N=230)

Very familiar 153

Somewhat familiar 70

Not familiar 7

503A Compounding pharmacy (a pharmacy that prepares compounded Responses, n (N=230) medications prescribed to meet a patient-specific need)

Very familiar 118

Somewhat familiar 91

Not familiar 21

503B Outsourcing facility (a facility that compounds larger quantities without a Responses, n (N=230) patient-specific prescription)

Very familiar 97

Somewhat familiar 86

Not familiar 47

Table 16. Products obtained from a 503B outsourcing facility

Product Responses, n (N=290)a

Amitriptyline / Ketoprofen / Oxymetazoline 1

Budesonide 2

Calcium gluconate 2

Droperidol 2

Epinephrine 11

Epinephrine for ophthalmic administration 16

Epinephrine / Lidocaine for ophthalmic administration 31

Epinephrine / Bupivacaine / Fentanyl 3

Fentanyl 10

Flurbiprofen 3

Flurbiprofen for ophthalmic administration 6

Hydromorphone 5

Ipamorelin 1

Ketoprofen / Nifedipine 3

Lidocaine / Epinephrine / Tetracaine 13

Meperidine 3

Morphine 5

Naloxone 5

Neomycin 5

Phentolamine 1

Promethazine 5

Remifentanil 4

Sufentanil 2

Tramadol 2

None of the above 75

Do not obtain any compounded drugs from 503B 74 outsourcing facility aSurvey respondents allowed to select multiple products.

Table 17. Type of specialty procedures performed at ambulatory surgery facility

Procedure Type Responses, n (N=686)a

Dental 23

Dermatology 9

Endoscopy 65

Neurosurgery 22

Obstetrics/gynecology 39

Ophthalmology 115

Otolaryngology 58

Orthopedics 89

Pain 80

Plastics 72

Podiatry 74

Otherb 40 aSurvey respondents were allowed to select multiple procedure types. bNo respondents provided description for ‘Other’ procedure type.

CONCLUSION Epinephrine bitartrate was nominated for inclusion on the 503B Bulks List as a topical gel and various injectable products to be used as local anesthetic and to treat acute bronchospasm; anaphylaxis; angioedema; asthma; blood coagulation disorder; bradycardia; bronchospasm prophylaxis; cardiac arrest; cardiopulmonary resuscitation; chloroquine overdose; congestion of mucosa; excessive uterine contraction; glaucoma; hypersensitivity reaction; hypotension; laryngotracheobronchitis (croup); mydriasis induction; nasal congestion; pulseless electrical activity; septic shock; status asthmaticus; surgical bleeding; syncope due to complete heart block or carotid sinus hypersensitivity; urticarial; ventricular asystole; ventricular fibrillation. Epinephrine bitartrate is approved in Abu Dhabi and Belgium. From the literature review, epinephrine was used for anesthesia and analgesia in various routes, including caudal, epidural, infiltration, perineural, and topical. Topical use of epinephrine in combination with lidocaine and tetracaine was common. In several of the included studies, epinephrine was added to another analgesic, such as lidocaine, bupivacaine, etidocaine, fentanyl, or levobupivacaine to enhance and/or prolong the effect of these analgesics. From the interviews, all SMEs had experience using epinephrine. Several SMEs stated that epinephrine is used mainly in resuscitation, with one SME who specified that IV epinephrine was used for blood pressure support or refractory bradycardia and sometimes as a local infiltration to cause vasoconstriction. Another SME mentioned using epinephrine as a test dose before certain injections. Several SMEs commented on epinephrine as a topical/local anesthetic product. One SME used a combination local anesthetic product (epinephrine and lidocaine) daily and did not see a need for this to be compounded. This SME had rarely had patients with allergies to the preservative in the product. A SME specializing in palliative care would like a topical formulation to limit local bleeding for “tacky” wounds, but this would not be a commonly used product. Another SME stated that they always see epinephrine in sprays when they perform surgery. A SME specializing in dermatology mentioned using lidocaine with low dose epinephrine for skin biopsies. One SME expressed that the nominated combinations made sense to them and stated that they see the potential benefits because “people like [epinephrine since] it reduces any bleeding.” There were several interview comments related to compounded products and use of outsourcing facilities. One SME stated that there is a potential use for LET to be stocked in the office, while another SME mentioned they have compounded LET cream. For TAC, a SME expressed that cocaine is a scheduled drug and that they were not sure if “you can dispense that relatively easily out of bulk compounding.” A SME expressed that using outsourcing facilities to compound epinephrine helps with efficiency and drugs from outsourcing facilities have “extended stability dating.” While a hospital representative commented that they compound or outsource approximately half of their high-volume products (which includes epinephrine). For epinephrine drips and operating room epinephrine syringes, they compound those in- house. A SME also expressed trying to get epinephrine prefilled if possible due to shifts with shortages and supplies. From the responses to the surveys distributed to professional medical associations, 12 out of 14 respondents (86%) used epinephrine either alone or in combination with other substances. The most common indication respondents used compounded epinephrine for were anaphylaxis/hypersensitivity reactions, local anesthesia, and surgical bleeding. The respondents used compounded epinephrine either alone or in combination due to a lack of commercial products in an appropriate dosage form, strength or combination, patient allergies or conditions preventing use of commercial products, or no commercially available products with epinephrine alone or in combination. One respondent used compounded epinephrine in combination with lidocaine due to “cost, efficacy, access”. Five respondents stocked non-

30 patient-specific compounded epinephrine either alone or in combination with other substances at their practice. Two hundred thirty people responded to the survey distributed via the ASCA. Eleven respondents obtained single-agent epinephrine from a 503B outsourcing facility, 16 obtained epinephrine for ophthalmic administration, 31 obtained epinephrine in combination with lidocaine for ophthalmic administration, 13 obtained epinephrine in combination with lidocaine and tetracaine, and 3 obtained epinephrine in combination with bupivacaine and fentanyl.

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418. Wheeler M, Patel A, Suresh S, et al. The addition of clonidine 2 microg.kg-1 does not enhance the postoperative analgesia of a caudal block using 0.125% bupivacaine and epinephrine 1:200,000 in children: a prospective, double-blind, randomized study. Paediatr Anaesth. 2005;15(6):476-483. 419. Willett J, Reader A, Drum M, Nusstein J, Beck M. The anesthetic efficacy of diphenhydramine and the combination diphenhydramine/lidocaine for the inferior alveolar nerve block. J Endod. 2008;34(12):1446-1450. 420. Winnie AP, Masters RW, Durrani Z, Patel KP. Motor block outlasts sensory block. A unique characteristic of etidocaine? Reg Anesth. 1984;9(3):146-153. 421. Wuethrich PY, Kessler TM, Burkhard FC. The effects of thoracic epidurally administered drugs on urethral sphincter function in women: a pooled analysis. Pain Med. 2013;14(8):1248-1253. 422. Yadeau JT, Paroli L, Kahn RL, et al. Addition of pregabalin to multimodal analgesic therapy following ankle surgery: a randomized double-blind, placebo-controlled trial. Reg Anesth Pain Med. 2012;37(3):302-307. 423. Yamamoto H, Sakura S, Wada M, Shido A. A prospective, randomized comparison between single- and multiple-injection techniques for ultrasound-guided subgluteal sciatic nerve block. Anesth Analg. 2014;119(6):1442-1448. 424. Yamamoto H, Sakura S, Yokokawa N, Shido A, Saito Y. Effects and complications of local anesthetic spread pattern during ultrasound-guided subgluteal sciatic nerve block: A prospective, randomized, double-blind study. Eur J Anaesthesiol. 2012;29:120. 425. Yanli Y, Eren A. The effect of extradural ketamine on onset time and sensory block in extradural anaesthesia with bupivacaine. Anaesthesia. 1996;51(1):84-86. 426. Yau G, Gregory MA, Gin T, Oh TE. Obstetric epidural analgesia with mixtures of bupivacaine, adrenaline and fentanyl. Anaesthesia. 1990;45(12):1020-1023. 427. Yoon HJ, Do SH, Yun YJ. Comparing epidural surgical anesthesia and spinal anesthesia following epidural labor analgesia for intrapartum cesarean section: A prospective randomized controlled trial. Korean J Anesthesiol. 2017;70(4):412-419. 428. Youngstrom PC, Cowan RI, Sutheimer C, Eastwood DW, Yu JC. Pain relief and plasma concentrations from epidural and intramuscular morphine in post-cesarean patients. Anesthesiology. 1982;57(5):404-409. 429. Yu CM, Youngstrom PC, Cowan RI. Post-cesarean epidural morphine: Double-blind study. Anesthesiology. 1980;53(3 SUPPL.):S216. 430. Zanfini BA, Biancone M, Triunfo S, et al. Comparison of ropivacaine plasma concentration with or without epinephrine for quadratus lumborum block 2 (QLB2) in cesarean section under spinal anesthesia (SA)-preliminary study. Reg Anesth Pain Med. 2019;44(10):A121. 431. Wu C, Ma W, Cen Q, Cai Q, Wang J, Cao Y. A comparison of the incidence of supraventricular arrhythmias between thoracic paravertebral and intercostal nerve blocks in patients undergoing thoracoscopic surgery A randomised trial. Eur J Anaesthesiol. 2018;35(10):792-798. 432. Aisner J, Langenfeld J, Nemoyer R, et al. Liposomal bupivacaine (Exparel) reduces thoracic surgery post-operative pain and reduces length of stay, a retrospetive study. J Thorac Oncol. 2017;12(11):S2189. 433. Aljabri D, Sherman C, White L, et al. Comparative effectiveness of nerve blocks versus periarticular injections in total knee arthroplasty. Value Health. 2017;20(5):A211.

434. Ardon AE, Greengrass RA, Bhuria U, Porter SB, Robards CB, Blasser K. The use of paravertebral blockade for analgesia after anterior-approach total hip arthroplasty. Middle East J Anaesthesiol. 2015;23(1):81-89. 435. Arnold NI. Paracervical block with low doses of chloroprocaine. Fetal and maternal effects. JAMA. 1975;231(1):56-57. 436. Dahl V, Gierloff C, Omland E, Raeder JC. Spinal, epidural or propofol anaesthesia for out-patient knee arthroscopy? Acta Anaesthesiol Scand. 1997;41(10):1341-1345. 437. de Campo T, Macias-Loza M, Cohen H, Galindo A. Lumbar epidural anaesthesia and sensory profiles in term pregnant patients. Canadian Anaesthetists' Society Journal. 1980;27(3):274-278. 438. Gaiser RR, Cheek TG, Gutsche BB. Epidural lidocaine versus 2-chloroprocaine for fetal distress requiring urgent cesarean section. Int J Obstet Anesth. 1994;3(4):208-210. 439. Hanks RK, Pietrobon R, Nielsen KC, et al. The effect of age on sciatic nerve block duration. Anesth Analg. 2006;102(2):588-592. 440. Hansen JA, Kim TE, Mudumbai S, Mariano ER. Combined ultrasound and neurostimulation guided low-dose lumbar plexus block versus intrathecal morphine for total hip arthroplasty within an established analgesic clinical pathway. Reg Anesth Pain Med. 2011;36(5). 441. Hess PE, Pratt SD, Oriol NE. An analysis of the need for anesthetic interventions with differing concentrations of labor epidural bupivacaine: an observational study. Int J Obstet Anesth. 2006;15(3):195-200. 442. Hickey R, Candido KD, Ramamurthy S, et al. Brachial plexus block with a new local anaesthetic: 0.5 per cent ropivacaine. Can J Anaesth. 1990;37(7):732-738. 443. Hickey R, Hoffman J, Tingle LJ, Rogers JN, Ramamurthy S. Comparison of the clinical efficacy of three perivascular techniques for axillary brachial plexus block. Reg Anesth. 1993;18(6):335- 338. 444. Hutchins JL, Klimstra M, Harrison A. Interscalene block with liposomal bupivacaine for post operative pain control after shoulder surgery: A retrospective study. Reg Anesth Pain Med. 2015;40(5). 445. King MR, Paterno J, Jacob EA, et al. Combination femoral nerve block and multimodal analgesia reduces hospital length of stay in patients undergoing total knee arthroplasty. Reg Anesth Pain Med. 2013;38(4). 446. Kloepping C, Cohen S, Shah S, et al. Is epidural-PCA analgesia necessary for a third day post cesarean section pain. Reg Anesth Pain Med. 2013;38(4). 447. Koltun WA, McKenna KJ, Rung G. Awake epidural anesthesia is effective and safe in the high- risk colectomy patient. Dis Colon Rectum. 1994;37(12):1236-1241. 448. Li L, Beckman J, Beathe J, Gondipalli P, Zayas VM. Cervical spine disease is a risk factor for persistent phrenic nerve paresis following interscalene block for shoulder surgery. Reg Anesth Pain Med. 2011;36(5). 449. Liu CA, Sui J, Coté CJ, Anderson TA. Use of epinephrine in caudal anaesthesia increases stroke volume and cardiac output in children. Br J Anaesth. 2016;117:iii74. 450. Lowensohn RI, Paul RH, Fales S, Yeh SY, Hon EH. Intrapartum epidural anesthesia. An evaluation of effects on uterine activity. Obstet Gynecol. 1974;44(3):388-393.

451. Mark LO, Bengali R, Jacob EA, et al. Combined femoral nerve block and multimodal analgesia reduces early postoperative pain scores at rest and during physical therapy in patients undergoing total knee arthroplasty. Reg Anesth Pain Med. 2013;38(4). 452. Moore DC, Bridenbaugh LD, Bagdi PA, Bridenbaugh PO, Stander H. The present status of spinal (subarachnoid) and epidural (peridural) block: a comparison of the two technics. Anesth Analg. 1968;47(1):40-49. 453. Nader A, Doty R, Jr., Brodskaia A, Kendall MC, McCarthy RJ. Sensory testing of distal sural and posterior tibial nerves provides early prediction of surgical anesthesia after single-injection infragluteal-parabiceps sciatic nerve block. Anesth Analg. 2010;110(3):951-957. 454. Nader A, Kendall MC, Doty R, Jr., et al. Nerve stimulator-guided supplemental popliteal sciatic nerve block after a failed sciatic block does not increase the incidence of transient postoperative neurologic sequelae. Anesthesiology. 2011;115(3):596-603. 455. Rasmussen SB, Saied NN, Bowens C, Jr., Mercaldo ND, Schildcrout JS, Malchow RJ. Duration of upper and lower extremity peripheral nerve blockade is prolonged with dexamethasone when added to ropivacaine: a retrospective database analysis. Pain Med. 2013;14(8):1239-1247. 456. Raza SM, Vasireddy AR, Candido KD, Winnie AP, Masters RW. A complete regional anesthesia technique for cardiac pacemaker insertion. J Cardiothorac Vasc Anesth. 1991;5(1):54-56. 457. Roch JJ, Sharrock NE, Neudachin L. Interscalene brachial plexus block for shoulder surgery: a proximal paresthesia is effective. Anesth Analg. 1992;75(3):386-388. 458. Russell PH, Coakley CS. Re-evaluation of continuous caudal anesthesia for obstetrics. Surg Gynecol Obstet. 1964;119:531-534. 459. Sakr A, Cohen S, Chiricolo A, et al. Does increasing the concentration of epidural-PCA fentanyl for labor improve analgesia without effect to neonate? Anesth Analg. 2014;118(5):S187. 460. Shah B, Vyas AB, Mandowara N, Chauhan D, Thakker A, Karrupiah. Comparative study between 5% dextrose and normal saline in brachial plexus block for onset and duration of complete sensory and motor block. Research Journal of Pharmaceutical, Biological and Chemical Sciences. 2014;5(2):50-57. 461. Shen M, Tse J, Mehta T. The use of a simple nasal CPAP mask assembly for airway obstruction under supraclavicular block and MAC during arteriovenous fistula creation. Reg Anesth Pain Med. 2015;40(5). 462. Sinha SK, Abrams JH, Houle TT, Weller RS. Ultrasound-guided obturator nerve block: an interfascial injection approach without nerve stimulation. Reg Anesth Pain Med. 2009;34(3):261- 264. 463. Sisk AL, Dionne RA, Wirdzek PR. Evaluation of etidocaine hydrochloride for local anesthesia and postoperative pain control in oral surgery. J Oral Maxillofac Surg. 1984;42(2):84-88. 464. Small GA. Brachial plexus block anesthesia in children. JAMA (Chicago, Ill). 1951;147(17):1648-1651. 465. Syed S, Cohen S, Shah S, et al. Epidural-fentanyl-induced puritis: Self-administered versus nurse- administered intravenous naloxone. Reg Anesth Pain Med. 2013;38(1). 466. Warner DO, Warner MA, Ritman EL. Human chest wall function during epidural anesthesia. Anesthesiology. 1996;85(4):761-773.

467. Vertommen JD, Lemmens E, Van Aken H. Comparison of the addition of three different doses of sufentanil to 0.125% bupivacaine given epidurally during labour. Anaesthesia. 1994;49(8):678- 681. 468. Lucas DN, Ciccone GK, Yentis SM. Extending low-dose epidural analgesia for emergency Caesarean section. A comparison of three solutions. Anaesthesia. 1999;54(12):1173-1177. 469. Doughtery TB, Baysinger CL, Henenberger JC, Gooding DJ. Epidural hydromorphone with and without epinephrine for post-operative analgesia after cesarean delivery. Anesth Analg. 1989;68(3):318-322. 470. Martin SR, Baker SS, Muenzler WS. Retrobulbar anesthesia and orbicularis akinesia. Ophthalmic Surg. 1986;17(4):232-233. 471. Sites BD, Beach M, Gallagher JD, Jarrett RA, Sparks MB, Lundberg CJ. A single injection ultrasound-assisted femoral nerve block provides side effect-sparing analgesia when compared with intrathecal morphine in patients undergoing total knee arthroplasty. Anesth Analg. 2004;99(5):1539-1543; table of contents. 472. Hong JY, Lee IH, Shin SK, et al. Caudal midazolam does not affect sevoflurane requirements and recovery in pediatric day-case hernioplasty. Acta Anaesthesiol Scand. 2008;52(10):1411-1414. 473. Shah S, Cohen S, Zisa S, Collins B, Patel P, Barsoum S. Does the addition of ondansetron to iv- patient controlled naloxone further improves post c/s epidural -fentanyl induced pruritus treatment? Anesth Analg. 2012;114(5):S333. 474. Nasr M, Jabbour H, Habre SB. Intercostal nerve block versus bupivacaine pectoralis major infiltration in subpectoral breastaugmentation: A randomized controlled trial. Journal Medical Libanais. 2017;65(1):20-24. 475. Thankraj M, Abraham V, Afzal L, Natu. A comparative study of lignocaine and clonidine with lignocaine and adrenaline for epidural anaesthesia - A pilot study. Journal of Anaesthesiology Clinical Pharmacology. 1997;13(3):203-206.

APPENDICES Appendix 1. Search strategies for bibliographic databases MEDLINE search strategy 1 • Platform: Ovid • Years searched: Ovid MEDLINE and epub ahead of print, in-process and other non-indexed citations and daily 1946 to March 26, 2020 • Date last searched: March 28, 2020 • Limits: Humans (search hedge); English language • Number of results: 2731

1 exp epinephrine/ 55637

2 adrenalin$.tw. 22353

3 epimephrine.tw. 0

4 epinefran$.tw. 0

5 epinefrin$.tw. 17

6 epinephran$.tw. 1

7 epinephrin$.tw. 33503

8 levoadrenalin$.tw. 0

9 levoepinephrin$.tw. 3

10 racepinephrin$.tw. 4

11 or/1-10 78547

12 infusions, spinal/ 152

13 exp injections, spinal/ 15966

14 epidural space/ 4478

15 exp nerve block/ 21960

16 spinal$.tw. 263555

17 intraspinal$.tw. 4983

18 epidural$.tw. 41558

19 extradural$.tw. 6695

20 extra dural$.tw. 139

21 peridural$.tw. 2057

22 peri dural$.tw. 6

23 caudal$.tw. 45086

24 intracaudal$.tw. 11

25 arachnoid$.tw. 8047

26 subarachnoid$.tw. 35067

27 intrathecal$.tw. 23455

28 intra thecal$.tw. 74

29 perineural$.tw. 7286

30 peri neural$.tw. 63

31 extraneural$.tw. 1134

32 extra neural$.tw. 113

33 neuraxial$.tw. 2535

((gangli$ or nerv$ or neuro$ or paracervical$ or plexus or transvers$ abdomin$) adj2 34 35909 block$).tw.

35 or/12-34 434136

36 exp anesthesia/ 189800

37 exp analgesia/ 43540

38 exp pain/ 390010

39 pain management/ 32996

40 dt.fs. 2190148

41 ad.fs. 1396708

42 tu.fs. 2196097

43 pc.fs. 1267246

44 an?esth$.tw. 370803

45 analges$.tw. 120954

46 pain$.tw. 676639

47 or/36-46 5386999

48 and/11,35,47 3685

49 exp animals/ not humans/ 4683273

50 48 not 49 3151

51 limit 50 to english language 2731

MEDLINE search strategy 2 • Platform: Ovid • Years searched: Ovid MEDLINE and epub ahead of print, in-process and other non-indexed citations and daily 1946 to March 26, 2020 • Date last searched: March 28, 2020 • Limits: Humans (search hedge); English language • Number of results: 72

1 exp epinephrine/ 55637

2 adrenalin$.tw. 22353

3 epimephrine.tw. 0

4 epinefran$.tw. 0

5 epinefrin$.tw. 17

6 epinephran$.tw. 1

7 epinephrin$.tw. 33503

8 levoadrenalin$.tw. 0

9 levoepinephrin$.tw. 3

10 racepinephrin$.tw. 4

11 or/1-10 78547

12 administration, topical/ 38087

13 administration, cutaneous/ 21808

14 topical$.tw. 103115

15 percutaneous$.tw. 141677

16 cutaneous$.tw. 148862

17 transdermal$.tw. 14283

18 dermal$.tw. 52045

19 exp gels/ 50795

20 gel?.tw. 304210

21 or/12-20 775249

22 lidocaine/ 24244

23 lidocain$.tw. 21410

24 lignocain$.tw. 2889

25 or/22-24 32992

26 tetracaine/ 2602

27 amet?ocain$.tw. 167

28 tetracain$.tw. 2157

29 or/26-28 3417

30 and/11,21,25,29 75

31 exp animals/ not humans/ 4683273

32 30 not 31 73

33 limit 32 to english language 72

Embase search strategy 1 • Platform: Elsevier • Years searched: 1947 to present • Date last searched: March 28, 2020 • Limits: Humans (search hedge); English language • Number of results: 4326

1 epinephrine'/mj 49356

2 adrenalin*':ti,ab,tn 38293

3 epimephrine':ti,ab,tn 2

4 epinefran*':ti,ab,tn 0

5 epinefrin*':ti,ab,tn 29

6 epinephran*':ti,ab,tn 0

7 epinephrin*':ti,ab,tn 48363

8 levoadrenalin*':ti,ab,tn 0

9 levoepinephrin*':ti,ab,tn 4

10 racepinephrin*':ti,ab,tn 7

11 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 104690

12 intraspinal drug administration'/de 3444

13 epidural drug administration'/de 8848

14 intrathecal drug administration'/de 20957

15 intracaudal drug administration'/de 16

perineural drug administration'/de 265

16 epidural space'/de 6318

17 nerve block'/exp 41847

18 spinal*':ti,ab 362058

19 intraspinal*':ti,ab 6716

20 epidural*':ti,ab 58667

21 extradural*':ti,ab 8873

22 extra dural*':ti,ab 238

23 peridural*':ti,ab 2986

24 peri dural*':ti,ab 12

25 caudal*':ti,ab 58164

26 intracaudal*':ti,ab 17

27 arachnoid*':ti,ab 12159

28 subarachnoid*':ti,ab 49589

29 intrathecal*':ti,ab 34652

30 intra thecal*':ti,ab 230

31 perineural*':ti,ab 11631

32 peri neural*':ti,ab 186

33 extraneural*':ti,ab 1541

34 extra neural*':ti,ab 159

35 neuraxial*':ti,ab 4259

((gangli* OR nerv* OR neuro* OR paracervical* OR plexus OR 'transvers* abdomin*') 36 52200 NEAR/2 block*):ti,ab

#12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 37 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR 607755 #33 OR #34 OR #35 OR #36

38 anesthesia'/exp 385620

39 analgesia'/exp 169703

40 pain'/exp 1364541

41 drug dose':lnk 622308

42 drug administration':lnk 1723135

43 drug therapy':lnk 3853707

44 an$esth*':ti,ab 538113

45 analges*':ti,ab 178272

46 pain*':ti,ab 1037947

47 #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 OR #45 OR #46 6186410

48 #11 AND #37 AND #47 5984

49 [animals]/lim NOT [humans]/lim 6010640

50 #48 NOT #49 5189

51 #48 NOT #49 AND [english]/lim 4326

Embase search strategy 2 • Platform: Elsevier • Years searched: 1947 to present • Date last searched: March 28, 2020 • Limits: Humans (search hedge); English language • Number of results: 115

1 epinephrine'/mj 49356

2 adrenalin*':ti,ab,tn 38293

3 epimephrine':ti,ab,tn 2

4 epinefran*':ti,ab,tn 0

5 epinefrin*':ti,ab,tn 29

6 epinephran*':ti,ab,tn 0

7 epinephrin*':ti,ab,tn 48363

8 levoadrenalin*':ti,ab,tn 0

9 levoepinephrin*':ti,ab,tn 4

10 racepinephrin*':ti,ab,tn 7

11 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 104690

12 topical drug administration'/de 81600

13 cutaneous drug administration'/de 619

14 transdermal drug administration'/de 8898

15 topical*':ti,ab 146272

16 cutaneous*':ti,ab 213765

17 transdermal*':ti,ab 20847

18 dermal*':ti,ab 73061

19 gel'/exp 73660

20 gel$':ti,ab 357623

21 #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 856676

22 lidocaine'/de 74974

23 lidocain*':ti,ab,tn 29925

24 lignocain*':ti,ab,tn 4014

25 #22 OR #23 OR #24 78921

26 tetracaine'/de 7471

27 amet$ocain*':ti,ab,tn 321

28 tetracain*':ti,ab,tn 2980

29 #26 OR #27 OR #28 7869

30 #11 AND #21 AND #25 AND #29 128

31 [animals]/lim NOT [humans]/lim 6010640

32 #30 NOT #31 124

33 #30 NOT #31 AND [english]/lim 115

Appendix 2. Summary of included studies

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

52 Patients scheduled for elective • Group 1: General anesthesia without cesarean section epinephrine (20) “General anesthesia for • Group 1 (0%, mean 29.4 y ± • Group 2: Spinal tetracaine with Neonatal Neurologic cesarean section is more Abboud et al., Not defined 1.6) epinephrine (18) and Adaptive depressant than regional 1985, US79 • Group 2 (0%, mean 27.9 y ± • Group 3: Epidural 2-chloroprocaine (7) Capacity Scores anesthesia during the first few 1.2) or epidural lidocaine with epinephrine hours of life.” • Group 3 (0%, mean 28.2 y ± (7) 1.1) Uterine activity, progress of labor, “We conclude that addition of 28 Parturients at term with no fetal heart rate, epinephrine to chloroprocaine obstetric or medical complications maternal blood during epidural anesthesia in who elected to have epidural • Group I: Chloroprocaine with pressure, newborn the normal parturient has no Abboud et al., Not defined anesthesia for labor and delivery epinephrine (14) Apgar scores, adverse effects on mother, 1987, US77 • Group I (0%, mean 21.3 y ± • Group II: Chloroprocaine (14) neonatal acid-base fetus, neonate, or the progress 0.9) status, Neurologic of labor and that it • Group II (0%, mean 24.7 y ± and Adaptive significantly prolongs the 1.6) Capacity Scoring duration of anesthesia.” System

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

“Bisulfite-free chloroprocaine provides satisfactory anesthesia for labor and 100 Parturients at term with no delivery and does not differ obstetric or medical complications from the old formulation that who elected to have epidural contains bisulfite. The addition Double - • Group I: Chloroprocaine with Duration of Abboud et al., anesthesia for labor and delivery of epinephrine during epidural blinded, epinephrine (49) analgesia, quality of 1988, US78 • Group I (0%, mean 23.7 y ± anesthesia in the normal randomized • Group II: Chloroprocaine (51) analgesia 0.7) parturient has no adverse • Group II (0%, mean 25.7 y ± effects on mother, fetus, 0.7) neonate, or the progress of labor and it significantly prolongs the duration of anesthesia.”

Study 1 Study 1 All the agents gave satisfactory • Group 1: Etidocaine 0.5% 20 mL (9) operating conditions except for • Group 2: Etidocaine 1% 20 mL (9) etidocaine 0.5%. • Group 3: Etidocaine with epinephrine Study 2 Study 1 (9) • Group 4: Bupivacaine (9) Etidocaine 1% had an effect 44 Patients undergoing lower • Group 5: Bupivacaine with epinephrine equal to bupivacaine 0.5% and abdominal gynecological Analgesia (8) a slightly shorter duration of operations (100%, range 23-56 y) effectiveness, spread Abdel-Salam et Double-blind, action. The degree of motor 83 Study 2 of analgesia, motor al., 1975, UK cross-over paralysis was greater with Study 2 block, duration of • Group 1: Etidocaine 1% and analgesia etidocaine, especially if 40 Postoperative patients (100%, bupivacaine 0.5% (10) epinephrine was added. range 23-56 y) • Group 2: Etidocaine 1% with Epinephrine had little effect on epinephrine and bupivacaine 0.5% with the degree or duration of epinephrine (10) blockade achieved with • Group 3: Etidocaine 1% and bupivacaine but with bupivacaine 0.75% (10) etidocaine it increased both the • Group 4: Etidocaine 1% and etidocaine effectiveness and the degree of 1% with epinephrine (10) motor paralysis.

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"Both LIA [local infiltration Affas et al., 2011, 40 Patients undergoing total knee Differences in • Group F: Femoral block with analgesia] and femoral block Sweden84 arthroplasty (TKA) under spinal average pain Randomized, ropivacaine (19) provide good analgesia after anesthesia intensity at rest and parallel clinical TKA. LIA may be considered • Group F (40%, mean 69 y, upon movement Affas et al., 2012, 1:1 trial • Group LIA: Peri- and intraarticular to be superior to femoral block range 53-88) during the first 24 Sweden85 infiltration with ropivacaine, ketorolac, since it is cheaper and easier to • Group LIA (55%, mean 67 y and epinephrine (20) hours after TKA range 29-85) perform"

Pain scores at rest, • Group 1: Extradural bupivacaine and during abduction of epinephrine before skin incision and 45 Patients undergoing the ipsilateral arm saline after skin incision (not provided) and after cough, posterolateral thoracotomy for • Group 2: Extradural saline before skin lung resection recorded on visual Double-blind, incision and bupivacaine and analogue scale Thoracic extradural block with • Group 1 (87%, range 37-77 Aguilar et al., placebo- epinephrine after incision (not (VAS) and verbal bupivacaine did not produce an y) 1996, Spain86 controlled, provided) rating scale (VRS) early preemptive effect after • Group 2 (80%, range 31-72 crossover • Group 3: Saline before and after skin after surgery, total thoracotomy. y) incision (not provided) successful PCEA • Group 3 (73%, range 30-71 Post-operatively all patients received demands recorded y) patient-controlled epidural analgesia after surgery, arterial (PCEA) with bupivacaine, epinephrine, and blood gas after fentanyl surgery

"The pain relief provided by an • Group 1: VATS with a paravertebral Exparel® block in 150 Patients who underwent block using Exparel® (50) thoracotomy patients compares thoracotomy or a video-assisted • Group 2: VATS with a paravertebral favorably to that of VATS Aisner et al., 2017, thoracoscopic surgery (VATS) block using Marcaine® ™ 1% with Pain scores, opiate procedures in the immediate Not defined US432 using either Exparel® or epinephrine (53) use and extended postoperative Marcaine® with epinephrine (sex, • Group 3: Thoracotomy with Exparel® period, and that Exparel® age not provided) (32) paravertebral nerve blocks may • Group 4: VATS lobectomy with a also improve hospital length of Marcaine® ™ block (15) stay."

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

• Group 1: Ropivacaine 0.2% 20 mL with epinephrine 1:400,000 followed by ropivacaine 0.2% at 5 mL/hour with patient-controlled boluses of 5 mL The study was terminated every 30 minutes (28) prematurely due to a change in Randomized, 69 patients scheduled for primary • Group 2: Ropivacaine 0.2% 20 mL standard practice. There was placebo- unilateral TKA with epinephrine 1:400,000 followed no evidence that varying the Albrecht et al., by ropivacaine 0.1% at 10 mL/hour Time to discharge 88 controlled, • Group 1 (53.6%, mean 61 y) concentration and volume of a 2012, Canada with patient-controlled boluses of 10 readiness double-blind • Group 2 (56.3%, mean 63 y) fixed dose ropivacaine infusion mL every 30 minutes (32) study • Group 3 (48.5%, mean 63 y) for femoral nerve block • Group 3: Ropivacaine 0.375% 30 mL influences the time to with epinephrine 1:400,000 followed discharge readiness after TKA. by normal saline at 1 mL/hour with patient-controlled boluses of 10 mL every 30 minutes (33)

• Group 1: Ultrasound-guided 44 Patients undergoing “Compared with ISB, small- interscalene block (ISB) (22) arthroscopic shoulder surgery volume SCB results in • Group 2: Ultra-sound guided small- Aliste et al., 2018, Randomized • Group 1 (45%, mean 58.4 y ± Pain scores at 30 equivalent postoperative volume supraclavicular block (SCB) Canada89 trial 8.7) minutes analgesia and a lower (22) • Group 2 (68%, mean 58 y ± incidence of Both groups received levobupivacaine and 14.1) hemidiaphragmatic paralysis.” epinephrine

40 Patients undergoing • Group 1: Interscalene block (ISB) (20) "Compared with ICB-SSB, arthroscopic shoulder surgery • Group 2: Infraclavicular-suprascapular ISB provided non-equivalent Aliste et al., 2018, Randomized • Group 1 (45%, mean 50.6 y ± Pain scores at 30 90 block (ICB-SSB) (20) (i.e., lower) postoperative pain Canada trial 8.0) minutes Both groups received levobupivacaine scores 30 min after • Group 2 (45%, mean 57.9 y ± epinephrine arthroscopic shoulder surgery." 9.3)

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

44 Patients undergoing • Group 1: Interscalene block (ISB) (22) "Compared with ISB, CCB • Group 2: Costoclavicular brachial results in equivalent Aliste et al., 2019, Randomized arthroscopic shoulder surgery Pain scores at 30 plexus block (CCB) (22) postoperative analgesia while Canada91 trial • Group 1 (45%, mean 54.72 y minutes ± 12.1) Both groups received levobupivacaine and circumventing the risk of • Group 2 (36%, 53.5 y ± 10.4) epinephrine hemidiaphragmatic paralysis.”

Pain scores, time after surgery to first ambulation, • Group 1: Nerve block (514) PAI has proven to provide cumulative • Group 2: Periarticular injection (PAI) better patient satisfaction with Aljabri et al., Retrospective 997 Patients undergoing TKA postoperative (483) pain control, earlier and further 2017, US433 study (sex, age not provided) distance walked, Both groups received ropivacaine, mobilization, and quicker postoperative length epinephrine, ketorolac, and morphine discharges. of stay, and discharge disposition.

VAS pain score, degree of motor and sensory block, time to administration of 30 Patients scheduled for first systemic or oral "Interscalene brachial plexus outpatient arthroscopic shoulder analgesic, total block with low-dose • Group 1: Bupivacaine with Al-Kaisy et al., Double-blind, surgery morphine and oral bupivacaine is a useful and epinephrine (15) 1998, Canada87 randomized • Group 1 (80%, mean 32 y ± analgesic selective analgesic technique • Group 2: Saline (15) 12) consumption, for outpatient shoulder • Group 2 (60%, mean 33 y ± incidence of nausea arthroscopic surgery." 14) and vomiting, block- related side effects, hospital discharge time

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

66 Patients with irreversible pulpitis of permanent mandibular Subjective signal of “The 3 anesthetic solutions • Group 1: Articaine and epinephrine molars during a pulpectomy lip numbness, pulpal tested did not exhibit 100% Prospective, (22) procedure anesthesia, and anesthesia success for Allegretti et al., randomized, • Group 2: Lidocaine and epinephrine • Group 1 (45.5%, mean 28.7 absence of pain conventional IANB [inferior 2016, Brazil92 double-blind, (22) y) during the alveolar nerve block] of the clinical study • Group 2 (40.9%, mean 30.3 • Group 3: Mepivacaine and epinephrine pulpectomy mandibular molars in patients y) (22) procedure with irreversible pulpitis.” • Group 3 (27.3%, mean 33.9 y) Circulatory effects “While clinical experience of epidural analgesia with regional blockade for Amaranath et al., 1 Patient undergoing a total hip and their patients with cardiomyopathy Case report Mepivacaine with epinephrine 1986, US37 replacement (100%, 69 y) significance in a is limited, the epidural patient with dilated technique offers potential cardiomyopathy advantages in select cases.”

• Group 1: Left lateral position, turned supine immediately after injections (not provided) • Group 2: Sitting position, turned supine "The posture did not influence Prospective, 51 Patients undergoing immediately after injection (not the extension of analgesia, Andersen et al., Extension of randomly transurethral resection of the provided) which was found to be 1981, Denmark96 analgesia allocated study prostate gland (100%, 60-87 y) • Group 3: Sitting position, turned supine positively correlated to the 5 minutes after injection (not provided) volume of mepivacaine." The patients in each group were given either 15 mL or 20 mL of mepivacaine with epinephrine

75 Patients undergoing total hip • Group E: Continuous epidural infusion arthroplasty (THA) of ropivacaine with morphine (37) "Wound infiltration combined Andersen et al., Randomized • Group E (46%, mean 61 y ± • Group A: Would infiltration and a Hip pain using a with 1 intraarticular injection 2007, Denmark93 clinical trial 13) single-shot intraarticular injection with VAS can be recommended for • Group A (47%, mean 62 y ± ropivacaine, ketorolac, and epinephrine patients undergoing THA." 14) (38)

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"High-volume infiltration analgesia is effective in knee Randomized, Postoperative pain in 12 Patients undergoing bilateral All patients received saline in one knee and arthroplasty and due to its Andersen et al., double-blind, each leg assessed knee arthroplasty (58%, range 57- ropivacaine with epinephrine in the other simplicity, may be preferable 2009, Denmark95 placebo- using a Numeric 87 y) knee compared with other analgesic controlled trial Rank Scale (NRS) techniques in knee arthroplasty."

Randomized, There was no clinically 12 Patients undergoing bilateral All patients received ropivacaine with Postoperative pain in Andersen et al., double-blind, relevant analgesic effect of total hip arthroplasty (58%, range epinephrine in one hip and saline in the each hip assessed 2011, Denmark94 placebo- intraoperative high-volume 41-82 y) other hip using a VAS controlled trial infiltration analgesia.

"T12-L2 PBV results in Mean opioid moderate opioid consumption, consumption in IV 20 Patients undergoing anterior Paravertebral block (PVB) at T12, L1, and low VAS scores, preservation Ardon et al., 2015, morphine Case series total hip arthroplasty (ATHA) L2 using ropivacaine with epinephrine and of hip motor function, and may US434 equivalents and (65%, 56-91y) dexamethasone (20) be an effective regional worst recorded VAS anesthesia technique for pain scores ATHA."

• Group 1: Tetracaine with epinephrine Phenylephrine produced a 30 Patients scheduled for (not provided) Spread and duration clinical useful prolongation of Armstrong et al., Randomized, transurethral resection of the • Group 2: Tetracaine with of sensory and motor tetracaine while epinephrine 1983, UK97 double-blind prostate or other urological phenylephrine (not provided) loss only prolonged anesthesia in procedure (100%, range 50-80 y) • Group 3: Tetracaine (not provided) the lower segments.

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

Presence of sedation, lightheadedness, 43 Patients requesting epidural duration and The addition of epinephrine Prospective, labor analgesia • Group C: Sufentanil (22) intensity of improves the side effect profile Armstrong et al., randomized, • Group C (100%, mean 26.1 y • Group E: Sufentanil with epinephrine analgesia, of epidural sufentanil while 2002, Canada98 double-blind ± 5.3) (21) respiratory prolonging the duration of study • Group E (100%, mean 27.6 y depression, motor analgesia. ± 4.6) blockade, pruritus, nausea, vomiting

Paracervical blocks are safe for Arnold et al., 261 Patients in labor (0%, age not Paracervical block using chloroprocaine Effectiveness and Not defined the mother and do not affect 1975, US435 provided) with epinephrine (261) duration of block Apgar scores.

Local anesthesia success, child report "There was higher success and • Group 1: Inferior alveolar nerve block of pain for Parallel group, 57 Patients undergoing routine less pain with IANB. There (IANB) (29) administration of split mouth, restorative procedures in was no significant difference Arrow et al., 2012, • Group 2: Buccal infiltration (BI) (28) anesthesia and randomized, mandibular posterior teeth in local analgesia success Australia99 Both groups received articaine with dental treatment, controlled • Group 1 (45%, mean 11.9 y) between articaine and epinephrine at one visit and lidocaine with observer rating of design • Group 2 (29%, mean 12.9 y) lignocaine when delivered via epinephrine at the other visit pain, parent report of BI." pain, postoperative complications

“One year after TKA we found no differences between FNB • Group 1: FNB with ropivacaine (not and LIA on knee function. provided) FNB is associated with lower Bakker et al., • Group 2: Local infiltration analgesia 80 Patients scheduled for fast Pain scores, knee maximum pain scores one year 2017, The Randomized (LIA) with ropivacaine and epinephrine track TKA (sex, age not provided) function after surgery as compared to Netherlands100 (not provided) LIA. LIA patients were almost Both groups received an infiltration of 6 times more likely to use ropivacaine and epinephrine analgesics one year after TKA.”

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

Randomized, 254 Patients undergoing TKA • Group 1: LIA with ropivacaine, Length of stay, “LIA is a safe adjuvant to FNB prospective, • Group 1 (31%, mean 70.63 y Barastegui et al., ketorolac, and epinephrine with FNB short-term pain to reduce perioperative pain controlled, ± 7.71) 2017, Spain101 (120) control, patient’s during the first 36 hours after single-blind • Group 2 (22%, mean 69.25 y • Group 2: FNB only (134) satisfaction TKA.” trial ± 8.08)

34 Patients undergoing Prospective, posterolateral thoracotomy Adding epinephrine to VAS, spirometry, Baron et al., 1996, randomized, • Group 1 (44%, mean 61.7 y ± • Group 1: Fentanyl (16) continuous thoracic epidural mean blood Canada102 double-blind 1.9) • Group 2: Fentanyl and epinephrine (18) infusions decreases fentanyl pressure, heart rate trial • Group 2 (72%, mean 60.2 y ± requirements. 3.7)

“Initiating an epidural infusion 15 minutes after subarachnoid medication is administered and 5 minutes after an epidural test dose will maintain the • Group 1: 0.9% saline (23) Pain levels, degree analgesia with minimal side 89 Patients in labor • Group 2: Bupivacaine 0.125% with of motor block, Prospective, effects. Using an infusion of • Group 1 (0%, range 18-41 y) fentanyl (22) maternal blood Beilin et al., 2002, randomized, bupivacaine 0.125% with • Group 2 (0%, range 24-44 y) • Group 3: Bupivacaine 0.04% with pressure, Bromage US103 double-blinded fentanyl 2 mcg/mL maintains • Group 3 (0%, range 18-44 y) fentanyl and epinephrine (22) score, nausea, study the analgesia for longer than duration of • Group 4 (0%, range 19-40 y) • Group 4: Bupivacaine 0.0625% with either bupivacaine 0.0625% anesthetic fentanyl (22) with fentanyl 2 mcg/mL or bupivacaine 0.04% with fentanyl 2 mcg/mL and epinephrine 1:600,000, but it produces more motor block.”

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

“Addition of dexmedetomidine • Group 1: Interscalene block with to levobupivacaine for Prospective, 48 Patients undergoing levobupivacaine and epinephrine (25) interscalene brachial plexus Bengisun et al., double-blind, arthroscopic shoulder surgery • Group 2: Interscalene block with VAS pain score block decreases pain scores 2014, Turkey104 randomized • Group 1 (32%, 50.4 y ± 12.9) levobupivacaine, epinephrine, and and increases patient study • Group 2 (30%, 55.9 y ± 8.5) dexmedetomidine (23) satisfaction after arthroscopic subacromial decompression.”

• Group 1: Patients without low back 25 Patients receiving lumbar pain undergoing herniorrhaphy or There was a statistically epidural anesthesia perineal operations (10) Onset and Benzon et al., significant difference between Not defined • Group 1 (sex not provided, • Group 2: Patients with low back pain completeness of 1981, US105 the 2 groups regarding the range 25-60 y) receiving epidural steroids (15) anesthesia onset of anesthesia. • Group 2 (sex not provided, All patients received mepivacaine, range 22-60 y) epinephrine, and methylprednisolone acetate

“Levobupivacaine and • Group 1: Levobupivacaine, sufentanil, Motor block level, Randomized, 47 Patients undergoing cesarean bupivacaine were equally Bergamaschi et and epinephrine (24) sensory block level, double-blind, section effective for epidural block in al., 2005, Brazil106 • Group 2: Bupivacaine, sufentanil, and maternal clinical trial • Group 1 (0%, 27.95 y ± 5.56) patients undergoing cesarean epinephrine (23) complications • Group 2 (0%, 25.91 y ± 5.27) section.”

Loss of motor Alkalinization of mepivacaine 20 Patients scheduled for axillary • Group 1: Bicarbonate (11) function, loss of Berman et al., Double-blind, produces no clinical advantage plexus block (sex, age not • Group 2: Control (9) sensory function, 1988, US107 randomized in axillary brachial plexus provided) Both groups received mepivacaine plasma mepivacaine block. epinephrine level

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

• Group 1: LIA plus placebo adductor “There was no difference in Biswas et al., 201 Patients undergoing unilateral canal block (ACB) (62) either the primary outcome of 2017, Canada108 TKA • Group 2: LIA plus ACB using TUG test on POD • Group 1 (34%, mean 64.2 y ± Prospective, ropivacaine with epinephrine (68) [postoperative day] 2, other Biswas et al., 8.1) Timed Up and Go randomized, • Group 3: LIA plus ACB using immediate functional 2018, Canada109 • Group 2 (46%, mean 64.2 y ± (TUG) test double-blind ropivacaine with epinephrine plus secondary outcomes, or in 8.2) Ghosh et al., 2015, intrathecal morphine (64) global functional outcome at 3 • Group 3 (45%, mean 64.6 y ± Canada183 All groups received LIA with ropivacaine, months postoperatively across 9.1) ketorolac, and epinephrine all 3 groups.”

• Intracaine 1.5% (1)* • Intracaine 5% in oil (3)* “From the results obtained in • Metycaine 1.5% (32) this series of cases, it is • Pontocaine 0.075% (27)* evident that brachial plexus • Pontocaine 0.10% (77)* block is an adequate form of 1512 Patients receiving brachial • Pontocaine 0.15% (481)* Need for additional anesthesia for any operation of Bonica et al., Cases blocks (sex not provided, 2.5-96 anesthesia, duration the upper extremity, and that 1950, US38 • Pontocaine 0.25% (120)* y) • Pontocaine 0.15% with procaine 1% of block with proper instructions, a (38)* thorough knowledge of • Procaine 1% (23)* anatomy and observations of • Procaine 2% (710) certain principles, any operator *Epinephrine added to local anesthetic can obtain good results.” solution in 1418 blocks

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

“The use of 4% articaine for the inferior alveolar nerve block was clinically more effective in the onset of subjective and objective Controlled, anesthesia as compared with randomized, Onset of anesthesia, 22 Patients undergoing surgical • Study group: Lidocaine with the use of 4% lidocaine. Based single-blind, anesthetic duration, Boonsiriseth et al., removal of lower impacted third epinephrine (22) on the pain scores from the prospective, surgical time, and 2017, Thailand110 molars (sex not provided, mean 21 • Comparative group: Articaine with visual analogue scale, 4% split-mouth VAS value of intra- y) epinephrine (22) lidocaine provided more comparative operative pain analgesia during the procedure, study and patients noted less intraoperative pain than with 4% articaine; however, the difference was not clinically significant.”

Knee Society score, nausea, micturition problems, lower 40 Patients undergoing a • Group A: Spinal anesthesia with limb dysfunction, unicompartmental knee bupivacaine and sufentanil and a pain using a VAS, “Our findings and those of Randomized, replacement (UKR) postoperative infiltration of the tissues Borgwardt et al., opiate consumption, others support the concept of controlled • Group A (41%, range 50-81 around the knee join with bupivacaine 2009, Denmark111 day of discharge, accelerated postoperative study y) and epinephrine (17) rehospitalization, care.” • Group C (48%, range 44-86 • Group C: Spinal/epidural technique contact with a y) with bupivacaine and morphine (23) general physician or nurse, level of satisfaction

“Injection of three different Prospective, Detection threshold 45 Patients undergoing • Group 1: Ropivacaine (15) anesthetic solutions results in a Bosserez et al., randomized, for cold sensation, arthroscopic surgery (sex, age not • Group 2: Levobupivacaine (15) similar decrease in functioning 2010, Belgium112 double-blind warm sensation, cold provided) • Group 3: Levobupivacaine with of A-delta and C-fibers within study pain, heat pain epinephrine (15) the ipsilateral C5 dermatome.”

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

Effectiveness of analgesia, duration “Many patients receiving of analgesia, 130 Patients in labor epidural analgesia for relief of patient’s ability to Prospective, • Group 1 (0%, mean 30.3 y ± • Group 1: Fentanyl (53) the pain of labor obtain Breen et al., 1993, ambulate, mode of randomized, 5.2) • Group 2: Bupivacaine, epinephrine, satisfactory analgesia with US113 delivery, differences double-blind • Group 2 (0%, mean 30.8 y ± and fentanyl (77) fentanyl alone or a low-dose between nulliparous 4.9) mixture of bupivacaine, and multiparous fentanyl, and epinephrine.” women, patient satisfaction

“Peripheral nerve block, alone or combined with nitrous oxide-oxygen, is the anesthetic procedure of choice. With Bridenbaugh et al., • Tetracaine, hyaluronidase, and Cases 3 Patients (67%, range 19-63 y) Anesthesia peripheral nerve block, any 1965, US39 epinephrine (2) • Tetracaine and epinephrine (1) type of emergency surgery can be performed on the patient in shock without making the shock worse.”

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

Intercostal nerve block • Group 1: Etidocaine 0.25% 60 mL with epinephrine (10) • Group 2: Etidocaine 0.5% 30 mL with epinephrine (11) • Group 3: Etidocaine 0.5% 60 mL with “Etidocaine has proved 221 Patients undergoing intra- epinephrine (10) efficacious and safe, with no Bridenbaugh et al., Not defined abdominal surgery (sex, age not Sensory block observable central nervous 1973, US115 An additional 135 patients received provided) system or cardiovascular side etidocaine 0.5% 60 mL with epinephrine effects in the doses used.” Epidural block • Group 1: Etidocaine 0.25%-1.5% 20 mL with epinephrine (50) • Group 2: Etidocaine 1% 30 mL with epinephrine (5)

Study 1: Intercostal nerve block Study 1 • Tetracaine and epinephrine (not 22 Patients undergoing upper provided) abdominal surgery (sex, age not • Etidocaine with epinephrine (not “Etidocaine proved to produce Clinical Bridenbaugh et al., provided) provided) Onset and duration an onset of anesthesia double-blind 1974, US114 of anesthesia equivalent to lidocaine and trials Study 2 Study 2: Lumbar epidural block • Lidocaine with epinephrine (not more rapid than tetracaine.” 31 Patients undergoing lower provided) abdominal gynecologic surgery (0%, age not provided) • Etidocaine with epinephrine (not provided)

The addition of epinephrine to etidocaine for lumbar epidural Onset of sensory Clinical 50 Patients undergoing abdominal • Group 1: Etidocaine (not provided) and intercostal nerve block Bridenbaugh et al., anesthesia, level and double-blind hysterectomy (0%, age not • Group 2: Etidocaine with epinephrine may provide some protection 1974, US116 time of complete study provided) (not provided) against systemic toxicity but sensory anesthesia has little benefit on the clinical effect of the drug.

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

Time to full Matched, 116 Patients undergoing analgesia, maximum paired sample, transurethral investigations or • Group 1: Carticaine with epinephrine number of random Brinklov et al., operations (58) dermatomes that Carticaine has comparable allocation, 1977, Denmark117 • Group 1 (100%, range 20-83 • Group 2: Lidocaine with epinephrine became analgetic, clinical properties as lidocaine. double-blind, y) (58) duration of stratum-fixed • Group 2 (100%, range 24-80 analgesia, motor dose trial y) blockade

46 Patients undergoing “The addition of adrenaline did thoracotomy for lung resection • Group 1: Meperidine and epinephrine Consumption of not influence PCEA Bryson et al., Randomized • Group 1 (sex not provided, (22) PCEA, pain scores meperidine consumption, 2007, Canada118 study 63.4 y ± 8.1) • Group 2: Meperidine (224) using a VAS analgesia outcomes, or QoR • Group 2 (sex not provided, [quality of recovery].” 60.0 y ± 8.7)

“PVB provide excellent analgesia when faced with the 1 Patient undergoing left partial Buckenmaier et Paravertebral nerve HOCM [hypertrophic Case report mastectomy with axillary Ropivacaine and epinephrine (1) al., 2002, US40 blocks (PVB) obstructive cardiomyopathy] dissection (0%, 72 y) patient requiring major breast surgery.”

• Group 1: Mepivacaine, tetracaine, “Buprenorphine-local 60 Patients undergoing upper epinephrine, and buprenorphine anesthetic axillary perivascular extremity surgery followed by an IM injection of normal brachial plexus block provided Prospective, saline (20) • Group 1 (60%, range 19-70 Quality and duration postoperative analgesia lasting Candido et al., randomized, • Group 2: Mepivacaine, tetracaine, y) of analgesia, VAS 3 times longer than local 2002, US119 double-blind epinephrine followed by an IM • Group 2 (75%, range 20-61 pain score anesthetic block alone and study injection of buprenorphine (20) y) twice as long as buprenorphine • Group 3: Mepivacaine, tetracaine, • Group 3 (55%, range 19-68 given by IM injection plus epinephrine followed by an IM y) local anesthetic-only block.” injection of normal saline (20)

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

“The alkalinization allowed the Randomized, 70 Patients undergoing cesarean • Group 1: Mepivacaine with Sensory and motor surgery to proceed more double-blind, section under epidural anesthesia epinephrine (35) Capogna et al., block, onset time, rapidly, significantly placebo- • Group 1 (0%, mean 29.8 y ± • Group 2: Mepivacaine with 1991, Italy120 time to peak effect, decreasing the time between controlled 6.0 epinephrine pH-adjusted with sodium duration of block epidural block and delivery of study • Group 2 (0%, mean 32.1 y ± bicarbonate (35) 5.3) the infant.”

• Group 1: Ropivacaine 0.5% 20 mL (12) Sensory and motor “The addition of epinephrine • Group 2: Ropivacaine 0.5% 20 mL block, hemodynamic 48 Patients scheduled for did not provide any significant Cederholm et al., with epinephrine (12) changes, skin Randomized transurethral surgery (100%, range prolongation of the sensory or 1994, Sweden121 • Group 3: Ropivacaine 0.75% 20 mL resistance level, skin 42-74 y) motor block, nor any influence (12) blood flow, skin upon the sympathetic block.” • Group 4: Ropivacaine 0.75% 20 mL temperature with epinephrine (12)

• Group A: Racemic bupivacaine with “We did not notice any Cesar-Komar et 28 Patients with complex regional Efficiency of the epinephrine (14) significant differences between al., 2009, Randomized pain syndrome (CPRS) (sex, age brachial plexus • Group B: Bupivacaine with the two LA's [local Slovenia122 not provided) block epinephrine (14) anesthetics] used in the study."

Pain of needle insertion, anesthetic “Digital and local anesthesia of Single-center, • Group 1: Local infiltration using injection and finger lacerations with prior prospective, 55 Patients with simple, short, lidocaine (27) suturing, patient application of LET to all Chale et al., 2006, randomized, traumatic lacerations of the finger • Group 2: Digital block using lidocaine satisfaction, time wounds results in similar pain U123S controlled (71%, range 11-82 y) (28) until anesthetic of needle insertion, anesthetic clinical trial All patients received topical onset, presence of infiltration, and pain of lidocaine/epinephrine/tetracaine (LET) wound infection and suturing.” persistent numbness

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

Time from start of “Both lumbar extradural • Group 1: General anesthesia (35) anesthesia to the morphine and caudal • Group 2: Lumbar extradural morphine, administration 105 Patients undergoing extradural morphine have good Chen et al., 1993, bupivacaine, Xylocaine, and supplemental Randomized hemorrhoidectomy surgery (75%, efficacy for postoperative Taiwan124 epinephrine (35) analgesics, amount range 18-70 y) analgesia and their adverse • Group 3: Caudal extradural morphine, of pethidine effects were minor and bupivacaine, Xylocaine, and injection, adverse acceptable.” epinephrine (35) effects

“The use of pre-emptive anaesthesia in orthognathic • Group A: No regional block (25) surgery may reduce the overall Prospective, 50 Patients undergoing • Group B: Regional bilateral block with amounts of medications Chen et al., 2016, triple-blind, bimaxillary surgery Mean arterial levobupivacaine (25) required for hypotensive Taiwan125 randomized, pressure • Group A (32%, mean 26.6 y) Both groups received an infiltration of anaesthesia, facilitate the controlled trial • Group B (24%, mean 26.6 y) epinephrine with levobupivacaine into the intraoperative control of blood areas of planned incision pressure, and decrease intraoperative blood loss.”

• Continues femoral nerve block (cFNB): LIA with normal saline, cFNB bolus 120 Patients undergoing primary and infusion with ropivacaine (40) Choi et al., 2016, tri-compartmental TKA • Single injection femoral nerve block There is no clinically Canada127 • cFNB (44%, mean 64.0 y ± (sFNB): LIA with normal saline, cFNB Numeric rating scale significant difference between Randomized, 7.4) bolus with ropivacaine, cFNB infusion (NRS) for pain with cFNB LIA and sFNB for pain blinded Choi et al., 2016, • sFNB (51%, mean 65.2 y ± with normal saline (39) movement during physiotherapy on Canada126 9.2) • LIA: LIA with ropivacaine, postoperative day 2 after TKA. • LIA (49%, mean 65.9 y ± epinephrine, and ketorolac, fascia iliaca 8.0) bolus and infusion with normal saline (41)

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

96 Patients undergoing tubeless percutaneous nephrolithotomy • Group 1: No local analgesic infiltration (TPCNL) or nerve blockade (32 cases) “NTI is safe and effective in Prospective, • Group 1 (68.8%, mean 56.56 • Group 2: Intercostal nerve block Choi et al., 2018, Pain score using a alleviating early postoperative randomized, y ± 13.08) (ICNB) with ropivacaine and South Korea128 VAS pain for patients who controlled trial • Group 2 (68.8%, mean 54.06 epinephrine (32 cases) underwent TPCNL.” y ± 16.25) • Group 3: Nephrostomy tract infiltration • Group 3 (68.8%, mean 57.88 (NTI) with ropivacaine and epinephrine y ± 13.8) (32 cases)

“In conclusion, the addition of 100 Patients who requested a low dose of clonidine (5 • Group BE: Bupivacaine with epidural analgesia during mcg/mL) to a 10-mL injection epinephrine (25) Claes et al., 1995, childbirth of 0.125% bupivacaine plus • Group BES: Bupivacaine with Belgium129 • Group BE (0%, 27 y ± 3.3) epinephrine 1:800,000 and epinephrine and sufentanil (25) Onset and duration Double-blind • Group BES (0%, 29.5 y ± 0.75 mcg/mL sufentanil has • Group BEC: Bupivacaine with of analgesia, pain on study 4.9) potential advantages in Claes et al., 1998, epinephrine and clonidine (25) visual analog score • Group BEC (0%, 26.7 y ± epidural analgesia during Belgium130 • Group BESC: Bupivacaine with 4.5) childbirth and increases both epinephrine, sufentanil, and clonidine • Group BESC (0%, 28.4 y ± the quality and duration of (25) 4.5) analgesia with few side effects.”

“When considering Pain assessed using levobupivacaine and a verbal numeric ropivacaine for brachial plexus Double-blind, 54 Patients requesting brachial • Group 1: Ropivacaine with epinephrine rating scale (VNRS), anesthesia, levobupivacaine Cline et al., 2004, randomized, plexus anesthesia for surgery of (25) patient satisfaction, should be considered when US131 prospective the upper extremity • Group 2: Levobupivacaine with duration of motor postoperative analgesia is a investigation • Group 1 (76%, 27.0 y ± 7.5) epinephrine (29) • Group 2 (83%, 29.7 y ± 10.9) blockade, duration concern but not when an early of sensory analgesia return of motor activity is required.”

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

• Group 1: Epidural patient-controlled analgesia (PCA) using buprenorphine, bupivacaine, and epinephrine (26) “Epidural patient-controlled • Group 2: Epidural PCA using fentanyl, 78 Patients undergoing elective Pain on visual analgesia in all three groups Cohen et al., 1992, Randomized, bupivacaine, and epinephrine (26) cesarean section (0%, age not analog scale, patient provided excellent analgesia, US135 double-blind provided) • Group 3: Epidural PCA using fentanyl satisfaction permitted ambulation, and was and bupivacaine (26) without serious side effects.” All patients received epidural anesthesia using chloroprocaine with epinephrine, followed by bupivacaine with epinephrine

• Group 1: Epidural patient- controlled “Epidural PCA had no serious analgesia (PCA) using fentanyl, side effects and achieved a bupivacaine, and epinephrine (125) high level of patient 250 Patients undergoing elective • Group 2: Epidural PCA using Pain on visual satisfaction. Those receiving Cohen et al., 1993, Randomized, cesarean section sufentanil, bupivacaine, and analog scale, side sufentanil made fewer PCA US134 double-blind • Group 1 (0%, mean 30 y ± 5) epinephrine (125) effects, overall requests but had a significantly • Group 2 (0%, mean 30 y ± 6) All patients received epidural anesthesia satisfaction greater incidence of vomiting using chloroprocaine with epinephrine, during the infusion and followed by bupivacaine with epinephrine dizziness after the termination for surgery of the infusion.”

“Epidural opioid infusion with low dose bupivacaine and epinephrine achieved a high patient satisfaction in both groups without serious • Group I: Epidural fentanyl, 100 Patients requesting epidural Pain on visual maternal or neonatal side Cohen et al., 1996, Randomized, bupivacaine, and epinephrine (50) block for labor (0%, age not analog scale, patient effects. Patients receiving US133 double-blind • Group II: Epidural sufentanil, provided) satisfaction sufentanil 1 mcg/mL required bupivacaine, and epinephrine (50) less total bupivacaine than those receiving fentanyl 2 mcg/mL and substantially fewer requested a bupivacaine rescue dose.”

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

“Gravity flow administration • Group 1: Gravity flow (298) of local anesthetic-opioid o Vaginal delivery patients received solution during epidural block bupivacaine, sufentanil, and Changes in maternal for obstetrics was associated epinephrine (189) heart rate and blood with fewer signs of systemic o Cesarean delivery patients received pressure, signs of drug absorption and Prospective, Cohen et al., 1997, 600 Patients in labor (0%, age not lidocaine, sufentanil, and intravascular cardiovascular perturbations randomized US132 provided) epinephrine (109) injection, adverse than was the traditional bolus study • Group 2: Bolus injection (290) effects of epidural injection. This study supports o Vaginal delivery patients received bupivacaine- the current opinion that slow bupivacaine, sufentanil, and sufentanil administration of local epinephrine by gravity flow (185) anesthetic during epidural Cesarean delivery patients received block contributes to freer lidocaine, sufentanil, and epinephrine (105) adverse events.”

100 Patients undergoing cesarean • Group 1: Fentanyl with epinephrine section Pain intensity at rest, (25) The addition of epinephrine • Group 1 (0%, mean 28.8 y ± pruritus, sedation, • Group 2: Fentanyl with bupivacaine and bupivacaine to epidural 5.2) nausea, vomiting, (25) fentanyl for post-cesarean Cohen et al., 1998, Randomized. • Group 2 (0%, mean 29.6 y ± backache, urinary • Group 3: Fentanyl and epinephrine (25) section pain relief provided US137 double-blind 4.5) retention, uterine • Group 4: Fentanyl, bupivacaine, and superior analgesia compared • Group 3 (0%, mean 30.4 y ± cramping, motor epinephrine (25) with fentanyl alone or with 4.3) block, patient All groups received lumbar epidural epinephrine. • Group 4 (0%, mean 30.2 y ± satisfaction anesthesia using lidocaine with epinephrine 3.8)

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

48 Patients undergoing cesarean delivery under epidural anesthesia • Group 1: Ropivacaine 0.2%, fentanyl, “0.025% ropivacaine PCEA • Group 1 (0%, mean 29.4 y ± and epinephrine (12) combined with fentanyl and 5.8) Lowest mean pain epinephrine provided effective Randomized, • Group 2: Ropivacaine 0.1%, fentanyl, Cohen et al., 2015, • Group 2 (0%, mean 30.4 y ± score at rest, lowest pain relief after cesarean double-blind and epinephrine (12) US136 6.3) motor block that section with early ambulation study • Group 3: Ropivacaine 0.05%, fentanyl, • Group 3 (0%, mean 33.7 y ± and epinephrine (12) allowed ambulation and without sensory loss, 5.1) • Group 4: Ropivacaine 0.025%, urinary retention, or increase • Group 4 (0%, mean 34.2 y ± fentanyl, and epinephrine (12) of side-effects.” 6.2)

Success or failure of “It is recommended that 100 Patients undergoing should the anesthetic, • Bupivacaine with epinephrine (not interscalene blockade be more Conn et al., 1987, surgery with interscalene brachial development of any Not defined provided) commonly considered as a US138 and cervical plexus block (52%, complications, • Etidocaine with epinephrine (not form of anesthesia for shoulder range 20-87 y) response of the provided) surgery.” patient

Single-center, Rate of recurrence, “The addition of epinephrine Cordoba- prospective, 44 Patients (70 toes) undergoing • Group 1: Mepivacaine with duration of may reduce the need for a Fernandez et al., randomized, chemical partial nail matricectomy epinephrine (36 toes) anesthetic effect, tourniquet and produce better 139 2015, Spain single-blind (47.7%, mean 26.2 y ± 15.82) • Group 2: Mepivacaine (34 toes) postoperative pain and longer perioperative pain trial and bleeding control.”

80 Patients undergoing laparoscopic gynecological • Group 1: Transversus abdominis plane surgery Clonidine added to ropivacaine (TAP) block using ropivacaine (2) • Group 1 (0%, mean 37.4 y ± for TAP blocks did not • Group 2: TAP block using ropivacaine Randomized 6.5) Total venous plasma produce a reduction in plasma Crawford et al., with clonidine (20) controlled • Group 2 (0%, mean 37.1 y ± ropivacaine ropivacaine concentrations 2019, Australia140 • Group 3: TAP block using ropivacaine study 8.2) concentrations suggesting a lack of with epinephrine (20) • Group 3 (0%, mean 36.8 y ± vasoconstrictor effect during • Group 4: TAP block with ropivacaine 10.5) TAP blocks. and subcutaneous clonidine (20) • Group 4 (0%, mean 36.6 y ± 6.8)

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

Pain rating using a Epidural epinephrine produces Randomized, VAS, sensitivity to segmental hypoalgesia, which double-blind, • Epinephrine (15) pinprick and cold, Curatolo et al., 15 Patients (66.7%, range 21-31 in addition to its placebo- • Clonidine (15) pressure pain 1997, Denmark141 y) vasoconstrictive properties, controlled, • Normal saline (15) tolerance, provides a rationale for use to cross-over Patients received each intervention electromyographic enhance epidural analgesia. reflex responses

82 Patients undergoing lower limb surgery • Group 1: Bupivacaine and epinephrine • Group 1 (55%, mean 55 y ± (20) Adding lidocaine to Controlled, 16) • Group 2: Ropivacaine and epinephrine Sensory onset time bupivacaine or ropivacaine Cuvillon et al., randomized, • Group 2 (60%, mean 51 y ± (20) for sciatic and produces a faster onset of a 2009, France142 double-blind, 17) • Group 3: Bupivacaine, lidocaine, and femoral nerve blocks femoral-sciatic block but study • Group 3 (71%, mean 46 y ± epinephrine (21) reduces block duration. 18) • Group 4: Ropivacaine, lidocaine, and • Group 4 (62%, mean 45 y ± epinephrine (21) 16)

116 Patients who underwent To prevent vasovagal events, • Group 1: Experienced vasovagal events shoulder arthroscopy adequate IV fluids should be (20) D'Alessio et al., Retrospective • Group 1 (60%, mean 34 y ± Occurrence of administered, β-blockers • Group 2: No vasovagal events (96) 1995, US143 analysis 16) vasovagal reaction should be administered early, All patients received epinephrine in their • Group 2 (70%, mean 40 y ± or an anticholinergic should be local anesthetic for interscalene block (ISB) 17) prophylactically administered. • “Propofol anaesthesia results • Group 1: Spinal anesthesia with Degree of pain using in the shortest stay in the Dahl et al., 1997, 91 Patients undergoing knee lidocaine (32) a VAS, need for operation theatre but a higher Randomized Norway436 arthroscopy (65%, range 18-68 y) • Group 2: Lumbar epidural block using rescue analgesia, degree of postoperative pain mepivacaine with epinephrine (29) side effects and a higher cost of drugs and • Group 3: Propofol (30) disposables.”

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

“Epidural analgesia for parturients using low dose bupivacaine and sufentanil works well and is well tolerated by parturients. This 140 Patients in labor method is as good as high-dose bupivacaine and has fewer • Group B (0%, mean 31 y ± • Group B: Epidural bupivacaine (45) Pain on visual side-effects, such as motor 5.1) • Group BS: Epidural bupivacaine and analog and verbal Dahl et al., 1999, Randomized, block and urinary retention. • Group BS (0%, mean 30 y ± sufentanil (46) scale, degree of Norway144 double-blind The addition of low-dose 4.5) motor block, patient • Group BSE: Epidural bupivacaine, epinephrine results in satisfaction • Group BSE (0%, mean 30 y sufentanil, and epinephrine (49) significantly better analgesia. ± 5.3) Thus, we suggest further investigations of low-dose epidural analgesia for labour with the combination of local anaesthetic, sufentanil and epinephrine.”

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

• Group P: Posterior approach used for sciatic nerve block (60) o Lidocaine and epinephrine (15) o Bupivacaine and epinephrine (15) o Bupivacaine, lidocaine, and epinephrine (15) o Bupivacaine, etidocaine, and “In conclusion, the most epinephrine (15) suitable techniques for • Group L: Lateral approach used for blocking the sciatic nerve sciatic nerve block (60) proximally are via either the o Lidocaine and epinephrine (15) 180 Patients undergoing surgery Sensory and motor posterior (which remains the Dalens et al., o Bupivacaine and epinephrine (15) Randomized of the leg, ankle or foot (63%, block, duration of easiest approach) or the lateral 1990, France145 o Bupivacaine, lidocaine, and range 3 months – 18 y) block route, which is of special value epinephrine (15) when the patient cannot be o Bupivacaine, etidocaine, and placed in the lateral position epinephrine (15) (extensive wounds, unstable • Group A: Anterior approach used for fractures of the limb).” sciatic nerve block o Lidocaine/epinephrine (15) o Bupivacaine/epinephrine (15) o Bupivacaine/lidocaine/epinephrine (15) o Bupivacaine/etidocaine/epinephrine (15)

Deep vein 132 Patients undergoing hip • Group 1: Spinal anesthesia using thrombosis, arterial tetracaine with epinephrine; blood gas, peri- “In elective hip surgery, surgery cinchocaine was used in 13 patients operative blood loss, regional blockade may result Davis et al., 1981, Randomized • Group 1 (17%, mean 81 y ± due to tetracaine being unavailable (64) postoperative in less surgical haemorrhage New Zealand146 8.2) • Group 2: General anesthesia using morbidity and compared with relaxant- • Group 2 (13%, mean 78 y ± diazepam, fentanyl, and pancuronium mortality, narcotic anaesthesia.” 8.6) (68) cardiovascular changes

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

• Group 1: Chloroprocaine 2% (16) Time of onset of • Group 2: Chloroprocaine 3% (10) hypalgesia, time The addition of bupivacaine to • Group 3: Chloroprocaine 3% with de Campo et al., 57 Patients in active labor (0%, required to block chloroprocaine did not Not defined epinephrine (10) 1980, US437 age not provided) T10, S1, and S3 to significanly increase the • Group 4: Bupivacaine 0.25% (10) S5, duration of duration of the blockade. • Group 5: Chloroprocaine 3% with anesthesia bupivacaine (11)

45 Patients undergoing THA • Group 1: Psoas compartment-sciatic Pain score using a “Levobupivacaine, • Group 1 (27%, mean 60.6 y ± nerve block (PCSNB) using VAS, degree of de Leeuw et al., Randomized, bupivacaine and ropivacaine 16.7) levobupivacaine with epinephrine (15) motor block 2008, The double-blind are equally effective for • Group 2 (20%, mean 69.1 y ± • Group 2: PCSNB using ropivacaine (Modified Bromage Netherlands147 trial PCSNB in patients undergoing 10.7) with epinephrine (15) Scale), extent of total hip arthroplasty.” • Group 3 (20%, mean 69.4 y ± • Group 3: PCSNB using bupivacaine sensory block 12.8) with epinephrine (15)

42 Patients with a mandibular • Group 1: Tramadol (21) Randomized, Preoperative submucosal molar • Group 2: Placebo (21) De Pedro-Munoz double-blind, Success of IANB, administration of tramadol • Group 1 (52.4%, mean 40.35 et al., 2017, placebo- duration of sensory significantly improved the y) All patients received inferior alveolar nerve Spain148 controlled, block success of IANB compared to • Group 2 (47.6%, mean 37.07 blocks (IANB) using articaine with clinical trial placebo. y) epinephrine

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

Presence of paresthesia, overall satisfaction, need for additional local “The addition of epinephrine anesthetic, time to to ropivacaine improves the 401 Patients undergoing cesarean • Group 1: Ropivacaine with fentanyl T6, maximum Prospective, safety and quality of epidural Denny et al., 2015, section (201) sensory level, time double-blind anesthesia when administered US149 • Group 2: Ropivacaine, fentanyl, and to incision, duration study • Group 1 (0%, mean 32 y ± 5) by gravity flow via the epinephrine (200) of surgery, time to Hustead needle for cesarean • Group 2 (0%, mean 31 y ± 5) return of pain, time sections.” to return to Bromage 2, exteriorization of uterus, efficacy of sensory block

“In conclusion, both the doses 1 mcg/kg and 0.5 mcg/kg of fentanyl with bupivacaine 0.25% when administered 60 Patients undergoing lower • Group I: Caudal block using caudally provided satisfactory abdominal and lower limb surgery bupivacaine, fentanyl 1 mcg/kg, and Onset and duration surgical anaesthesia without Desai et al., 2008, • Group I (83%, mean 4 y ± epinephrine (30) Randomized of anesthesia and any haemodynamic India150 1.5) • Group II: Caudal block using analgesia disturbances with prolonged • Group II (83%, mean 4.1 y ± bupivacaine, fentanyl 0.5 mcg/kg, and duration of analgesia with 1.1) epinephrine (30) fentanyl 1 mcg/kg as compared to 0.5 mcg/kg without any major postoperative complication.”

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

66 Patients undergoing surgery of Etidocaine and bupivacaine the stomach or gall bladder Part 1: Upper midline incision with epinephrine are Part 1 • Group 1: Etidocaine on one side and comparable with regard to duration of sensory block, • Group 1 (sex not provided, bupivacaine on the other side (13) etidocaine without epinephrine mean 56 y) • Group 2: Etidocaine with epinephrine did not provide the same Dhuner et al., Double-blind, • Group 2 (sex not provided, on one side and bupivacaine with Duration of duration of sensory block as 1975, Sweden151 randomized mean 43 y) epinephrine on the other side (11) analgesia when epinephrine was present, Part 2 Part 2: Right subcostal incisions etidocaine acts as a • Group 1 (sex not provided, • Group 1: Etidocaine (21) vasodilator, and blood level mean 56 y) • Group 2: Etidocaine with epinephrine studies of etidocaine do not • Group 2 (sex not provided, (21) show any differences when mean 46 y) epinephrine is used.

“Peripheral nerve blocks at the 3 Patients undergoing carpal Dilger et al., 2005, level of the elbow are an Case report tunnel release surgery (sex not Mepivacaine, tetracaine, and epinephrine (3) Postoperative pain US41 excellent anesthetic choice for provided, range 66-86 y) carpal tunnel release surgery.”

Time to anesthetic “In mechanical effect, duration of matricectomies, the addition of anesthetic effect, epinephrine to the local pain when anesthetic anesthetic can obviate the use Short-term, 36 Patients undergoing effect had worn off of a tourniquet and provides Diz Mellado et al., randomized, • Group 1: Mepivacaine with mechanical matricectomies and during the rest greater control of pain 2019, Spain152 longitudinal epinephrine (18) (40.7%, range 13-77 y) of the day using a immediately after the study • Group 2: Mepivacaine (18) VAS, increase in intervention. This can improve swelling around the the patient’s perception and eponychium, post- comfort when faced with this operative bleeding surgical procedure.”

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

The report of a patient with pulmonary hypertension, end stage renal disease, anemia, Doan et al., 2017, 1 Patient with pulmonary Intraneural injection with chloroprocaine, Bilateral sciatic Case report and gangrene who underwent US42 hypertension (0%, 67 y) mepivacaine, and epinephrine nerve blockade successful bilateral amputation with bilateral sciatic nerve blockade.

56 Patients undergoing forearm “Low-dose epinephrine offers and hand surgery more stable hemodynamics • Group 1: Epinephrine and lidocaine • Group 1 (68%, mean 35.7 y ± and similar blockade, and thus Randomized, (19) Duration of Dogru et al., 2003, 7.2) may be beneficial for patients double-blind • Group 2: Saline, lidocaine, and analgesia, motor Turkey153 • Group 2 (58%, mean 33.1 y ± undergoing forearm and hand study epinephrine (19) block 7.3) surgery who are at risk for • Group 3: Saline and lidocaine (18) • Group 3 (78%, mean 33.7 y ± tachycardia and/or 8.4) hypertension.”

“This case demonstrates that unexpected complications can still occur even after days of normal operation. Based on Complication of our previous experience, we Dooley et al., 1 Patient undergoing arthroscopic contralateral upper Case report Ropivacaine with epinephrine believe this to be a rare but 2010, US43 lysis of adhesions (0%, 56 y) extremity sensory potentially serious event that block requires awareness by those discharging patients with continuous infusions of local anesthetics.”

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

“In view of the reduced Duration of toxicity and shorter onset of 19 Patients undergoing major postoperative action of etidocaine relative to • Group 1: Bupivacaine with epinephrine shoulder surgery analgesia, total dose bupivacaine and the similarity Dorman et al., (10) Randomized • Group 1 (20%, mean 64.5 y ± of morphine of postoperative analgesia 1994, US154 • Group 2: Etidocaine with epinephrine 11.4) required during the between agents, etidocaine (9) • Group 2 (56%, mean 68.5 y ± first 24 hours after may be a preferable agent for 8.0) surgery brachial plexus blockade for major shoulder surgery.”

• Group 1: Buccal infiltration (BI) using “Supplemental LIs [lingual 80 Patients with irreversible articaine with epinephrine (40) infiltration] are not Prospective, • Group 2: Buccal plus lingual (BLI) recommended for pulpitis Pain during Dou et al., 2013, randomized, infiltration with articaine and administration in mandibular • Group 1 (55%, range 20-59 treatment using a China155 single-blind epinephrine (40) molars with irreversible y) VAS study • Group 2 (65%, range 21-55 All patients received inferior alveolar nerve pulpitis, because they do not y) block (INFB) using lidocaine with improve the anaesthetic epinephrine success after IANB plus BI.”

30 Patients undergoing cesarean Intensity of pain “The addition of epinephrine Prospective, section • Group 1: Hydromorphone (15) using a VAS, to epidural hydromorphone Dougherty et al., randomized, • Group 1 (0%, mean 26.1 y ± • Group 2: Hydromorphone plus duration of hastened onset and prolonged 1989, US469 double-blind 3.7) epinephrine (15) analgesia, side the duration of analgesia after study • Group 2 (0%, mean 25.7 y ± effects cesarean section.” 3.9)

100

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

“There was no advantage in the use of bupivacaine in concentrations exceeding Time taken to 100 Patients undergoing lower 0.5%. achieve blockade, uterine segment caesarean section Etidocaine 1.5% may be of • Group 1: Bupivacaine 0.5% (40) quality and • Group 1 (0%, mean 28.0 y ± some value in situations where Dutton et al., • Group 2: Bupivacaine 0.75% (40) completeness of Randomized 0.7) minimal delay in establishing 1984, UK156 motor and sensory • Group 2 (0%, mean 29.4 y ± • Group 3: Etidocaine with epinephrine adequate extradural blockade, duration 0.9) (20) blockade for surgery is of analgesia and • Group 3 (0%, mean 29.5 y ± desirable, but in view of its motor blockade 1.4) comparatively poor analgesic effects, routine use is not recommended.”

Duration of local Epidural sufentanil causes 40 Patients undergoing total • Group 1: Sufentanil with epinephrine anesthesia, considerable cardiorespiratory Prospective, abdominal hysterectomy (20) ventilatory depression in the setting of Dyer et al., 1992, randomized, • Group 1 (0%, mean 41.4 ± • Group 2: Normal saline with disturbances, general anesthesia and should South Africa157 double-blind 4.8) epinephrine (20) cardiovascular be used with caution in the trial • Group 2 (0%, mean 40.6 ± All patients received lidocaine with disturbances, side spontaneously breathing, 6.1) epinephrine effects anesthetized patient.

“At this time we believe no Randomized, sweeping conclusions can be Ellis et al., 2013, non-blinded, 15 Patients with cutaneous • Local infiltration using lidocaine (7) Pain with procedure, made about optimal US158 non-inferiority, abscesses (sex, age not provided) • Topical application of LET gel patient satisfaction management of pain control clinical trial (lidocaine-epinephrine-tetracaine) (8) for abscess I&D [incision and drainage].”

Peak expiratory flow Bilateral ICB given after (PEF) rate, forced 94 Patients undergoing upper surgery did not improve Engberg et al., • Group 1: Control (37) vital capacity (FVC), Randomized abdominal surgery (41%, range respiratory function, whereas 1985, Sweden159 • Group 2: Intercostal block (ICB) using forced expiratory 19-75 y) unilateral ICB had positive etidocaine with epinephrine (57) volume (FEV ) in 1 1 effects. second

101

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

“LAT gel worked as well as Physician and TAC gel for topical anesthesia patient rated 100 Patients with face or scalp in facial and scalp lacerations. Prospective, • Group 1: LAT gel (lidocaine, effectiveness of lacerations less than 7 centimeters Considering the advantages of Ernst et al., 1995, randomized, epinephrine, tetracaine) (48) anesthesia during with no mucosal involvement a noncontrolled substance and US35 double-blind • Group 2: TAC gel (tetracaine, wound closure, • Group 1 (79%, range 5-16 y) less expense, LAT gel appears clinical trial epinephrine, cocaine) (47) patient reported • Group 2 (72%, range 5-17 y) to be better suited than TAC number of sutures gel for topical anesthesia in causing pain laceration repair in children.”

“LAT worked at least as 95 Patients with lacerations on the effectively as TAC for topical face or scalp less than 7 anesthesia in facial and scalp Prospective, centimeters with no mucosal • Group 1: LAT (lidocaine, epinephrine, Anesthesia lacerations. Considering the Ernst et al., 1995, randomized, involvement tetracaine) (48) effectiveness, advantages of a noncontrolled US161 double-blind • Group 1 (83%, mean 33 y ± • Group 2: TAC (tetracaine, epinephrine, number of sutures substance and less expense, study 11) cocaine) (47) causing pain LAT seems to be better suited • Group 2 (77%, mean 34 y ± that TAC for topical anesthesia 13) in laceration repair.”

“LAT gel compared favorably with injectable buffered 66 Patients with simple linear Randomized, • Group 1: LAT gel (lidocaine, lidocaine for local anesthesia lacerations 1.5-10 centimeters Pain of injection or Ernst et al., 1997, prospective, epinephrine, tetracaine) (33) effectiveness and was long application, pain of US160 comparison • Group 2: Buffered lidocaine with significantly less painful to • Group 1 (15%, mean 29 y) suturing trial epinephrine (33) apply. It may be the preferred • Group 2 (39%, mean 30 y) local anesthetic for this reason.”

102

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

“Two-level epidural analgesia • Group 1: Epidural ropivacaine and for PFS and SSI in AIS endotracheal anesthesia with Pain at rest and in [adolescent idiopathic 80 Patients undergoing posterior sevoflurane, postoperative epidural motion, bowel scoliosis] can be successfully Ezhevskaya et al., Prospective, spinal fusion (PSF) and segmental analgesia using ropivacaine, fentanyl, activity, patient used both during and after 2012, Russia163 randomized spinal instrumentation (SSI) (sex, and epinephrine (45) satisfaction, surgery, providing a reliable age not specified) • Group 2: General anesthesia using intraoperative blood multilevel nociception, less sevoflurane and fentanyl, postoperative loss blood loss and patient systemic administration of opioids (35) satisfaction.”

“Single-shot and then • Group 1: Two-level thoracic epidural continuous epidural anesthesia anesthesia (EA) using ropivacaine with Clinical outcome, can be successfully used to Prospective, 135 Patients undergoing scoliosis fentanyl Ezhevskaya et al., systemic provide better pain control, randomized surgery (sex not provided, range • Group 2: General anesthesia using 2013, Russia162 hemodynamics, less blood loss, and study 12-25 y) sevoflurane with fentanyl stress response modulation of the endocrine All patients received EA with ropivacaine, and haemostatic stress fentanyl, and epinephrine response.”

• Group 1: Two-level thoracic epidural “Thus, stage epidural analgesia anesthesia (EA) using ropivacaine with in the surgical correction of fentanyl, postoperative analgesia with scoliosis can be successfully 135 Patients undergoing scoliosis Blood loss, Ezhevskaya et al., EA using ropivacaine, fentanyl, and used both during and after Randomized surgery (sex not provided, range coagulation 2013, Russia164 epinephrine (70) surgery, providing a reliable 12-25 y) parameters • Group 2: General anesthesia using multi-level nociception, less sevoflurane and fentanyl, postoperative blood loss, and modulation of analgesia with opioids (65) the endocrine stress response.”

103

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

“Combined epidural/general anesthesia and postoperative • Group 1: Epidural anesthesia using epidural analgesia produced ropivacaine, fentanyl, and epinephrine better pain control, less 85 Patients undergoing and general anesthesia with bleeding, and a lower surgical Prospective, reconstructive spinal surgery sevoflurane, postoperative epidural Pain assessment, Ezhevskaya et al., stress response than general randomized • Group 1 (56%, mean 47.9 y ± analgesia with ropivacaine, fentanyl, serum cytokine 2013, Russia166 anesthesia with postoperative trial 13.2) and epinephrine (45) assessment systemically administered • Group 2 (65%, mean 44.3 y ± • Group 2: General anesthesia using narcotic analgesia. This 15.7) sevoflurane and fentanyl, postoperative technique deserves further analgesia with opioids (40) study in the setting of major spinal surgery.”

“Epidural anesthesia and • Group 1: Continuous epidural analgesia PCEA with ropivacaine and and endotracheal anesthesia with opioids through the placed sevoflurane during surgery and Prospective, Hemodynamic epidural catheters before 335 Patients undergoing major continuous epidural analgesia with Ezhevskaya et al., randomized, parameters, pain at surgery provided better spine surgery (sex, age not ropivacaine, fentanyl, and epinephrine 2014, Russia165 comparative rest and in motion, analgesia, less postoperative specified) after surgery (170) study morbidity morbidity, blood loss • Group 2: General anesthesia with decreasing, patient satisfaction sevoflurane and fentanyl and systemic and early discharge from opioids after surgery (165) hospital.”

• Group 1: Epidural and endotracheal anesthesia with sevoflurane and “Comprehensive anesthetic epidural analgesia using ropivacaine, protection in spinal deformity fentanyl, and epinephrine, surgery based on epidural 350 Patients with degenerative Prospective, postoperative epidural anesthesia using Postoperative pain anesthesia provides adequate Ezhevskaya et al., diseases undergoing spinal randomized ropivacaine, fentanyl, and epinephrine using a VAS, blood antinociceptive effects, 2014, Russia167 deformity surgery (39.1%, range study (205) loss, hemodynamics inhibition of endocrine and 15-65 y) • Group 2: Inhalation anesthesia using metabolic stress response and sevoflurane and continuous fentanyl, correction of hemostasis postoperative anesthesia using IV problems.” morphine (145)

104

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

“These results demonstrate similarity between the 2 methods. We prefer • Group 1: Psoas compartment block 99 Patients undergoing total hip periarticular anesthetic Prospective, (PCB) using ropivacaine (49) Pain using a VAS, Fahs et al., 2018, arthroplasty infiltration over PCB due to randomized, • Group 2: Periarticular block using total narcotic US168 • Group 1 (47%, 65 y ± 8) improved immediate study ropivacaine, epinephrine, morphine, consumption • Group 2 (56%, 68 y ± 8) postoperative pain scores and and ketorolac (50) avoidance of potential symptoms associated with nerve blockade.” • Group 1: Patient-controlled local Prospective, “TEA provides superior analgesia (PCLA) using ropivacaine randomized, 50 Patients undergoing open postoperative pain relief with Fant et al., 2011, (25) parallel group, radical retropubic prostatectomy Pain on coughing better preservation of Sweden169 • Group 2: Thoracic epidural analgesia double-blind (RRP) (100%, range 53-73 y) expiratory muscle strength (TEA) using ropivacaine, fentanyl, and study compared with PCLA.” epinephrine (25) “By using epidural analgesia in Pain score at rest, the first 7 days 38 Patients undergoing total knee range of motion, postoperatively, we achieved replacement • Group 1: Spinal anesthesia using Randomized, satisfaction, improved early rehabilitation Farag et al., 2005, • Group 1 (41%, mean 64 y ± bupivacaine with epinephrine (22) prospective sedation, urinary due to excellent pain relief US170 13) • Group 2: Epidural anesthesia using study retention, frequency effect and an antithrombotic • Group 2 (19%, mean 63 y ± ropivacaine with epinephrine (16) of deep venous effect with an efficacy 8) thrombosis (DVT) comparable to low molecular- weight heparin.”

105

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

Duration of analgesia, loss of “Epidural anaesthesia using cold sensation, 60 Patients undergoing caesarean • Group 1: Chloroprocaine (20) chloroprocaine with adrenaline Prospective, motor block, blood section • Group 2: Chloroprocaine with has a quick onset and moderate Feng et al., 2012, randomized, pressure, heart rate, • Group 1 (0%, mean 28 y ± 3) epinephrine (20) duration and is an attractive China171 double-blind oxygen saturation, • Group 2 (0%, mean 30 y ± 3) alternative to lidocaine and trial • Group 3: Lidocaine with epinephrine pain using a VAS, adrenaline or chloroprocaine • Group 3 (0%, mean 31 y ± 4) (20) fetal and neonatal alone for caesarean section.” satus, postdelivery uterine contraction

“This study suggests that • Group 1: Bupivacaine without opioid 48 Patients undergoing unilateral epidural infusions of (16) total knee replacement bupivacaine and meperidine • Group 2: Bupivacaine with meperidine • Group 1 (18.8%, mean 70 y ± Sensory anesthesia, slow regression of sensory Ferrante et al., (16) Randomized 3) verbal numerical anesthesia and the 1993, US172 • Group 2 (43.8%, mean 68 y ± • Group 3: Bupivacaine with fentanyl pain score development of pain, in 2) (16) contrast to infusions of • Group 3 (43.8%, mean 63 y ± All patients received a loading dose of bupivacaine alone or 4) etidocaine with epinephrine bupivacaine and fentanyl.”

Mepivacaine with epinephrine Plasma levels of 10 Patients undergoing forearm can be safely administered in Finucane et al., mepivacaine, time to Not defined and hand surgery (70%, mean Mepivacaine with epinephrine divided doses into the axillary 1989, US173 peak plasma 38.1 y ± 14.8) sheath within a 31-minute mepivacaine level period.

46 Patients undergoing peripheral Pain intensity at rest Prospective, and motion using a arterial bypass surgery of the • Group 1: Ropivacaine, fentanyl, and randomized, VAS, upper sensory Forster et al., lower extremities epinephrine (21) Epinephrine did not improve controlled, blockade, motor 2003, Finland175 • Group 1 (71%, range 51-81 • Group 2: Ropivacaine and fentanyl epidural lumbar analgesia. double-blind blockade, respiratory y) (25) study • Group 2 (52%, range 41-88 rate, blood pressure, y) pulse, sedation

106

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

70 Patients undergoing unilateral • Group 1: Ropivacaine, fentanyl, and Randomized, TKA Epinephrine did not improve Forster et al., epinephrine (35) Pain scores using a double-blind • Group 1 (17%, mean 67 y ± lumbar continuous epidural 2008, Finland174 • Group 2: Ropivacaine and fentanyl VAS investigation 11) analgesia after TKA. • Group 2 (29%, mean 69 y ± (35) 9) Sciatic nerve block can be Franco et al., 20 Patients undergoing foot Sensory anesthesia, performed in the subgluteal Not defined Mepivacaine with epinephrine (20) 2006, US176 surgery (40%, mean 43 y ± 15) patient satisfaction area at 10 centimeters from the midline.

“We did not find significant differences between the two 80 patients undergoing surgery of • Group 1: Axillary (AX) block (40) Prospective, approaches in procedural pain the hand, forearm, or elbow • Group 2: Infraclavicular (IC) block Frederiksen et al., randomized, Maximal procedural and patient’s acceptance. The • Group 1 (45%, mean 50 y ± (40) 2010, Denmark177 single-blind pain using a VAS choice of approach may 16) Both groups received ropivacaine, study depend on the • Group 2 (45%, mean 50 y ± mepivacaine, and epinephrine 16) anaesthesiologist’s experience and the patient’s preferences.”

• Metycaine 1.5% (39) • Metycaine 1.5% with epinephrine (7) “The frequency of clinically • Metycaine 2% (48) successful blocks was 79 Frumin et al., 128 Patients (sex, age not • Xylocaine 1% (10) Series Success of block percent, which suggests that 1952, US178 specified) • Xylocaine 1% with epinephrine (3) the technic has practical • Xylocaine 2% (7) clinical value.” • Xylocaine 2% with epinephrine (10) • Miscellaneous (4)

107

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

“Labat’s approach of the sciatic nerve provides no better Comfort during • Group 1: Posterior popliteal sciatic thigh tourniquet tolerance than 118 undergoing foot surgery block using a VAS, Prospective, nerve block (60) the popliteal approach. The Fuzier et al., 2005, • Group 1 (38%, mean 46 y ± sensory block, randomized, • Group 2: Labat’s sciatic nerve block popliteal approach is as France179 15) duration of thigh blinded study (58) efficient but more comfortable • Group 2 (52%, mean 48 y ± tourniquet tolerance, All patients received mepivacaine with for the patient and is the 16) success rate epinephrine preferred technique for below- knee surgery.”

109 Patients undergoing emergent Speed of onset, “Lidocaine 1.5% is an • Group 1: Chloroprocaine with cesarean section effect on the attractive alternative to Gaiser et al., 1994, Retrospective epinephrine (29) • Group 1 (0%, mean 26.6 y ± neonate, need for chloroprocaine for urgent US438 review • Group 2: Lidocaine with epinephrine 6.3) supplemental cesarean section in a mother (80) • Group 2 (0%, mean 24.4 y ± analgesia with an epidural catheter.” 8.1) Degree of analgesia, “Initiating an infusion of REF maternal blood Double-blind, 34 Patients in labor [ropivacaine, epinephrine, • Group 1: Normal saline (18) pressure, heart rate, Gaiser et al., 2000, randomized, • Group 1 (0%, mean 26.6 y ± fentanyl] prolongs the duration • Group 2: Ropivacaine, fentanyl, and sensory level, degree US180 prospective 6.4) of analgesia but also results in epinephrine (16) of motor block, pain study • Group 2 (0%, mean 26.2 y ± a greater decrease in blood and pruritis using a 6.6) pressure.” VAS

• Group 1: Ultrasound guided nerve Block time, patient “Our data suggests that in stimulation (USNB) (not provided) comfort during Randomized, 68 Patients presenting for elective comparison to NS, USNB is Galassi et al., • Group 2: Traditional nerve stimulation block, overall block, prospective unilateral upper extremity surgery associated with less pain, 2010, US181 (NS) (not provided) surgery and study (sex, age not provided) anxiety, and improved patient All patients received bupivacaine, anesthesia comfort.” mepivacaine, and epinephrine experience

108

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

Intensity of pain at rest and on “Under the circumstances of 60 Patients undergoing total hip • Group 1: Ultrasound-guided movement using a our study, in patients suprainguinal fascia iliaca Randomized, arthroplasty (THA) VAS, opioid undergoing THA, SFICB compartment block (SFICB) (30) Gasanova et al., controlled, • Group 1 (sex not provided, consumption, provided the similar pain relief 182 • Group 2: Periarticular infiltration (PAI) 2019, US observer- mean 56.2 y ± 13.6) nausea, vomiting, compared with PAI, but was (30) blinded study • Group 2 (sex not provided, need for rescue associated with muscle Both groups received ropivacaine with mean 59.0 y ± 11.2) antiemetics, weakness at 6 hours epinephrine sensation to cold postoperatively.” temperature

“I feel certain that further clinical study and basic research on the choroid and its association with the ciliary body is necessary before the glaucoma problem can be 65 Cataract operations (52%, age solved. I know certainly that Amount of motor Gifford Jr et al., not provided) Orbital injection of Novocain with the percentage of vitreous loss Series of cases block, vitreous 1949, US44 epinephrine in cataract surgery can be 40 Glaucoma operations (sex, age pressure not provided) greatly reduced by using a deep orbital injection that produces a motor block of the extraocular muscles as well as more complete anesthesia, and a lowering of the intraocular pressure.”

“Following the administration of the local anesthetic into the 31 Patients receiving caudal • Ropivacaine with epinephrine (not caudal epidural space, there Goeller et al., Prospective, Caudal epidural epidural blocks (sex not provided, provided) was a 2016, US184 observational pressure changes mean 2.21 y ± 2.2) • Bupivacaine with epinephrine (not marked, but transient, increase provided) in the pressure within the epidural space.”

109

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

Epidural morphine and fentanyl deliver approximately the same pain relief without 381 Patients who received depressing respirations; epidural preservative-free Analgesia efficacy, Goodman et al., however, epidural morphine Chart review morphine or epidural fentanyl • Fentanyl with epinephrine (108) frequency of side 2014, US185 may cause more nausea and/or after cesarean section (0%, age not • Morphine (273) effects pruritus. Epidural fentanyl can specified) be continued beyond the time the epidural morphine will have worn off.

• Group 1: Portal injection using Intraoperative pain lidocaine, intraarticular injection using using a VAS, "Any of the three anaesthetic lidocaine with epinephrine, FNB using 59 Patients undergoing operative surgical operating techniques tested provide placebo (20) or diagnostic knee arthroscopy conditions, reliable intraoperative patient • Group 2: Portal injection using • Group 1 (45%, mean 41.1 y ± intraoperative use of and surgical conditions for Goranson et al., placebo, intraarticular injection using Randomized 16.5) sedation and outpatient knee arthroscopy, 1997, Canada186 placebo with epinephrine, FNB using • Group 2 (79%, mean 44.9 y ± analgesia, time to Patient discomfort chloroprocaine with epinephrine (19) 15.8) discharge, patient postoperatively was • Group 3 (55%, mean 36.4 y ± • Group 3: Portal injection using satisfaction score, considerable in all groups and 14.5) placebo, intraarticular injection using postoperative requires further investigation." lidocaine, FNB using chloroprocaine analgesia (20)

“Paravertebral block is an easy and relatively safe procedure Patient satisfaction, Thoracic paravertebral block (PVB) using for breast surgery. The analgesic Goravanchi et al., 5 Patients undergoing surgery for preservative-free clonidine, preservative- combination of clonidine, Case series consumption, side 2012, US45 breast cancer (0%, range 46-63 y) free dexamethasone, ropivacaine, and dexamethasone, and effects, epinephrine (5) epinephrine with ropivacaine complications in PVB produced analgesia lasting 6 days.”

110

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

There was no clinical 32 Patients undergoing unilateral Time of sensory difference in the onset of • Group 1: Bupivacaine with epinephrine block, onset of neural blockade between Randomized, TKA Greengrass et al., (16) motor block, time to bupivacaine and ropivacaine. double-blind • Group 1 (25%, mean 68 y ± 1998, US187 • Group 2: Ropivacaine with epinephrine request first The duration of analgesia of trial 8) • Group 2 (44%, mean 68 y ± (16) analgesic, evidence bupivacaine was prolonged by 8) of block regression 4 hours compared to ropivacaine.

1946 Patients in labor Nulliparas • Mepivacaine (0%, mean 23.3 y) • Mepivacaine with Nulliparas (957) epinephrine (0%, mean 23.5 • Mepivacaine (370) y) Duration of Mepivacaine alone was as • Mepivacaine with epinephrine (332) Double-blind, • Lidocaine with epinephrine anesthesia, need for effective in relieving labor Gunther et al., • Lidocaine with epinephrine (255) randomized (0%, mean 23.1 y) oxytocic pain as mepivacaine with 1972, US188 study Multiparas (989) augmentation of epinephrine and lidocaine with Multiparas labor, pain relief epinephrine. • Mepivacaine (0%, mean 27.6 • Mepivacaine (378) y) • Mepivacaine with epinephrine (351) • Mepivacaine with • Lidocaine with epinephrine (260) epinephrine (0%, mean 27.2 y) • Lidocaine with epinephrine (0%, mean 27.1 y)

111

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

“The authors found evidence for better pain relief and improved expiratory muscle Postoperative pain at function in patients receiving 60 Patients post-radical retropubic • Group 1: Patient-controlled analgesia rest and on low thoracic epidural analgesia Double-blind, prostatectomy (PCA) using IV morphine and epidural coughing, analgesic compared with patient- Gupta et al., 2006, randomized, • Group 1 (100%, mean 64.5 y placebo (30) consumption, total controlled analgesia for radical Sweden189 comparison ± 4.9) • Group 2: PCA using placebo, epidural PCA consumption, retropubic prostatectomy. Low study • Group 2 (100%, mean 61.1 y ropivacaine, fentanyl, and epinephrine opioid-related side thoracic epidural analgesia can ± 4.3) (30) effects be recommended as a good method for postoperative analgesia after abdominal surgery.”

“Although blockade using the 50 Patients undergoing lower leg • Group 1: Popliteal block (PB) using the lateral approach took longer to surgery lateral approach (25) Motor block, accomplish, both techniques Hadzic et al., • Group 1 (44%, mean 51 y ± • Group 2: PB using the posterior Randomized sensory block, resulted in clinically 1998, US191 16) approach (25) postoperative pain acceptable anesthesia in the • Group 2 (64%, mean 49 y ± Both groups received alkalinized distribution of the sciatic 14) mepivacaine with epinephrine nerve.”

"Infraclavicular brachial plexus block with a short- Postoperative pain, acting local anesthetic was • Group 1: Infraclavicular brachial quantity of 50 Patients undergoing hand or associated with time-efficient plexus block (INB) using alkalinized analgesics used, wrist surgery anesthesia, faster recovery, chloroprocaine with epinephrine (25) ambulation, home Hadzic et al., • Group 1 (48%, mean 45 y ± fewer adverse events, better Randomized • Group 2: General anesthesia (GA) readiness, incidence 2004, US190 15) analgesia, and greater patient using dolasetron, midazolam, fentanyl, of adverse events, • Group 2 (44%, mean 40 y ± acceptance than GA followed and propofol and infiltration with whether patients can 16) by wound infiltration with a bupivacaine (25) bypass the post- local anesthetic in outpatients anesthesia care unit undergoing hand and wrist surgery."

112

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

“We conclude that age may Duration of sensory, 74 Patients undergoing unilateral • Group 1: Patients 18-35 years old (37) affect peripheral nerve blocks block, duration of knee arthroscopy • Group 2: Patients 55-80 years old (37) and that more investigation is Hanks et al., 2006, Prospective motor block, • Group 1 (sex not provided, All patients received sciatic nerve block needed to determine the US439 study duration of complete mean 27 y ± 5) with mepivacaine with sodium bicarbonate pharmacologic, physiologic, sensory and motor • Group 2 (sex not provided, and epinephrine and chronologic factors behind block mean 63 y ± 6) these findings.”

“Based on this small retrospective study, spinal analgesia with intrathecal 12 Patients undergoing total hip • Group 1: Intrathecal bupivacaine with Opioid consumption morphine may provide Hansen et al., Retrospective arthroplasty (sex, age not morphine (6) in first 24 hours superior pain relief in the first 2011, US440 review provided) • Group 2: Lumbar plexus block using postoperatively 24 hours after surgery ropivacaine with epinephrine (6) compared to single-injection, low-dose lumbar plexus block.”

“Despite the unusually large nerve diameters observed on ultrasound, using a standard 1 Patient undergoing surgical local anesthetic solution did Hardman et al., Interscalene block using ropivacaine with Case report repair for humeral fracture (0%, Nerve block not result in an abnormally 2011, US46 epinephrine 57 y) long duration of action nor subsequent temporary or permanent sensorimotor deficits.”

113

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

“In the absence of dose- response pharmacologic data for perineural and parenteral dexamethasone administration, 1 Patient undergoing repair of Popliteal and saphenous nerve block using Hardman et al., and given the multi-factorial Case report peroneal tendon injury (100%, 32 bupivacaine, dexamethasone, and Nerve block 2014, US47 nature of post-block peripheral y) epinephrine nerve injury, caution is advised against routine perineural administration of dexamethasone.”

“The addition of adrenaline 1/200,000 enhanced the efficiency of the block defined in terms of its speed of onset and intensity of analgesia. It also resulted in lower blood • Group 1: Mepivacaine (8) levels of local anaesthetic • Group 2: Mepivacaine with drug. The addition of 41 Patients undergoing surgery Degree of motor hyaluronidase caused a Harley et al., Randomized, epinephrine (11) requiring brachial plexus block paralysis and significantly higher incidence 1969, Sweden192 double-blind • Group 3: Mepivacaine with (63%, age not provided) hyaluronidase (12) sensory impairment of failure of block with poor • Group 4: Mepivacaine, epinephrine, analgesic spread, reduced and hyaluronidase (10) intensity of analgesia and higher blood levels of local anaesthetic drug. The combination of the two with 1% mepivacaine conferred no advantage over the use of mepivacaine by itself.”

114

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

203 Patients with lacerations less “Pretreatment of minor than 3 centimeters requiring tissue lacerations with lidocaine– Harman et al., Randomized, Pain reported during 193 adhesive repair epinephrine–tetracaine before 2012, Canada placebo- • Group 1: LET (105) application of tissue • Group 1 (62%, mean 5.07 y ± tissue repair with adhesive controlled, • Group 2: Placebo (98) adhesive using a Harman et al., 3.94) decreased patient discomfort 6 blinded trial VAS 2013, Canada • Group 2 (57%, mean 4.21 y ± and increased the proportion of 3.62) pain-free repairs.”

“We recommend that patients with persistent pain and paresthesia in the inguinal region following surgery Harms et al., 1984, 1 Patient with genitofemoral Genitofemoral nerve block using should have a Case reports Resolution of pain US48 neuralgia (0%, 56 y) bupivacaine, lidocaine, and epinephrine (1) local ilioinguinal nerve block. If this is unsuccessful in affecting relief of symptoms, a paravertebral block of L-1 and L-2 should be considered.”

The addition of epinephrine to epidural ropivacaine for cesarean section administered by gravity technique is associated with fewer epidural Time to pain score blood vessel punctures, Randomized, • Group 1: Ropivacaine with fentanyl greater than 5, time Hasan et al., 2013, 300 Patients undergoing cesarean readjustments or reinsertions double-blind (150) to recovery from US194 section (0%, age not provided) of the catheters, improved study • Group 2: Ropivacaine, fentanyl, and motor block, patient quality of the block, less epinephrine (150) satisfaction sedation, shorter time to incision and surgery duration without affecting time to return of pain, recovery of motor block, or overall satisfaction.

115

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

“Addition of 8 mg • Group 1: Popliteal sciatic nerve block dexamethasone to 0.5% 56 Patients undergoing foot and using bupivacaine, epinephrine, and bupivacaine-epinephrine Randomized, ankle surgery dexamethasone (28) Time until complete significantly prolongs the Hauritz et al., controlled, • Group 1 (75%, mean 57.1 y ± • Group 2: Popliteal sciatic nerve block return of duration of sensorimotor 195 2018, Denmark double-blind 15.1) using bupivacaine, epinephrine, and sensorimotor popliteal sciatic nerve study • Group 2 (75%, mean 56.6 y ± placebo (28) functions blockade, and reduces pain and 14.6) All patients received a saphenous nerve opioid consumption in patients block using bupivacaine with epinephrine after major hind foot and ankle surgery.”

• Group 1: IV patient-controlled opioid Mean pain intensity “IV-PCA was noninferior to Randomized, analgesia (PCA) using ketobemidone 143 Patients undergoing open on postoperative TEA for the treatment of Hausken et al., controlled, (66) liver resection days 0-5 using a postoperative pain in patients 2019, Norway196 noninferiority • Group 2: Thoracic epidural analgesia • Group 1 (57%, mean 65.6 y) numeric rating scale undergoing open liver trial (TEA) using bupivacaine, fentanyl, and • Group 2 (62%, mean 67.1 y) (NRS) resection.” epinephrine (77)

• Group A: Anesthetic solution at room “The speed of onset of sensory 24 Patients undergoing unilateral temperature (12) blockade was significantly upper limb orthopedic surgery • Group B: Anesthetic solution warmed Onset of sensory Heath et al., 1990, Double-blind increased when the • Group A (50%, mean 48.6 y to 37°C (12) blockade, onset of UK197 study temperature of the local ± 6.6) All patients received brachial plexus block motor block anaesthetic solution was • Group B (25%, mean 54.5 y using an anesthetic solution containing increased to 37°C.” ± 4.8) bupivacaine, prilocaine, and epinephrine

116

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

“The maximal plasma concentration of the 50% enantiomeric excess mixture (S75/R25) 0.5% bupivacaine • Group 1: Infragluteal parabicipital with 1:200,000 of epinephrine sciatic nerve block (IG) using 50% achieved in the parasacral 28 Patients undergoing unilateral, enantiometric excess bupivacaine with Need for approach was superior to that elective surgery of ankle or foot epinephrine (14) supplementary of the infragluteal sciatic nerve Helayel et al., Prospective, • Group 1 (79%, mean 38 y ± • Group 2: Parasacral sciatic nerve block analgesia, serum block. Patients with 2008, Brazil198 randomized 14) (PS) using 50% enantiometric excess concentration of compromised organic function • Group 2 (93%, mean 35 y ± bupivacaine with epinephrine (14) bupivacaine such as those with heart, liver, 11) All patients received a FNB using lidocaine or lung diseases could benefit with epinephrine from the infragluteal approach, since lower plasma levels of the enantiomeric excess (S75/R25) mixture of bupivacaine are achieved.”

“In conclusion, we have presented four cases in which • Lumbar epidural anesthesia (LEA) Blood pressure preeclamptic patients were Heller et al., 1986, 4 Patients with preeclampsia (0%, Case series using lidocaine with epinephrine (2) before and after given LEA with local US49 13-26 y) • LEA using bupivacaine, lidocaine, epidural anesthetic solutions containing epinephrine (2) epinephrine. In no case was the hypertension enhanced.”

• Group 1: Ultra-sound guided adductor canal block (ACB) using bupivacaine, "An ACB provides equivalent 147 Patients undergoing epinephrine, and clonidine (74) analgesia after medial UKA Prospective, unicondylar knee arthroplasty • Group 2: Nerve stimulator-guided when compared with a PCB. In double-blind, Pain scores using a Henshaw et al., (UKA) psoas compartment block (PCB) using addition, the ACB caused randomized, numeric rating scale 2016, US199 • Group 1 (55%, mean 63 y ± bupivacaine, epinephrine, and significantly less motor equivalency (NRS) 10.2) clonidine (73) weakness. An ACB should be trial • Group 2 (47%, mean 63 y ± All patients received a posterior capsular considered for postoperative 10.5) injection using bupivacaine, epinephrine, analgesia after medial UKA." morphine, and ketorolac

117

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• Group 1: Epidural using bupivacaine, fentanyl, sodium bicarbonate, and “Although epidural analgesia epinephrine (24) with a low concentration of • Group 2: Spinal-epidural (CSE) using Pain score using a Prospective, local anesthetic and opioid Hepner et al., 50 Patients in labor (0%, age not bupivacaine and fentanyl (26) VAS, patient randomized, mixture takes longer to 2000, US200 provided) If additional analgesia was requested, both satisfaction, motor double-blind produce complete analgesia, it groups received bupivacaine, fentanyl, block is a satisfactory alternative to epinephrine, and sodium bicarbonate and an CSE.” infusion of bupivacaine, fentanyl, and epinephrine

“Neither the total interventions Total interventions nor intervention rate per hour (any supplemental 4493 Patients in labor • HIGH: bupivacaine 0.125% and varied significantly with the medications given • HIGH (0%, mean 29.8 y ± fentanyl (701) concentrations of bupivacaine Retrospective, via epidural catheter, Hess et al., 2006, 5.6) • MED: bupivacaine 0.0625% and used in this study. Lower observational or increases in rate US441 • MED (0%, mean 29.7 y ± fentanyl (1285) concentrations produced fewer study of infusion) 5.6) side effects including • LOW: bupivacaine 0.04%, fentanyl, requiring an • LOW (0%, mean 30.2 y ± hypotension, while the higher and epinephrine (2507) anesthesia care 5.6) concentration resulted in less provider breakthrough pain.”

156 Patients undergoing orthopedic hand and forearm • Group 1: Superior trunk paresthesia “The location of the elicited Quality of surgery (100) paresthesia should be noted anesthesia, location • Group 1 (sex not provided, • Group 2: Middle paresthesia (29) when performing subclavian Hickey et al., of elicited Not defined mean 45.2 y ± 15.7) perivascular blocks because 1989, US50 • Group 3: Inferior trunk paresthesia (27) paresthesia, • Group 2 (sex not provided, the particular trunk stimulated All patients received subclavian incidence of mean 45.1 y ± 17.0) may influence the development perivascular block of the brachial plexus successful anesthesia • Group 3 (sex not provided, using mepivacaine, tetracaine, epinephrine of anesthesia.” mean 49.3 y ± 16.7)

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48 Patients undergoing upper Lidocaine hydrocarbonate does extremity surgery • Group 1: Lidocaine hydrochloride with Quality of not offer any significant Hickey et al., • Group 1 (84%, mean 44.7 y ± epinephrine (25) Randomized anesthesia, sensory advantage over lidocaine 1990, US201 14.8) • Group 2: Lidocaine hydrocarbonate and motor block hydrochloride in interscalene • Group 2 (65%, mean 46.0 y ± with epinephrine (23) brachial plexus block. 11.1)

“The present study indicates that ropivacaine 0.5 per cent, even without epinephrine, 32 Patients undergoing upper provides excellent sensory and motor blockade of prolonged Open label, extremity surgery • Group 1: Ropivacaine (15) Rapidity of onset, Hickey et al., duration. If comparative nonrandomized • Group 1 (87%, mean 43.9 y ± • Group 2: Ropivacaine with epinephrine duration of sensory 1990, US442 studies indicate that it is at study 11.3) (17) and motor block • Group 2 (94%, mean 44 y ± least as effective as 12.8) bupivacaine, then ropivacaine may replace bupivacaine because of its decreased toxicity.”

• Group 1: Anesthetic injected into the 60 Patients undergoing upper back of the artery (20) extremity surgery • Group 2: Anesthetic injected into the There was no significant • Group 1 (100%, mean 51.2 y front of the artery (20) difference in the number of Hickey et al., Sensory and motor Randomized ± 14.2) patients requiring 1993, US443 • Group 3: Half of the anesthetic injected block • Group 2 (100%, mean 56.8 y behind and half in front of the artery supplementation for the ± 12.5) (20) surgical procedure. • Group 3 (95%, mean 59.3 y ± All patients received mepivacaine with 14.5) epinephrine

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Discontinuation of sevoflurane to tracheal extubation, Caudal midazolam added to 59 Patients undergoing response to verbal ropivacaine did not influence Prospective, • Group 1: Ropivacaine with hernioplasty stimuli, drinking sevoflurane requirement or Hong et al., 2008, randomized, epinephrine (29) • Group 1 (100%, median 1.9 water, self-voiding, recovery but improved South Korea472 double-blind • Group 2: Ropivacaine with midazolam y, interquartile range 1.2-3.0) discharge, postoperative analgesia study and epinephrine (30) • Group 2 (100%, median 2.3 postoperative pain, compared with ropivacaine y, interquartile range 1.2-4.8) motor block, alone. postoperative sedation

Level of anesthetic Adding fentanyl to lidocaine 61 Patients undergoing cesarean block, time to onset Prospective, • Group 1: Epidural lidocaine, fentanyl, does not speed up the onset of section of T4-sensory block, Hong et al., 2010, randomized, and epinephrine (31) block but improves the quality • Group 1 (0%, mean 30.8 y ± maximum height of South Korea203 double-blind • Group 2: Epidural lidocaine, normal of analgesia with fewer side 4.4) the block, study saline, and epinephrine (30) effects in emergency top-up • Group 2 (0%, mean 29.3 y ± postoperative pain for cesarean section. 2.3) using a VAS

"Subcostal TAP block does not 52 Patients scheduled for Patients randomized to receive: Randomized, Cumulative improve the analgesia provided laparoscopic cholecystectomy • Group 1: Transversus abdominis plane placebo- morphine by multimodal analgesia after Houben et al., • Group 1 (42%, mean 50.6 y ± block (TAP) with 0.375% controlled, consumption during laparoscopic cholecystectomy. 2019, Belgium204 12.9) levobupivacaine, epinephrine (26) double-blind first 24 hours after It allows for a small reduction • Group 2 (23%, mean 47.5 y ± • Group 2: TAP block with 0.9% saline, study surgery in intra-operative sevoflurane 16.0) epinephrine (26) requirements."

Patients randomized to receive: "This study shows that a mixture of bupivacaine and • Group 1: Bupivacaine (20) Onset time, need for lignocaine provided an 79 Patients presenting for elective • Group 2: Bupivacaine, epinephrine Howell et al., top-up, anesthetist excellent alternative to Not defined cesarean section (0%, mean 33 y ± (20) 1990, UK205 and patient bupivacaine alone and was 5.1) • Group 3: Lidocaine, epinephrine (19) satisfaction superior to 2% lignocaine with • Group 4: Bupivacaine, lidocaine, adrenaline for elective epinephrine (20) Caesarean section."

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"In conclusion, we determined that epinephrine prolonged the duration of epidural morphine All patients received test dose of 1% plain analgesia after surgery by 60 Patients undergoing elective xylocaine, then main dose of 2% xylocaine, studying two groups of 60 Visual analog scales lower extremity surgery both without epinephrine, then randomized patients each in a randomized for pain and itching Huang et al., 1993, Randomized, • Group A (60%, mean 45.1 y to receive: double-blinded fashion...The 3, 7, 12 and 24 hours Taiwan206 double-blinded ± 2.5) • Group A: Epidural morphine, saline results of this study suggested after epidural • Group B (53%, mean 43.5 y (30) that due to the high incidence morphine ± 2.7) • Group B: Epidural morphine, and severity of side effects, the epinephrine (30) use of epinephrine-morphine mixture should be abandoned despite excellent analgesia effects in our patients."

"We believe that the technique 20 Patients requiring surgical Hullander et al., Sciatic nerve block with mepivacaine, described provides a more Not defined procedures on a lower extremity Success of block 1991, US51 epinephrine (20) reliable and efficient method (sex not provided, 18-67 y) for block of the sciatic nerve."

"Although retrospective in nature, this study shows the Patients received either: benefits of decreased opioids • Group 1: Interscalene block with 20 and increased duration of Retrospective mL ropivacaine, clonidine, epinephrine Total opioid use in Hutchins et al., 30 Patients undergoing shoulder analgesia with liposomal case matched (15) first 72 hours after 2015, US444 surgery (sex, age not provided) bupivacaine compared to study • Group 2: Interscalene block with 10 surgery ropivacaine in an interscalene mL bupivacaine, liposomal block for postoperative bupivacaine (15) analgesia after shoulder surgery."

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"We conclude that adding 1 g/mL of clonidine to a 34 Patients scheduled for All patients received pre-operative ropivacaine infraclavicular moderately painful ambulatory infraclavicular brachial plexus block with perineural infusion does not unilateral orthopedic surgery of mepivacaine, epinephrine, bicarbonate; Pain score, patient- Randomized, provide clinically relevant Ilfeld et al., 2003, the upper extremity randomly assigned to receive post- controlled bolus double-blind, improvements in analgesia, US207 • Group 1 (23.5%, mean 49 y ± operative infusion: doses, oral analgesic controlled sleep quality, or oral analgesic 14) • Group 1: Ropivacaine 0.2% (17) use, sleep quality requirements for ambulatory • Group 2 (23.5%, mean 51 y ± • Group 2: Ropivacaine 0.2%, clonidine patients having moderately 15) (17) painful upper extremity surgery."

20 Patients scheduled for All patients received pre-operative "We conclude that adding moderately painful ambulatory mepivacaine, epinephrine, clonidine clonidine 2 g/mL to a unilateral orthopedic surgery of Randomized, through interscalene perineural catheter; Most intense pain ropivacaine interscalene Ilfeld et al., 2005, the shoulder double-blind, randomly assigned to receive post- during the day after perineural infusion does not US208 • Group 1 (60%, mean 47 y ± controlled operative infusion: surgery decrease breakthrough pain 17) • Group 1: Ropivacaine (10) intensity the day after • Group 2 (40%, mean 50 y ± • Group 2: Ropivacaine, clonidine (10) surgery." 15)

"This study did not find evidence to support the All patients received pre-operative hypothesis that, for popliteal- popliteal-sciatic nerve block with sciatic perineural catheters 100 Patients scheduled for mepivacaine, epinephrine; randomly placed using ultrasound moderately painful orthopedic assigned for perineural catheter placement: Average surgical guidance and a needle-in-plane surgery of the foot and/or ankle Ilfeld et al., 2011, • Group 1: 0-1 cm beyond the needle tip pain on numeric technique, inserting the Not defined • Group 1 (36%, mean 45 y ± US209 for post-operative analgesia with rating scale day after catheter a minimum distance 16) ropivacaine infusion (50) surgery (0-1 cm) past the needle tip • Group 2 (38%, mean 47 y ± • Group 2: 5-6 cm beyond the needle tip improves (or worsens) 17) for post-operative analgesia with postoperative analgesia ropivacaine infusion (50) compared with inserting the catheter a more traditional distance (5-6 cm)."

122

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114 Patients scheduled to undergo Randomized to receive axillary brachial "An ultrasound-guided 2- upper limb surgery plexus block: Success rate of Prospective, injection axillary block may be Imasogie et al., • Group 1 (43%, mean 44.9 y ± • Group 1: 2 Injections of ropivacaine, block, defined as randomized, as effective as, and more time 2010, Canada210 15.5) epinephrine (58) anesthesia adequate double-blind efficient than, a 4-injection • Group 2 (67%, mean 45.8 y ± • Group 2: 4 Injections of ropivacaine, for surgery technique." 18.7) epinephrine (56)

"Regional anesthesia in the critically ill patient can improve respiratory function, 86-year-old woman with multiple mental status and patient cardiac comorbidities, Jackson et al., Femoral and sciatic nerve block Adequacy of comfort, and is an essential Case report coagulopathy and septic joint 2017, US52 mepivacaine, epinephrine, bupivacaine analgesia consideration in a multimodal presented for prosthetic knee approach. Relevant to this washout case, regional anesthesia can also prevent detrimental cardiac complications."

"This study showed that the C/B combination was characterized by a clinically Patients randomized to receive interscalene and statistically significant 29 Patients scheduled to undergo brachial plexus block with: faster onset than the L/B Randomized, elective shoulder arthroscopy • Group C/B: 2-chloroprocaine, Time to onset of combination for interscalene Jafari et al., 2008, prospective, • Group C/B (33%, mean 57.7 epinephrine, sodium bicarbonate (15) complete motor blocks. Although both US211 double-blind y ± 10.9) • Group L/B: lidocaine, epinephrine, block mixtures offered an adequate trial • Group L/B (64%, mean 53.2 sodium bicarbonate (14) intraoperative anesthetic, faster y ± 12.8) All groups then received bupivacaine, onset of action of 2- epinephrine chloroprocaine can facilitate the early recognition of an unsuccessful block."

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"The placement of the epidural catheter in the thoracic, rather than the lumbar, region was 77-year-old woman with buccal Epidural with pre-operative 2- Sensory and motor Jeyaram et al., selected in an attempt to Case report pemphrigus presented for chloroprocaine, epinephrine; then post- anesthesia after 1974, US53 minimize decreases in blood cholecystectomy operative tetracaine, epinephrine injection pressure by lessening the extent of the sympathetic block."

"Thoracic PVBs [paravertebral nerve blocks], provided Success of block at satisfactory procedural 10 minutes, severity Patients received either: anesthesia and post-procedural 10 Patients with amyotrophic of pain on numerical • Local skin infiltration performed with analgesia in patients with ALS lateral sclerosis scheduled for rating scale, Kalava et al., lidocaine, epinephrine [amyotrophic lateral sclerosis] Case series placement of percutaneous analgesic 2016, US54 undergoing a PRG radiologic gastrostomy tube (50%, • Paravertebral nerve blocks at thoracic requirement in first levels 7, 8 and 9 with ropivacaine, [percutaneous radiologic mean 66.6 y, range 58-78 y) 24 hours, quality of dexamethasone, epinephrine gastrostomy tube] placement, sleep, satisfaction and this technique is now with pain control routine practice at our institution."

"In conclusion, no differences in analgesia were seen between continuous PSOAS (psoas 60 Patients undergoing total knee Patients randomized to receive: compartment) blockade and Kaloul et al., replacement • Group 1: Patient-controlled analgesia continuous three-in-one FEM 2004, Canada212 • Group 1 (35%, mean 69.5 y ± (PCA) with morphine (20) blockade for postoperative 48-hour post- 4.9) • Group 2: PCA plus continuous femoral pain relief in patients Not defined operative morphine • Group 2 (40%, mean 66.7 y ± nerve block (20) undergoing TKR [total knee Kaloul et al., consumption 12.1) replacement]. As the former 2004, Canada213 • Group 3: PCA plus continuous psoas • Group 3 (35%, mean 68.9 y ± compartment (posterior lumbar plexus) has been associated with 6.9) block (20) severe complications, the latter may be the regional anesthetic technique of choice in patients undergoing TKR."

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"TAP [transverse abdominis 56 Patients undergoing plane] block does not improve At conclusion of procedures, patients laparoscopic hysterectomy Post-operative pain postoperative QoR-40 scores Randomized, randomized to receive: Kane et al., 2012, • Group 1 (0%, mean 46.2 y ± and recovery on or VAS [visual analog scale] single-blinded, • Group 1: Transverse abdominis plane US214 5.1) QoR-40 on post- pain scores following controlled trial (TAP) block (28) • Group 2 (0%, mean 43.5 y ± operative day 1 laparoscopic hysterectomy, nor • Group 2: Control, no block (28) 7.9) does it decrease narcotic pain medication use."

"Ultrasound-guided bilateral ESP block may provide 54 Patients scheduled for Patients randomized to receive: Degree of analgesia adequate postoperative pain Randomized, Kang et al., 2019, laparoscopic living donor • ITM Group: Intrathecal morphine (27) on numeric rating control after living liver donor non-inferiority South Korea216 hemihepatectomy (sex, age not • ESP Group: Erector spinae plane block scale at 24 hours hepatectomy, but it showed trial provided) with ropivacaine, epinephrine (27) after surgery comparably less analgesic efficacy than that of ITM during the first 24 hours."

All patients received pre-operative 72 Patients scheduled for interscalene brachial plexus block with "Intravenous DEX at a dose of unilateral arthroscopic shoulder ropivacaine and epinephrine, randomized 2.0 μg/kg significantly surgery to 4 groups: increased the duration of • Control group (78%, mean • Control Group: IV normal saline (18) ISBPB [interscalene brachial Prospective, 47.8 y ± 14.4) • DEX 0.5: IV dexmedetomidine at 0.5 plexus block] analgesia Kang et al., 2018, double-blind, Duration of • Dexmedetomidine (DEX) 0.5 mcg/kg (18) without prolonging motor South Korea217 randomized analgesia (61%, mean 53.7 y ± 13.6) • DEX 1.0: IV dexmedetomidine at 1 blockade and reduced the controlled trial • DEX 1.0 (55%, mean 49.7 y mcg/kg (18) cumulative opioid ± 12.5) • DEX 2.0: IV dexmedetomidine at 2 consumption at the first 24 • DEX 2.0 (61%, mean 52.9 y mcg/kg (18) hours in patients undergoing ± 10.5) • Dexmedetomidine administered over arthroscopic shoulder surgery." 30 min after induction

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All patients received pre-operative 66 Patients scheduled for interscalene brachial plexus block with "Co-administration of unilateral arthroscopic shoulder intravenous dexamethasone Kang et al., 2018, ropivacaine/epinephrine, randomized to 3 surgery (0.11 mg kg1) with South Korea219 groups: Randomized • Control (64%, mean 46.3 y ± dexmedetomidine (1.0mg kg1) • Control: IV normal saline (22) Time to first rescue controlled 16.6) significantly prolonged the • D1: IV dexamethasone at 0.11 mg/kg analgesic request Kang et al., 2019, study • Dexamethasone (68%, mean time to first rescue analgesic (22) South Korea218 46.1 y ± 17.0) request after single-shot • D2: IV dexamethasone at 0.11 mg/kg • Dexmedetomidine (59%, ISBPB in patients undergoing and IV dexmedetomidine at 1 mcg/kg mean 47.4 y ± 13.5) arthroscopic shoulder surgery." (22)

78 Patients scheduled for "The superior trunk block unilateral arthroscopic shoulder provided noninferior analgesia Randomized, surgery Pain intensity 24 compared with interscalene double- • Interscalene (50%, median 59 Patients randomized to receive: Kang et al., 2019, hour after surgery on brachial plexus block for up to blinded, y, interquartile range 44-64 • Interscalene brachial plexus block (40) South Korea215 numerical rating 24 h after arthroscopic noninferiority y) • Superior trunk block (38) scale shoulder surgery and resulted clinical trial • Superior trunk (60%, median in significantly less 56 y, interquartile range 42- hemidiaphragmatic paresis." 62 y)

"In summary, EM [epidural Patients randomized to receive lumbar 28 Patients scheduled for elective epidural anesthesia: morphine] appears to be less cesarean section Pain on visual effective when 2-CP [2- • Chloroprocaine, epinephrine (14) • 2-chloroprocaine (CP) (0%, analog scale, chloroprocaine] is used for • Lidocaine, epinephrine (14) Karambelkar et mean 29 y ± 4) cumulative amount LEA [lumbar epidural Not defined Both administered pre- and intra-operatively al., 1997, US220 • 2-CP, epinephrine (0%, mean Use of IV PCA anesthesia] compared to when for analgesia/anesthesia; after delivery, all 29 y ± 7) morphine in first 24 Lido [lidocaine] is used. The patients received epidural morphine and • Lidocaine, epinephrine (0%, hours addition of Epi [epinephrine] intravenous patient-controlled analgesia (IV mean 26 y ± 4) to 2-CP does not restore the PCA) efficacy of EM."

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"Fentanyl 75 mcg added to supraclavicular block with Plasma fentanyl mepivacaine 1.5% and before and 5, 15, 30, 5mcg/ml epinephrine did not All patients received supraclavicular 20 Patients scheduled for upper 45, 90 and 120 alter onset or duration of the brachial plexus block with mepivacaine, Prospective, extremity orthopedic surgery minutes after block; block compared to giving the epinephrine; randomized to receive fentanyl Kardash et al., randomized, • Intrabrachial (30%, mean 51 sensory and motor fentanyl intramuscularly. either: 1995, US221 double-blind y ± 17.6) block onset, time to There is the possibility of an • Intrabrachial (added to local anesthetic trial • Intramuscular (40%, mean completion and analgesic effect extending solution, 10) 53.7 y ± 10.5) duration; post- beyond the blocks. This effect, • Intramuscular (10) operative pain on if any, is short-lived and does visual analog scale not significantly improve postoperative pain management."

"The addition of epinephrine (1:200,000) to ropivacaine decreased the Cmax, delayed the Tmax, and decreased the bioavailability of the rapid 20 Patients undergoing unilateral absorption phase. This breast surgery Randomized to receive thoracic Arterial and venous Karmakar et al., confirms that epinephrine Randomized • Ropivacaine (0%, mean 38.9 paravertebral injection with either: concentration of 2005, Hong reduces and delays the study y ± 10.9) • Ropivacaine (10) ropivacaine at pre- Kong222 systemic absorption of • Ropivacaine, epinephrine • Ropivacaine, epinephrine (10) determined intervals ropivacaine from the thoracic (0%, mean 49.4 y ± 9.7) paravertebral space. Therefore, adding epinephrine to ropivacaine may be a useful strategy to reduce systemic ropivacaine toxicity."

127

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Patients randomized to receive bupivacaine, "The CSE mixture induced 63 Parturients in active labor sufentanil, epinephrine: Quality of analgesia long-lasting analgesia, with Kartawiadi et al., Randomized • Combined spinal-epidural • Spinal (CSE, 32) on visual analog fast onset and without motor 1996, Belgium223 trial (0%, mean 28.2 y ± 0.75) • Epidural (31) scale, total dose of block or hypotension. Pruritus • Epidural (0%, mean 29.1 y ± All patients received epidural top-ups with bupivacaine needed and headache were the major 0.7) same combination drawbacks of his technique."

All patients receive pre-operative 16 Patients undergoing open interscalene brachial plexus block with Motor and sensory "Our study has shown that shoulder surgery levobupivacaine, epinephrine, then block, pain on visual continuous interscalene Double-blind, Kean et al., 2006, • Group 1 (50%, mean 57.5 y, randomized for post-operative continuous analog scale, total infusion of levobupivacaine is randomized UK224 range 29-72 y) brachial plexus block with either: morphine dose (via an effective method of post- controlled trial • Group 2 (50%, mean 51.4 y, • Group 1: Levobupivacaine via catheter patient-controlled operative analgesia after major range 31-71 y) (8) analgesia) surgery of the shoulder." • Group 2: Sham (8)

"In conclusion, we have observed that extradural 51 Primigravid women in labor diamorphine produced • Group 1 (0%, mean 22.25 y, Patients randomized to receive: comparable analgesia of longer Randomized, range 17-28 y) • Group 1: Extradural diamorphine (18) Analgesia on linear duration than bupivacaine in Keenan et al., double-blind • Group 2 (0%, mean 23.7 y, • Group 2: Diamorphine, adrenaline (19) analog scale, the doses used. The addition of 1991, UK225 trial range 17-32 y) • Group 3: Bupivacaine (14) sedation adrenaline improved longer • Group 3 (0%, mean 24.3 y, term analgesia and duration of range 20-31 y) action with fewer paraesthesiae and reduced requirements for bupivacaine supplements."

128

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

All patients received supraclavicular 90 Patients scheduled for forearm "Clonidine in a dose of 1.5 brachial plexus block with lidocaine, and hand orthopedic surgery μg/kg body weight provided adrenaline, sodium bicarbonate, Onset and duration the fastest onset of sensory as • Group A (60%, mean 36 y ± bupivacaine; randomized to receive of sensory and motor well as motor block and the Kelika et al., 2017, Double-blind 9.5) adjuvant added to final volume of local block, duration of longest duration of India226 randomized • Group B (53%, mean 39.9 y anesthetic solution: post-operative postoperative analgesia and ± 9.7) • Group A: Tramadol 1 mg/kg (30) analgesia thus is a good additive to local • Group C (50%, mean 39.2 y • Group B: Clonidine 1 mcg/kg (30) anesthetic solutions for ± 9.2) • Group C: Clonidine 1.5 mcg/kg (30) brachial plexus blocks."

“For bupivacaine, decrease of mean arterial blood pressure 20 Patients scheduled for elective after 20 min and mean urological surgery under epidural Patients randomized to receive: maximum increase of ejection Kerkkamp et al., anesthesia • Group 1: Ropivacaine, epinephrine Randomly Hemodynamic fraction was more pronounced 1991, The • Group 1 (sex not provided, (10) allocated measures than ropivacaine. There was no Netherlands227 mean 47 y) • Group 2: Bupivacaine, epinephrine difference between the groups • Group 2 (sex not provided, (10) in the onset time, height of mean 55y) sensory block, change in stroke volume.”

“Ropivacaine 0.75% with epinephrine is an effective Patients randomized to receive: long-acting local anesthetic. 41 Patients scheduled for elective Quality of surgical Kerkkamp et al., • Group 1: Ropivacaine, epinephrine Duration of sensory block is Randomized urologic surgery anesthesia, onset of 1990, The (21) similar to that of bupivacaine double-blind • Group 1 (92%, 42.6 y ± 3.0) analgesia, motor Netherlands228 • Group 2: Bupivacaine, epinephrine 0.75% with epinephrine. • Group 2: (95%, 52.9 y ± 3.3) block (20) However, the motor block is less profound and of shorter duration.”

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"Although statistically significant differences exist in several nerve distributions between the onset of action of ropivacaine-chloroprocaine Randomized to receive supraclavicular Onset of anesthesia, versus ropivacaine alone, the Prospective, 60 Patients undergoing upper brachial plexus block with either: Kim et al., 2011, duration of block, modest gains achieved in randomized, extremity surgery (sex, age not • Ropivacaine, epinephrine, US229 pain on numeric hastening onset by the addition double-blinded provided) chloroprocaine (30) scale of chloroprocaine may not be • Ropivacaine, epinephrine (30) clinically significant. On the other hand, the addition of chloroprocaine significantly shortened the duration of the blocks."

Randomized to receive interscalene brachial plexus block with either: "Addition of epinephrine to • Group R20: 20 mL ropivacaine, saline ropivacaine prolonged the 65 Patients undergoing shoulder Kim et al., 2019, Prospective, (9) Duration of duration of analgesia after arthroscopy (sex, age not South Korea230 randomized • Group R10E 10 mL ropivacaine, analgesia interscalene BPB in patients provided) epinephrine (28) undergoing shoulder • R20E: 20 mL ropivacaine, epinephrine arthroscopic surgery." (28)

"This study demonstrated that perineural administration of Onset of sensory epinephrine, when combined Interscalene brachial plexus block, block, duration of with reduced dose of randomized to: 43 Patients undergoing shoulder sensory and motor ropivacaine, equally provided Kim et al., 2018, Randomized, • Group 1: 10 mL of ropivacaine, arthroscopy (sex, age not block, opioid the adequate postoperative South Korea231 controlled epinephrine (21) provided) consumption via analgesic effect by showing no • Group 2: 20 mL of ropivacaine, intravenous patient- statistical difference in sensory epinephrine (22) controlled analgesia and motor block duration after ISBPB without any adverse side effect."

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"In conclusion, using low dosage 0.5% levobupivacaine 10 mL in ultrasound-guided single shot ISBPB for patients undergoing arthroscopic shoulder surgery showed an 60 Patients undergoing shoulder excellent pain control effect of arthroscopy All patients received interscalene brachial less than 1 point of VNRS up • Group 1 (75%, mean 50.8 y ± plexus block with levobupivacaine, to 6 hours post-surgery. Pain on verbal Kim et al., 2012, 14.6) randomized to receive different additives: Furthermore, when 5 mg Not defined numerical rating South Korea232 • Group II (60%, mean 47 y ± • Group I: Normal saline (20) dexamethasone was used as an scale 15.5) • Group II: Dexamethasone 5 mg (20) adjuvant in the ISBPB, it • Group III (65%, mean 44.2 y • Group III: Epinephrine (20) showed excellent pain control ± 16.7) period extension of low VNRS up to 48 hours post-surgery without specific complications when compared to adding the same volume of adjuvant normal saline or 1:400,000 epinephrine."

All patients received spinal or general anesthesia: • Control: patients who underwent "In this retrospective study, surgery prior to use of combined spinal anesthesia plus femoral nerve block and multimodal combination femoral nerve analgesia (34) block and multimodal King et al., 2013, 70 Patients undergoing TKA (sex, • Test: patients who underwent surgery Retrospective Length of stay analgesic therapy significantly US445 age not provided) with femoral nerve block with reduced hospital length of stay. ropivacaine, epinephrine and Prospective data and larger multimodal analgesia, consisting of sample sizes are needed to pre-operative oral analgesics and intra- confirm these findings." operative periarticular injection with ketorolac, clonidine, ropivacaine, epinephrine (36)

131

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"Compared with EDA [epidural analgesia], ITM 80 Women undergoing surgery for [intrathecal morphine] is Patients allocated to receive epidural Kjölhede et al., gynecological abdominal simpler to administer and Open-label, infusion for post-operative analgesia with 2017, Sweden234 malignancy manage, is associated with randomized, either: • Epidural (0%, median 59 y, shorter hospital stay and controlled, • Epidural bupivacaine, adrenaline, Length of stay interquartile range 51.5-66 y) reduces opioid consumption Kjölhede et al., single-center fentanyl (40) • Intrathecal (0%, median 58.5 postoperatively with an 2019, Sweden233 study • Intrathecal bupivacaine, morphine, y, interquartile range 54-62.5 equally good QoL. ITM is clonidine (40) y) effective as postoperative analgesia in gynaecological cancer surgery."

"In this study, we 75 Patients scheduled for demonstrated a similar efficacy outpatient shoulder surgery between equal concentrations Patients randomized to receive interscalene of ropivacaine and • Bupivacaine (60%, mean 46 brachial plexus block with either: bupivacaine. In addition, Klein et al., 1998, Double-blind, y ± 14) Onset and duration • Bupivacaine 0.5%, epinephrine (25) increasing the concentration of US235 randomized • Ropivacaine 0.5% (40%, of block • Ropivacaine 0.5%, epinephrine (25) ropivacaine from 0.5% to mean 43 y ± 15) • Ropivacaine 0.75%, epinephrine (25) 0.75% fails to improve the • Ropivacaine 0.75% (52%, onset or duration of mean 41 y ± 14) interscalene brachial plexus block."

"During 48-72 hrs following Patient who received epidural PCA with C/S most p'ts still complained 112 Patients who received ropivacaine, fentanyl, epinephrine: of pain & requested to epidural PCA for post-operative • Group 1: Given the option to continue Kloepping et al., Patient satisfaction continue the epidural-PCA Not defined caesarean section pain; (0%, age treatment for 72 hours (78) 2013, US446 of pain treatment ropivacaine-fentanyl- not provided, groups did not • Group II: Discontinue at 48 hours and epinephrine which provided differ) receive oral oxycodone, excellent analgesia with acetaminophen, ibuprofen (34) minimal side effects."

132

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

59 Children aged 1-16 y scheduled for inpatient surgery "Both infusions provided Prospective, Patients randomized to receive epidural and post-operative epidural effective pain relief, and randomized, infusion with either: Pain on Maunuksela Kokki et al., 2002, analgesia epinephrine as an adjuvant to double-blind, • Sufentanil, ropivacaine (28) pain scale or visual Finland236 • No epinephrine (68%, mean continuous epidural sufentanil- parallel group • Sufentanil, ropivacaine, epinephrine analog scale 9 y, range 1-16 y) ropivacaine infusion seems to study (31) • Epinephrine (68%, mean 7 y, be useful in children." range 1-15 y)

Operative blood "Awake epidural anesthesia is 32 Patients who underwent loss, operative time, a safe and effective technique Patients had colectomy performed under: colectomy number of lymph in high-risk patients • Higher risk patients received awake Koltun et al., • Epidural (60%, mean 72 y, nodes in cancer undergoing colectomy and Retrospective epidural anesthesia (17) 1994, US447 range 56-84 y) specimens, achieves an operative risk that • Lower risk patients received general • General anesthesia (47%, perioperative compares favorably with anesthesia (15) mean 60 y, range 29-97 y) complications, day healthier patients receiving of hospital discharge general anesthesia."

"In conclusion, it appears that LET is superior to conventional anesthesia 59 Children ages 3-16 yrs with Patient pain, time including mepivacaine Prospective, dermal laceration needing suturing Patients randomized to receive: from initial infiltration in the pediatric propensity • LET (65%, mean 8.78 y ± Konigs et al., • LET gel (37) anesthetic emergency departments. score-matched 3.13) 2019, Germany36 • EMLA and mepivacaine infiltration application to skin Pretreatment with LET is multi-center • Eutectic mixture of local (22) closure, overall significantly less painful but study anesthetics (EMLA) (73%, satisfaction equally effective. Hence, we mean 9.57 y ± 4.22) recommend LET as a topical anesthetic in the pediatric emergency department."

133

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"This study demonstrates that 0.5% levobupivacaine, with or without the addition of epinephrine, provides good 108 Patients scheduled to undergo epidural anesthesia for lumbar elective lumbar spine surgery spine surgery, and all solutions Patients randomized to receive: are suitable for clinical use. • Plain levobupivacaine (46%, • Epidural with plain levobupivacaine The addition of epinephrine Prospective, mean 57 y ± 14) Time to onset, extent (35) decreases plasma local Kopacz et al., randomized, • Levobupivacaine with and duration of • Levobupivacaine with epinephrine anesthetic levels and improves 2001, US237 double-blinded epinephrine 1:200,000 (59%, sensory and motor 1:200,000 (37) intraoperative anesthetic study mean 54 y ± 18) blockade • Levobupivacaine with epinephrine quality. Decreasing the amount • Levobupivacaine with 1:400,000 (36) of added epinephrine from 5.0 epinephrine 1:400,000 (67%, to 2.5 g/mL reduced the mean 54 y ± 16) incidence of hypotension and tachycardia from 23% to 10% and 15% to 10%, respectively, although neither reduction was statistically significant."

"Continuous epidural anesthesia with C [2- 75 Patients scheduled for Patients with smaller stones randomly chloroprocaine], L [lidocaine] outpatient extracorporeal shock assigned to receive either: Duration of sensory or M [mepivacaine] appears anesthesia, time afe and effective for outpatient wave lithotripsy • 2-chloroprocaine 3%, epinephrine (28) from injection to surgical procedures such as • Chloroprocaine (64%, mean • Lidocaine 1.5 %, epinephrine (26) Kopacz et al., spontaneous ESWL [extracorporeal shock Not defined 44 y ± 6.3) 1990, US238 • Patients with multiple stones, large urination and to wave lithotripsy. In contrast to • Lidocaine (77%, mean 47 y ± stones, or stones anticipated to require patient discharge previous understanding, 6.6) prolonged cystoscopic manipulations from post-anesthesia mepivacaine produces • Mepivacaine (62%, mean 47 prior to ESWL received mepivacaine recovery unit significantly longer anesthesia y ± 15) 1.5%, epinephrine (21) and recovery times and may not be optimal for outpatient epidural use."

134

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

All patients received epidural (95) with bupivacaine and etidocaine with epinephrine, or sacral (24) or brachial 126 Patients scheduled for plexus (7) block with anorectal, lower abdominal, or mepivacaine/epinephrine. Patients under the upper or lower extremity surgery age of 35 years (young) randomly allocated • Young group 1: (100%, mean to 3 groups: "It is concluded that, in young 24 y ± 5.3) • Young group 1: diazepam 0.15 mg/kg, or middle-aged patients, supplementing conduction • Young group 2: (100%, mean ketamine 0.5 mg/kg (26) aneaesthesia with ketamine 0.5 22 y ± 4.1) • Young group 2: diazepam 0.15 mg/kg, Patient and nurse Korttila et al., mg/kg plus diazepam 0.15 Not defined • Young group 3: (100%, mean ketamine 1.5 mg/kg (22) post-operative 1978, Finland239 mg/kg is not associated with 22 y ± 4) • Young group 3: diazepam 0.3 mg/kg, questionnaire the untoward effects which can • Young control: (91%, mean ketamine 3 mg/kg (8) be expected after anaesthetic 23 y ± 4.6) • Young group control: no pre-/intra- doses of 1.5 mg/kg (or more) operative ketamine, diazepam (22) • Middle group 1: (52%, mean of ketamine." 52 y ± 12) • Patients over the age of 35 (middle) • Middle control: (53%, man randomly allocated to 2 groups: 50 y ± 10) • Middle group 1: diazepam 0.15 mg/kg, ketamine 0.5 mg/kg (29) • Middle group control: No pre-/intraoperative ketamine, diazepam (19)

135

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"The patients' good acceptance of any of the four premedications suggests that the role of the preoperative visit by the anaesthetist in 121 Patients scheduled for relieving anxiety before anorectal, lower abdominal, or All patients received epidural (72) with surgery may be as important as upper or lower extremity surgery bupivacaine and etidocaine with the effects of different drugs • Atropine, pethidine 1 (100%, epinephrine, spinal block with lidocaine Patient self- given as preanaesthetic mean 29 y ± 10) (28), or sacral (20) or brachial plexus (7) assessment of medication (LEIGH et al. Korttila et al., • Scopolamine, morphine block with mepivacaine, epinephrine; fatigue and 1977). If one wants patients 1980, Finland, Not defined (100%, mean 29 y ± 10) Patients randomly allocated to apprehension, nurse not to remember surgery US240 • Atropine, lorazepam 0.03 premedication: opinion on post- performed under regional mg/kg 1 (100%, mean 25 y ± • Atropine, pethidine (25) operative anxiety anaesthesia, one should prefer 8) • Scopolamine, morphine (29) and confusion the use of intravenous sedation • Atropine, lorazepam 0.06 • Atropine, lorazepam 0.03 mg/kg (31) before and during the mg/kg (100%, mean 23 y ± • Atropine, lorazepam 0.06 mg/kg (36) operation (KORTTILA 1980a, 6) 1980b,) instead of relying on the ability of intramuscularly administered premedication with scopolamine plus morphine or lorazepam to produce the amnesic action."

136

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"There were no statistically significant differences in proximal flow of mepivacaine Spread of local or in the success rate of the All patients received axillary block with anesthetic below 98 Patients undergoing hand block between the groups. mepivacaine, adrenaline, randomized to head of humerus, Randomized, surgery Signs of flow obstruction by Koschielniak- receive firm digital pressure: between head of two-parallel • Group 1 (47%, median 45 y, the head of the humerus were Nielsen et al., • Group 1: On neurovascular sheath humerus and group, double- range 18-80 y) seen in only eight patients. In 1995, Denmark241 during injection (49) coracoid process and blind • Group 2 (51%, median 46 y, the majority of patients local • Group 2: Below neurovascular sheath above coracoid range 18-76 y) anaesthetic spread above the during injection (49) process on coracoid process, which radiographs increased the success rate of the block, but did not guarantee an effective block."

120 Patients undergoing upper "Infraclavicular block had a Randomized to receive either: faster onset, better surgical extremity surgery Sensory and motor Koscielniak- Prospective, • I group: Infraclavicular (60) effectiveness and fewer • I group (63%, mean 51.1 y ± block, patient- Nielsen et al., randomized, • S group: Supraclavicular (60) adverse events. Block 16.9) reported post- 2009, Denmark242 single-blinded Brachial plexus block with ropivacaine, performance time and patients’ • S group (68%, mean 44.8 y ± operative pain mepivacaine, epinephrine acceptance of the procedure 17) were similar in both groups."

137

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"In conclusion, in the hands of anaesthetists experienced in nerve electrolocation the MNS technique of an initial axillary block by four separate 100 Patients undergoing surgery Randomized to receive axillary block with Onset of block, injections of 10 mL of the LA of the hand, wrist, or forearm Koscielniak- mepivacaine, adrenaline via: degree of motor produces faster and more Randomized, • TA group (66%, mean 47 y ± Nielsen et al., • TA group: Transarterial technique (50) block, post-operative extensive block than the TA double-blind 19) 1998, Denmark243 • MNS group: Multiple nerve stimulation pain on visual technique by two separate • MNS group (62%, mean 47 y technique (50) analog scale injections of 20 mL. Hence, ± 17) the MNS technique requires fewer supplementary blocks and results in faster patient readiness for surgery than the TA technique."

"In conclusion, both clinical and radiographic evidence in 90 Patients undergoing hand All patients received axillary block with this study showed that relaxing Onset of block, Randomized, surgery mepivacaine, adrenaline, randomized for or tensing the axillary sheath Koscielniak- degree of motor two parallel • Group AD (60%, median 36 arm to be placed in: by changing arm position Nielsen et al., block, post-operative group, single- y, range 18-75 y) • Group AD: Adducted position (45) during injection of local 1995, Denmark244 pain on visual blind study • Group AD (44%, median 49 • Group AB: Abducted position (45) anaesthetic facilitated neither analog scale y, range 20-77 y) During and for 10 minutes after injection circumferential nor proximal spread of solution and did not improve block effectiveness."

138

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"In conclusion, this study showed that the four targeted injections of 5 mL MEPE 1% (3.5 mg.kg -I) provided better surgical analgesia for hand 104 Patients undergoing surgery Patients randomized to receive axillary Onset of block, surgery, than the 80 mL single of the hand, wrist, or forearm Koscielniak- block by: degree of motor perivascular injection (12.0 Randomized, • Group T (52%, mean 45 y ± Nielsen et al., • Group T: Multiple target injections block, post-operative mg.kg-I), thus reducing the double-blind 15) 1999, Denmark245 (52) pain on visual need for supplementary blocks • Group S (62%, mean 46 y ± • Group S: Single injection (52) analog scale and shortening the anesthetic 17) time. Our findings speak in favour of the existence of non- communicating neural compartments in the axillary sheath."

"In conclusion, the results presented here show that the multiple injection technique employing a nerve stimulator, despite taking longer to perform than the single 80 Patients undergoing hand injection, resulted in more Onset of block, surgery Patients randomized to receive: rapid patient readiness for Koscielniak- degree of motor Double-blind, • Single injection (62%, mean • Axillary block by single injection (40) surgery. This was because of a Nielsen et al., block, post-operative randomized 42 y ± 16) • Multiple injections at least three plexus shorter block latency and 1997, Denmark246 pain on visual • Multiple injections (70%, 50 nerves (40) improved spread of analgesia. analog scale y ± 18) After supplementation, both methods had similar effectiveness and a similar incidence of adverse effects, but less mepivacaine was necessary when a multiple injection technique was used."

139

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"Local infiltration analgesia and femoral nerve block are comparable in the management 56 Patient undergoing primary All patients received preoperative intra- of postoperative pain after anterior cruciate ligament articular injection with ropivacaine, ACL reconstruction with reconstruction with epinephrine; randomized to receive: Consumption of hamstring tendon graft. Until semitendinosus and gracilis Kristensen et al., Randomized • Local infiltration analgesia with opioids, pain score randomised studies have tendon grafts 2014, Denmark247 controlled trial ropivacaine, epinephrine at harvest site on numeric rating investigated femoral nerve • Local infiltration analgesia and surgical site (28) scale block combined with (75%, mean 29.3 y ± 7.7) • Femoral nerve block with ropivacaine infiltration at the donor site, • Femoral nerve block (67%, (28) we recommend local mean 25.6 y ± 6.7) infiltration analgesia in ACL reconstruction with hamstring tendon graft."

"Both groups had a significant period of analgesia in the postoperative period. None of 50 Children <12 years undergoing the children in either group Randomized to receive caudal epidural with surgery below segmental level required parenteral analgesia. either: T10 Children's Hospital Though the group with Kumar et al., Randomized • Group A: Bupivacaine, epinephrine • Group A (sex not provided, Eastern Ontario Pain pethidine had a longer duration 1993, India248 controlled trial (25) mean 6.18 y ± 3.1) Scale (CHEOPS) of analgesia and sedation, the • Group B: Bupivacaine, pethidine, • Group B (sex not provided very high incidence of epinephrine (25) mean 7.57 y ± 3.6) vomiting and delay in urination observed in this group would preclude the use of pethidine routinely."

140

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"In summary, we report a case of excellent and prolonged analgesia after a single-shot QL block in a patient undergoing minimally invasive 71-year-old man scheduled for Quadratus lumborum block with hip replacement. Although this La Colla et al., Pain on numerical Case report minimally invasive total hip ropivacaine, dexmedetomidine, nerve block is effective, 2017, US55 rating scale replacement dexamethasone, epinephrine reliable, and easy to learn and perform, future prospective studies are needed to clarify the role of QL block in surgical procedures involving the hip."

"TP-TAP [trans-peritoneal transversus abdominis plane] Ultrasound is a safe and effective 26- and 41-year-old women confirmation of Lalezari et al., Case Patients received a trans-peritoneal modification to the traditional undergoing vertical sleeve successful delivery 2018, US56 presentation transversus abdominis plane block methods of performing a TAP gastrectomy of local anesthetic block. It may be done by the solution operating surgeon and does not require the use of ultrasound."

141

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"Mepivacaine - epinephrine was found to be more effective than the other local anesthetics. Loss of bearing down reflex after PDB was found in 31.2% Patients randomized to receive pudendal of the mothers and most nerve block: commonly when mepivacaine - epinephrine was used. Before delivery: Analgesic effect Inhibition of labor was slightly Prospective, • Mepivacaine (271) before and after more pronounced with Langhoff-Roos et consecutive, 1654 Parturients who had a • Mepivacaine, epinephrine (278) delivery, change in mepivacaine - epinephrine. al., 1985, randomized, vaginal delivery (0%, age not • Bupivacaine (249) urge to bear down, The different durations of the Sweden249 double-blind provided) need for local anesthetics did not affect study After delivery: supplemental the analgetic effect in clinical • Mepivacaine (290) anesthesia use. It is concluded that as the • Mepivacaine, epinephrine (291) adverse effects on labor are • Bupivacaine (275) quite common, PDB should not be given as a routine before delivery but may be offered liberally when pain in the pudendal area is a main part of the pain of childbirth."

93 Patients undergoing arm surgery • Mepivacaine group: (40%, Randomized to receive infraclavicular "Mixing 1.5% mepivacaine median 40 y, first, third peripheral nerve block with: (with epinephrine) with 0.5% Triple-blind quartiles: 28, 54 y) • Mepivacaine group: Mepivacaine, Onset of sensory and Laur et al., 2012, bupivacaine speeds up PNB randomized • Bupivacaine group: (26%, epinephrine (35) motor block, US250 sensory (motor) onset clinical trial median 43 y, first, third • Bupivacaine group: Bupivacaine (27) duration of block compared with 0.5% quartiles: 32, 59 y) • Mixed group: Mepivacaine, bupivacaine alone." • Mixed group: (30%, median epinephrine with bupivacaine (31) 36 y, first, third quartiles: 28, 48 y)

142

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"To conclude, in pediatric 58 Patients scheduled for orchidopexy, IV sufentanil was Randomized to one of 5 groups: Pain on visual unilateral orchidopexy similar to caudal sufentanil • Group IVSu: IV sufentanil, caudal analog score, time to • Group IVSu (100%, mean 3 y alone with regard to analgesia, saline (11) first administration ± 2) whilst the IV route was Prospective, • Group CSu: IV saline, caudal of analgesic, number • Group CSu (100%, mean 3 y accompanied with desirable double- sufentanil (12) of times that rescue Lauretti et al., ± 2) intraoperative sedation. While blinded, • Group CSuAdr: IV saline, caudal analgesic 2014, Brazil251 • Group CSuAdr (100%, mean adrenaline did not potentiate randomized, sufentanil, adrenaline (12) administered in first 4 y ± 2) caudal sufentanil, only controlled • Group CSuNeo: IV saline, caudal 24 hours after • Group CSuNeo (100%, mean neostigmine added to caudal sufentanil, neostigmine (12) surgery, quality of 3 y ± 2) sufentanil offered clinical • Group CSuNeoAdr: IV saline, caudal sleep on visual • Group CSuNeoAdr (100%, benefit over either caudal or IV sufentanil, neostigmine, adrenaline (11) analog scale mean 3 y ± 2) sufentanil alone, with regard to perioperative analgesia."

90 Patients undergoing surgery of "In conclusion, compared with the elbow, forearm, wrist, or hand Randomized to receive costoclavicular Onset time, success its single-injection counterpart, Layera et al., Randomized • Single injection (38%, 48.1 y block with either rate (surgical double-injection 2020, Chile252 trial ± 13.8) • Single injection technique (45) anesthesia), pain costoclavicular block results in • Double injection (31%, 49.9 • Double injection technique (45) scores shorter onset and total y ± 16.4) anesthesia-related times."

143

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"In conclusion, within the limits of the present study, no side effects were seen with small doses of clonidine for Randomized to receive extradural analgesia obstetric analgesia in a group with: of 25 patients. Much larger 50 Parturients who were • Group A: Bupivacaine, adrenaline, numbers would be required to candidates for extradural analgesia sufentanil (25) Duration of demonstrate the safety of the for labor Le Polain et al., Randomized, • Group B: Bupivacaine, adrenaline, analgesia provided drug in wider application. The • Group A: (0%, mean 30.6 y, 1993, Belgium253 double-blind sufentanil, clonidine (25) by first injection; addition of small doses of range 21-42 y) Subsequent to initial injection, patients in pain on verbal scale clonidine in a bolus regimen of • Group B: (0%, mean 28.7 y, both groups received further injections of 30 ug with bupivacaine 12.5 range 20-40 y) bupivacaine 12.5 mg, adrenaline 25 mcg mg with adrenaline and without sufentanil or clonidine sufentanil 10 ug produced better analgesia for episiotomy, but this benefit appeared not to be of great clinical significance."

"In conclusion, we have found that the addition of epinephrine significantly decreased the Cmax and the systemic plasma Arterial and venous 24 Patients having abdominal Randomized to receive epidural with: concentrations of ropivacaine plasma Prospective, hysterectomy • Epinephrine group: Ropivacaine with in the first hour after epidural Lee et al., 2002, concentrations of randomized, • Epinephrine (0%, mean 44 y epinephrine (12) injection in anesthetized Hong Kong254 ropivacaine at double-blinded ± 5) • Plain ropivacaine: Ropivacaine alone, women. Therefore, the intervals up to 180 • Plain (0%, mean 46 y ± 3) no epinephrine (12) addition of epinephrine to min ropivacaine may be a useful strategy to reduce the risk of systemic toxicity when it is injected epidurally."

144

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"Arthroscopy-guided suprascapular nerve block at the end of a rotator cuff repair was safe and less time- consuming than expected. Although this procedure did 30 Patients undergoing Pain on visual Randomized to receive suprascapular nerve not significantly reduce the arthroscopic rotator cuff repair analog scale, number Prospective, block with: post-operative pain, the post- Lee et al., 2015, • Group I (73%, mean 48.9 y of boluses and total randomized, • Group I: Ropivacaine, epinephrine (15) operative need for fentanyl South Korea255 ± 11.7) amount of fentanyl double-blinded • Group II: Saline (15) boluses as analgesia was • Group II (67%, mean 51.6 y from patient- After rotator cuff repair reduced significantly, and it ± 10.6) controlled analgesia would be beneficial if this procedure involved a sensory branch of axillary nerve block or was performed at the beginning of the arthroscopic procedure."

"LAT gel prior to the toilet and suture of minor lacerations is 40 Patients with clean, non-bite proven to be as efficacious as laceration Patients were randomized to receive: Pain on Prospective, LI [local infiltration] in terms Lee et al., 2013, • LAT (74%, mean 36.8 y ± • Lidocaine, adrenaline, tetracaine 1% administration of randomized of patient comfort and Singapore256 25.7) gel (23) anesthetic, efficacy trial effectiveness of anesthesia. • Lidocaine (71%, mean 46.2 y • Lidocaine infiltration (17) of anesthesia The complications are also ± 23) comparable to those treated with LI."

145

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"In conclusion, we determined that epinephrine prolonged the duration of epidural sufentanil analgesia after cesarean section by studying two groups of 10 patients each in a randomized double-blinded fashion. Group 1 received 50 mcg epidural sufentanil and group 2 received 50 mcg epidural sufentanil plus 300 mcg For cesarean section, all women received epinephrine. Duration of epidural bupivacaine 0.5% (epinephrine 20 Patients who chose epidural analgesia was significantly Prospective, limited to 15 mcg included in 3 mL test Pain on visual Leicht et al., 1990, anesthesia for elective cesarean longer (P < 0.05) in group 2, randomized, dose); for post-operative analgesia, women analog scale, US257 section; no significant difference with a mean of 348.7 t 80.2 double-blinded randomized to receive epidural: duration of analgesia in age, but not provided min, than in group 1, with its • Group 1: Sufentanil (10) mean of 266.7 + 80.2 min. • Group 2: Sufentanil, epinephrine (10) There were no significant differences between the groups with respect to time of onset of analgesia or subsequent parenteral narcotic requirement in the first 72 postoperative hours. However, there was a significantly higher incidence (P < 0.05) of side effects (pruritus, nausea) requiring treatment in group 2 patients."

146

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"Nulliparous parturients Patient randomized to receive: having induced labor and • Initial lumbar sympathetic block with receiving initial lumbar 36 Women who were undergoing bupivacaine 0.5%, fentanyl 25 mcg, sympathetic blocks had faster Pain on verbal Randomized, labor induction epinephrine 50 mcg (17) cervical dilation during the Leighton et al., analog scale, patient single-blinded • Lumbar sympathetic block • Epidural with bupivacaine 0.125%, first 2 h of analgesia, shorter 1999, Canada258 satisfaction with first pilot study (0%, mean 32 y ± 5) fentanyl 50 mcg, epinephrine 100 mcg second-stage labors, and a 2 hours of analgesia • Epidural (mean 32 y ± 3) (19) trend toward a lower dystocia For supplemental analgesia, all women cesarean delivery rate than did received epidural analgesia patients having epidural analgesia."

"In conclusion, addition of epinephrine 5 μg·mL−1 to ropivacaine for epidural administration during labour does not influence onset, duration or efficacy of sensory 21 Multiparous women blockade, placental transfer of undergoing planned induction of Maternal venous ropivacaine or neonatal Patients randomized to receive epidural labor plasma ropivacaine outcome. The magnitude of Leonard et al., with: Not defined • Ropivacaine only (0%, mean concentrations, time motor block is increased and 2002, Ireland259 • Ropivacaine 0.1% alone (11) 33.1 y ± 5.7) to onset, duration of initial systemic absorption of • Ropivacaine 0.1% and epinephrine (10) • Ropivacaine, epinephrine action the local anaesthetic delayed (0%, mean 33 y ± 3.6) when epinephrine is added. In view of these findings the addition of epinephrine 5 μg·mL−1 to ropivacaine for epidural administration cannot be recommended as part of routine practice."

147

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

All patients received infraclavicular block with lidocaine 1%/bupivacaine 0.25%, epinephrine; randomized to receive either: "Compared with its IV • IV dexamethasone: 0.5 mL of saline counterpart, PN was administered with the local dexamethasone (5 mg) 150 Patients undergoing surgery anesthetics (lidocaine, bupivacaine, provides a longer duration of of the forearm, wrist, or hand Leurcharusmee et epinephrine) and 0.5 mL of motor block, sensory block, Multicenter • IV dexamethasone (65%, Duration of motor al., 2016, Canada, dexamethasone (10 mg/ml) was and postoperative analgesia for randomized mean 42.5 y ± 15.5) block Thailand260 administered intravenously (75) US-guided infraclavicular • Perineural dexamethasone • Perineural dexamethasone: 0.5 mL of block. Future dose-finding (47%, mean 45.7 y ± 15.1) dexamethasone (10 mg/ml) was studies are required to administered with the local anesthetics elucidate the optimal dose of (lidocaine, bupivacaine, epinephrine), dexamethasone." and 0.5 mL of saline was administered intravenously (75)

"Costoclavicular and 90 Patients undergoing surgery of Patients randomized to receive paracoracoid ultrasound- the elbow, forearm, wrist, or hand infraclavicular brachial plexus block with guided infraclavicular blocks Leurcharusmee et Randomized, • Paracoracoid (42%, mean lidocaine, bupivacaine, epinephrine: resulted in similar onset times. al., 2017, Canada, observer- Onset time 40.9 y ± 16.2) • Paracoracoid (45) Furthermore, no intergroup Thailand261 blinded trial • Costoclavicular (62%, mean • Costoclavicular (45) differences were found in 42.8 y ± 16.4) terms of performance times and success rates."

148

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"Our results confirm that epidural anesthesia following All patients received epidural test dose of chloroprocaine compared with lidocaine/epinephrine; randomized to that following lidocaine 2% containing solutions is 53 Patients undergoing knee receive epidural: associated with an increased Levy et al., 1989, Randomized, arthroscopy; no differences • C group: Chloroprocaine plain (13) Presence and incidence of backache only US262 double-blind between groups in terms of sex or • CE group: Chloroprocaine, epinephrine severity of backache when we considered moderate age (sex, age not provided) (14) and sever backaches. The • L group: Lidocaine plain (13) addition of epinephrine to • LE group: Lidocaine/epinephrine (13) either local anesthetic seems to increase the number of backaches."

149

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"The results suggest that a history of cervical spine disease is a potential risk factor for persistent phrenic nerve paresis (PPNP) following shoulder surgery under interscalene brachial plexus block (ISB). Caution must be 6 Patients with history of cervical used when interpreting these spine disease who experienced results as nerve injury has been persistent phrenic nerve paresis Risk factors for reported following shoulder Li et al., 2011, Case- following interscalene brachial Interscalene brachial plexus block (6) persistent phrenic surgery under general US448 controlled plexus block and 6 patients as nerve paresis anesthesia without ISB. As matched control group (sex, age such, it is unclear whether the not provided) ISB contributed to the development of PPNP. Further evaluation is required to determine if epinephrine containing local anesthetic solutions contribute to nerve injury in the setting of preexisting cervical spine disease and surgical traction."

100 Parturients in active labor, "A low dose of epinephrine single gestation vertex All patients received epidural test dose of may be a useful adjuvant to Prospective, presentation lidocaine, epinephrine; randomized to epidural solutions in patients Li et al., 2019, randomized, • Bupivacaine, fentanyl (0%, Hourly frequency of receive epidural infusion: that are known to be at US263 double-blind mean 31.7 y ± 4.7) breakthrough pain • Bupivacaine, fentanyl (46) increased risk for breakthrough study • Bupivacaine, fentanyl, • Bupivacaine, fentanyl, epinephrine (54) pain without increasing other epinephrine (0%, mean 31.5 side effects." y ± 5)

150

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"In conclusion, the addition of a small dose of epinephrine to 120 Parturients with desire for epidural bupivacaine resulted epidural pain control for labor in a 30% reduction in the median effective dose for the • Bupivacaine (0%, mean 31 y Patients randomized to receive epidural initiation of labor pain relief Randomized, ± 5.4) with: and did not increase the side double-blind, • Bupivacaine, fentanyl (0%, Li et al., 2019, • Bupivacaine (40) effects. This effect was seen prospective mean 30.9 y ± 5.1) Pain on VAS US19 • Bupivacaine, fentanyl (40) even with the addition of dose-response • Bupivacaine, epinephrine • Bupivacaine, epinephrine (40) fentanyl to the epidural study (0%, mean 30.3 y ± 4.1) • Bupivacaine, fentanyl, epinephrine (40) solution. The addition of • Bupivacaine, fentanyl, epinephrine to a low epinephrine (0%, mean 31.7 concentration epidural solution y ± 5.9) may allow an even further reduction in the concentration of local anesthetic."

"We conclude that the choice 218 Patients undergoing Patients received interscalene brachial of nerve localization technique arthroscopic shoulder surgery plexus block with mepivacaine, epinephrine, Incidence of can be made based on the • Electrical stimulation: (sex Liguori et al., Prospective, sodium bicarbonate using either: postoperative patient’s and anesthesiologist’s not provided, mean 46 y ± 14 2006, US264 randomized • Electrical stimulation (109) neurologic comfort and preferences and • Mechanical stimulation: (sex • Mechanical paresthesia (109) symptoms not on concern for the not provided, mean 45 y ± development of post-operative 14) neurological symptoms."

151

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"In summary, 1.5% etidocaine with adrenaline 5 ug ml"1 , 0.5 % bupivacaine plain and 0.5 % bupivacaine with adrenaline 5 ug ml"1 all gave a satisfactory sensory block when used for extradural 27 Parturients scheduled for analgesia. After etidocaine elective cesarean section with adrenaline, the motor • Group Ea (0%, mean 32.7 y Patients randomized to receive extradural: Quality and blockade was more profound, Lindblad et al., ±) • Group Ea: Etidocaine, adrenaline (9) distribution of although its greater efficacy in Not defined 1987, Sweden265 • Group Bp (0%, mean 29.9 y • Group Bp: Bupivacaine plain (9) sensory and motor this respect is without ± 6.5) • Group Ba: Bupivacaine, adrenaline (9) block advantage to the operator or to • Group Ba (0%, mean 32.8 y the patient. The fetal ± 4.3) circulatory variables remained stable and within the normal limits, indicating that extradural anaesthesia with any of the three drug regimens studied is safe for the fetus if maternal hypotension is avoided."

"Epinephrine added to local anaesthetic injected for caudal anaesthesia produces significant increases in SV [stroke volume], CO [cardiac Patients received caudal anesthesia with 40 Pediatric patients who received Continuous non- output], and CI [cardiac index] Liu et al., 2016, Retrospective local anesthetic, either: caudal anesthesia (sex, age not invasive cardiac in children. Stroke volume and US449 analysis • With epinephrine (23) provided) output data CI changes attributable to • Without epinephrine (17) epinephrine added to local anaesthetic for caudal anaesthesia appear to take place only in children 6 months of age."

152

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"Ultrasound reduced the number of needle passes needed to perform interscalene 219 Patients scheduled to undergo All patients received interscalene block with block and enhanced motor shoulder arthroscopy mepivacaine, epinephrine, sodium Prospective, Post-operative block at the 5 min assessment; Liu et al., 2009, • Nerve stimulator (sex not bicarbonate; randomized to receive block randomized, neurological however, we did not observe US266 provided, mean 49 y ± 14) with either: controlled trial symptoms significant differences in block • Ultrasound (sex not provided, • Nerve stimulator guidance (108) failures, patient satisfaction or mean 48 y ± 16) • Ultrasound guidance (111) incidence, and severity of postoperative neurological symptoms."

"A satisfactory postoperative analgesia can be achieved with both epidural mixtures used in the study. Epidural fentanyl 42 Children scheduled for results in better analgesia, but significantly more PONV proximal osteotomy of the femur • Group SBA: Sevoflurane, epidural [post-operative nausea and • Group SBA (sex not infusion with bupivacaine 1.5 mg/ml, vomiting] and greater use of provided, median 6.5 y, range adrenaline 2 mcg/ml (14) antiemetic drugs. Omitting 4-11 y) • Group SBAF: Sevoflurane, epidural Lovstad et al., Pain, post-operative epidural fentanyl results in less Not defined • Group SBAF (sex not with bupivacaine 1 mg/ml, adrenaline 2 2001, Norway267 nausea and vomiting PONV, but significantly less provided, median 6 y, range mcg/ml, fentanyl 2 mcg/ml (16) profound analgesia and a need 3-11 y) • Group PBA: Propofol, fentanyl for additional treatment with • Group PBA (sex not anesthesia, epidural with bupivacaine i.v. opioids, in addition to a provided, median 6 y, range 1.5 mg/ml, adrenaline 2 mcg/ml (12) 55–75% higher epidural 4-11 y) bupivacaine infusion. Both epidural treatments result in high and similar patient satisfaction and no serious complications."

153

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"The results of this study would appear to show that there is a definite depression of uterine activity after • Lidocaine used in 38 of 65 injections administration of epidural 54 Parturients who received Lowensohn et al., • Propitocaine used in 27 of 65 injections anesthesia for the pain of Retrospective epidural injections during labor Intrauterine pressure 1974, US450 labor. This depression is (0%, age not provided) • Pontocaine added to 4 injections Epinephrine used in 55 of 65 injections related to the drug used, however, and not to the efficacy of the block or quantity of drug necessary to achieve the block."

90 Laboring women who required top-up for conversion to "In conclusion, we did not emergency cesarean section demonstrate any advantage of Prospective, • Bupivacaine (0% mean 32.5 Patients randomized to receive: using 2% lignocaine with Lucas et al., 1999, double-blind y ± 3.4) • Bupivacaine (30) Extended duration of adrenaline to extend low-dose UK468 randomized • Bupivacaine, lidocaine, • Bupivacaine, lidocaine, adrenaline (30) epidural analgesia epidural analgesia for trial adrenaline (0%, mean 31.7 y • Lidocaine, adrenaline (30) emergency Caesarean section. ± 5.4) We now routinely use 0.5% • Lidocaine, adrenaline (0%, bupivacaine in this situation." mean 31.2 y ± 4.2)

"The results of the present Patients randomized to receive: study, in which caudal, lumbar • Study 1 (25): Etidocaine 0.5%, peridural and brachial plexus epinephrine for caudal anesthesia (6), administrations of etidocaine 142 Patients in whom regional lumbar peridural anesthesia (6), were compared, revealed that Lund et al., 1975, anesthesia was performed for brachial plexus block (13) Venous plasma the highest blood levels were Not defined US268 various operative procedures (sex, • Study 2 (67): Lumbar peridural levels of etidocaine obtained following caudal age not provided) anesthesia with etidocaine 0.5-1.5%, injection, and that venous epinephrine (67) plasma levels of etidocaine • Study 3 (50): Peridural etidocaine 1% following lumbar peridural and with (21) or without (29) epinephrine brachial plexus administration were similar."

154

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

Patients randomized to receive: • Group 1: Peridural injection of lidocaine or mepivacaine (50) "The results obtained in this • Group 2: Peridural injection of study indicate that in man the lidocaine, prilocaine with and without Concentration of distributions of lidocaine, Lund et al., 1967, epinephrine (5) local anesthetics in mepivacaine, and prilocaine Not defined No information provided US269 • Group 3: Peridural injection of spinal fluid and out of the peridural space are lidocaine, mepivacaine with and venous blood similar when these drugs are without epinephrine (5) administered under identical • Group 4: Peridural injection of conditions." lidocaine, prilocaine, or mepivacaine (30)

"We conclude that etidocaine is an excellent long-acting local anaesthetic agent which possesses particular Onset time, duration advantages for Caesarean Lund et al., 1977, Patients undergoing cesarean Patients received etidocaine 0.75%, 1% and of analgesia, section. In addition, the Not defined US57 section (0%, age not provided) 1.5% with and without adrenaline maternal and fetal uv+ua/mv ratios following the blood concentrations extradural administration of etidocaine for this procedure were among the lowest ever reported for any local anaesthetic agent."

Patients received one of the following 1021 Patients receiving peridural, blocks: caudal, brachial plexus, and • Peridural (554) "This report reviews the initial miscellaneous peripheral nerve Lund et al., 1973, • Caudal (112) Onset time, duration clinical data on the new long- Not defined blocks for operative procedures, US58 • Brachial plexus (143) of anesthesia acting local anesthetic agent, therapeutic and diagnostic nerve etidocaine." blocks (sex not provided, range • Miscellaneous nerve blocks (212) 17-89 y) with etidocaine 0.5%, 0.75%, 1% and 1.5%

155

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"Epidural fentanyl or All patients received epidural anesthesia sufentanil in continuous with bupivacaine 0.5%, epinephrine, epidural infusion and patient- fentanyl; randomized to receive: Pain, number of Patients undergoing knee ligament controlled boluses in the doses Lutti et al., 2002, • Epidural bupivacaine, fentanyl (number patient-controlled Not defined reconstruction (sex not provided, used in this study have induced Brazil270 of patients not provided) boluses, opioid range 16-47 y) excellent postoperative • Bupivacaine, sufentanil (number of consumption analgesia. However, sufentanil patients not provided) caused more severe side

effects than fentanyl."

All patients received transversus abdominis plane (TAP) block with ropivacaine 0.2%, Pregnant women schedule for adrenaline 5 mcg/ml; randomized to Consumption of "TAP block is an effective and Lykoudi et al., Randomized, elective cesarean section (0%, age receive: additional analgesia, safe technique for 2016, Greece271 double-blind not provided) • Group A: TAP infusion of ropivacaine pain scores postoperative analgesia of CS." 0.2% (number of patients not provided) • Group B: Placebo

"A double-blind study of temperature readings on the lower extremities before and Patients received caudal anesthesia with: after caudal anesthesia in Temperature parturients using three • Mepivacaine (number of patients not readings at four sites different solutions, 1 percent provided) Lynas et al., 1970, Double-blind Parturients in labor (0%, age not on the lower mepivacaine, 1 percent • Mepivacaine, epinephrine (number of US272 study provided) extremities before mepivacaine with epinephrine, patients not provided) and after caudal and 1 percent lidocaine with • Lidocaine, epinephrine (number of anesthesia epinephrine, showed no patients not provided) statistically significant difference in the temperature rise of the lower extremities between the three solutions."

156

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

72 Parturients with term singleton "In summary, this study fetus suggests that PCEA [patient- controlled epidural anesthesia] • Continuous epidural infusion Pain on verbal scale, Randomized to one of 4 groups: is a safe and effective method (CEI) (0%, mean 25 yrs ± 1) prior to epidural • CEI Group: Physician-controlled of providing labor analgesia. • Patient-controlled epidural catheter, at initiation continuous epidural infusion with No complications directly anesthesia (PCEA) - of epidural infusion bupivacaine (18) related to PCEA use were Lysak et al., 1990, bupivacaine (B) (0%, mean and every hour until Not defined • B Group: PCEA with bupivacaine (16) encountered. Of solutions US273 26 yrs ± 1) delivery, motor • BF Group: PCEA with bupivacaine, tested, low hourly infusion • PCEA – bupivacaine, block using fentanyl (21) requirements and lack of fentanyl (BF) (0%, mean 25 Bromage, overall • BFE Group: PCEA with bupivacaine, significant adverse side effects yrs ± 1) satisfaction with favor use of 0.125% fentanyl, epinephrine (17) labor analgesia • PCEA – bupivacaine, bupivacaine plus fentanyl, 1 fentanyl, epinephrine (BFE) microgram/ml, for PCEA (0%, mean 27 ± 2) during labor."

"No clinical evidence of deep vein thrombosis, tachyphylactic reaction to 15 Patients scheduled for total All patients received epidural anesthesia for lidocaine, orthostatic joint replacement of a lower operation with etidocaine, epinephrine; hypotension, or motor block extremity randomized to receive: was demonstrated in any • Group 1 (0%, mean 70.4 y, • Group 1: Epidural fentanyl (5) Pain relief, Doppler patient. The addition of Lytle et al., 1991, Single-blind, range 63-87 y) • Group 2: Epidural fentanyl, lidocaine arterial flow studies lidocaine to the epidural US274 randomized • Group 2: (60%, mean 62.8 y, 0.75% (5) of lower extremities fentanyl infusion did not range 32-77 y) • Group 3: Epidural fentanyl, lidocaine improve pain relief or allow a • Group 3 (0%, mean 48.4 y, 1% (5) decrease in the rate of infusion. range 30-71 y) Patients in all groups had improved arterial flow to the lower extremities 24 hours postoperatively."

157

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"In conclusion, the combination of systemic and 40 Patients undergoing unilateral perineural dexamethasone video-assisted thoracoscopic Prospective, Randomized to receive intercostal nerve increases the duration of surgery double-blind block with: Pain by NRS-11 intercostal nerve block Maher et al., 2017, • Bupivacaine, epinephrine randomized • Bupivacaine, epinephrine (20) pain scores at 24 analgesia, decreases US275 (40%, mean 67.1 y ± 12.12) placebo- • Bupivacaine, epinephrine, hours postoperative opioid • Bupivacaine, epinephrine, controlled trial dexamethasone (20) requirements, and delays the dexamethasone (65%, mean development of restrictive 68.75 y ± 9.34) breathing patterns following VATS."

"This clinical research has established that CFNB, in Randomized to receive postoperative conjunction with analgesic continuous infusion femoral block with: Pain on visual 24 Patients undergoing anterior medication, provides Maldini et al., Prospective, • Levobupivacaine 0.375%, epinephrine analog scale, cruciate ligament repair (sex, age significant efficacy in 2007, Croatia276 randomized bolus, then levobupivacaine 0.125% tramadol and/or not provided) controlling postoperative pain infusion (12) diclofenac use beyond that achieved with • Saline bolus and infusion (12) medication alone (placebo group)."

"In summary, intercostal blocks combined with local infiltration is a simple and Randomized to receive: inexpensive anesthetic • Group A: Lidocaine, epinephrine for technique for ESWL, which 72 Patients undergoing infiltration and intercostal blocks (31) Patient and surgeon- obviates the complexities of Malhotra et al., extracorporeal shock wave Not defined • Group B: Bupivacaine 0.25% for rated anesthetic epidural anesthesia, general 1987, US278 lithotripsy (ESWL) (70%, mean infiltration and bupivacaine 0.5%, experience anesthesia, high frequency jet 46 y, range 21-74 y) lidocaine, epinephrine for intercostal ventilation, and invasive blocks (41) monitoring. We have found it to be safe, effective, and well accepted in the 72 patients we have treated."

158

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"The addition of a three-day ambulatory continuous All patients received interscalene brachial interscalene nerve block to a Randomized, plexus block with mepivacaine 1.5%, single-injection brachial plexus double- Patients undergoing shoulder epinephrine 2.5 mcg/ml; randomized to interscalene block for patients Malhotra et al., masked, manipulation for refractive receive: Pain scores, range of undergoing manipulation for 2012, US277 placebo- adhesive capsulitis (sex, age not • Perineural ropivacaine 0.2% infusion motion, opiate use shoulder adhesive capsulitis controlled pilot provided) (number not provided) provides analgesia during the study • Normal saline (number not provided) infusion and may improve for 3 days post-manipulation shoulder range-of-motion the day after manipulation."

"In conclusion, the addition of 5 mcg of isoproterenol to bupivacaine and sufentanil leads to a shorter duration of Randomized to receive epidural with: analgesia compared with a • Epinephrine Group: bupivacaine, solution of bupivacaine, 78 Laboring women at term sufentanil, epinephrine 12.5 mcg (39) sufentanil, and 12.5 mcg of • Epinephrine (0%, mean 29.5 Marcus et al., Double-blind, • Isoproterenol Group: bupivacaine, Contraction pain on epinephrine. Even if y ± 0.6) 1998, Belgium279 randomized sufentanil, isoproterenol 5 mcg (39) visual analog scale isoproterenol is superior to • Isoproterenol (0%, mean 28.9 If further analgesia requested after use of 3 epinephrine as a test dose for y ± 0.5) coded ampules (30 mL total), then all detecting the intravascular women received bupivacaine, epinephrine placement of an epidural catheter, the data from this study suggest that subsequent epidural injections should not contain isoproterenol."

159

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"In this retrospective study, femoral nerve block plus Patients in the test group received pre- multimodal analgesia operative multimodal oral analgesics significantly reduced early (celecoxib 400 mg, oxycodone continuous postoperative pain scores at release 10-20 mg, and acetaminophen 975 rest and during physical mg), femoral nerve block (20 mL of 0.2% therapy with ambulation. ropivacaine with epinephrine), and intra- 34 Patients who underwent total Pain score at rest Stronger significance was Mark et al., 2013, operative multimodal analgesia injection Retrospective knee arthroplasty (sex, age not and during physical noted for early ambulation. US451 (ketorolac 30 mg, epinephrine 0.5 mg, provided) therapy Our data suggests that this clonidine 0.08 mg, and ropivacaine 300 mg combination mode of therapy in normal saline with a final volume of 150 may also reduce pain scores ml) (3) immediately postoperatively

(POD 0), enabling very early Patients in the control group did not receive mobilization of patients these interventions (31) undergoing total knee arthroplasty. "

"In summary, we have presented a case in which the placement of a lumbar plexus block resulted in the unmasking of phantom leg pain that was alleviated by a 72-year-old woman presented for sciatic nerve block. An Martin et al., total hip arthroplasty; history of Lumbar plexus block and sciatic nerve Case report Pain score implication of this case report 2003, US59 below-the-knee amputation with block with levobupivacaine, epinephrine is that in addition to the intermittent phantom leg pain peripheral influence on the altered central processing that underlies phantom pain, neighboring peripheral nerves may play an important inhibitory role."

160

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"We conclude that in the context of Ibis study carbonated lidocaine, although faster in onset than Randomized to receive: mepivacaine, was not significantly different from • Axillary nerve block with lidocaine Onset time, duration, 42 Patients undergoing surgical lidocaine hydrochloride in Martin et al., Randomized, HCl, epinephrine (20) quality of procedures on the upper limb (sex onset time. Carbonated 1987, Canada280 double-blind • Lidocaine hydrocarbonate, epinephrine analgesia/anesthesia not provided, mean 46 y) lidocaine, lidocaine (20) during surgery hydrochloride and • Mepivacaine, epinephrine (2) mepivacaine hydrochloride were not different with respect to quality of analgesia, quality of motor block and duration of analgesia."

"In conclusion, our study indicates that the epidural injection of 10 mL of a solution containing morphine 2 mg ane epinephrine 1:200,000 is ineffective for relieving the Randomized to 5 different treatment groups: pain of labor. The 75 Laboring women • Group 1: Morphine, epinephrine (15) combination of bupivacaine • Group 1 (0%, mean 25 y) • Group 2: Morphine, bupivacaine (15) and orphine may provide Martin et al., Randomized, • Group 2 (0%, mean 23 y) • Group 3: Morphine, bupivacaine, Pain score, duration analgesia of longer duration 1985, Canada281 double-blind • Group 3 (0%, mean 24 y) epinephrine (15) of analgesia but the increased incidence of • Group 4 (0%, mean 24 y) • Group 4: Bupivacaine (15) side effects precludes its use. • Group 5 (0%, mean 23 y) • Group 5: Bupivacaine, epinephrine Bupivacaine 0.25% or (15) bupivacaine 0.25% with epinephrine 1:200,000 may not be ideal for labor, but it still remains the closed approximation to what could be described as the ideal agent."

161

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"It is suggested that retrobulbar injection be given first, Patients undergoing surgical Martin et al., Prospective Retrobulbar injection with bupivacaine, Akinesia of the followed by evaluation or ophthalmic procedures (sex, age 1986, US470 case series lidocaine, epinephrine, hyaluronidase orbicularis muscle orbicularis function, and that not provided) facial nerve block be added only as needed."

"The use of intraosseous technique with 4% articaine shows promising results 70 Patients with acute pulpitis in regarding comfort and Double-blind mandibular molars: Randomized to receive either: Pain on visual Martinez Martinez reduction of the need for randomized • Intraosseous (46%, mean • Intraosseous injection (35) analog scale, need et al., 2016, additional anesthesia. The uncontrolled 42.14 y ± 13.95) • Inferior alveolar nerve block with for additional Colombia282 intraosseous technique is study • Inferior alveolar nerve block articaine and epinephrine (35) anesthesia probably the best alternative (54%, mean 41.82 y ± 18.83) when deep pulpar anesthesia is required in mandibular molars."

"We believe that we used a relatively safe protocol for the 1 In-patient presenting to the procedures and for operating room for hip resurfacing postoperative pain with history of systemic management that allowed for McCutcheon et al., mastocytosis and receiving Toleration of this patient to have a Case report Ropivacaine with epinephrine (1) 2012, US60 subarachnoid block for surgical procedures successful hip resurfacing and anesthesia and lumbar plexus uneventful recovery and block for post-operative analgesia believe that this management (100%, 58 y) plan can serve as a guideline for acute pain management for this patient population."

162

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"Parasternal block and local 17 Inpatients receiving cardiac anesthetic infiltration of the surgery via median sternotomy sternotomy wound and Randomized, under parasternal block and local mediastinal tube sites with placebo- anesthetic infiltration: McDonald et al., • Levobupivacaine with epinephrine (8) Effects on pain and levobupivacaine can be a controlled, • Levobupivacaine with 2005, US283 • Placebo (9) respiratory function useful analgesic adjunct for double-blind epinephrine (100%, mean 61 patients who are expected to study y ± 9) undergo early tracheal • Placebo (88.89%, mean 64 y extubation after cardiac ± 11) surgery."

Patients randomized to receive epidural 57 Parturients scheduled for anesthesia with: "Overall, there was no elective cesarean section under • Group 1: Lidocaine or bupivacaine, evidence of a statistically epidural anesthesia post-operative epidural sufentanil (14) significant influence of • Group 1 (0%, mean 31.2 y ± • Group 2: Lidocaine or bupivacaine Onset, efficacy, and epinephrine on the intensity of 3.9) with epinephrine, post-operative McMorland et al., duration of analgesia. Neither is there any Not defined • Group 2 (0%, mean 33.4 y ± epidural sufentanil (13) 1990, Canada284 analgesia, incidence statistical evidence of any 4.6) • Group 3: Epidural lidocaine or of side effects difference among the four • Group 3 (0%, mean 32.3 y ± bupivacaine, post-operative sufentanil groups on measures of 3.3) with epinephrine (15) pruritus, onset time, duration • Group 4 (0%, mean 30.8 y ± • Group 4: Lidocaine or bupivacaine or maximum intensity." 5.0) with epinephrine, post-operative sufentanil with epinephrine (15)

163

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"The TFP block provides effective analgesia at the ICBG harvest site, with discernable effects up to 24-48h postoperatively. There was • Ultrasound (US)-guided transversalis significant reduction in 30 Inpatients undergoing iliac fascia plane (TFP) block with perioperative opioid crest bone graft harvesting (ICBG) McVicar et al., ropivacaine and epinephrine (not Pain scores, opioid consumption up to 8h Not defined and elective upper limb surgery 2013, Canada285 reported) consumption postoperatively in the performed under brachial plexus • Placebo dextrose solution (not intervention group. Total IV block (sex and age not specified) reported) PCA morphine consumption was similar between groups, but we attribute this to pain at the primary surgical site once the brachial plexus block had worn off."

"Ultrasound guided popliteal sciatic nerve block markedly reduces the requirement for postoperative diclofenac and • Ultrasound guided block of sciatic 32 Inpatients undergoing morphine consumption and Micic et al., 2011, nerve at popliteal level with: Numeric rating scale Not defined calcaneo-stop surgery (sex not results in lower pain scores Croatia286 • Levobupivacaine and epinephrine (16) (NRS) specified, range 8-12 y) during the first 24 hours • Paracetamol and morphine (16) compared to multimodal parenteral analgesia in children undergoing calcaneo-stop surgery."

164

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"The addition of morphine to levobupivacaine 0.5% in 40 Inpatients scheduled for • Levobupivacaine with epinephrine (not bilateral superficial cervical thyroidectomy under general Mohamed et al., Double-blind reported) Pain assessment plexus blocks gives better and anesthesia and bilateral superficial 2005, Egypt287 study • Levobupivacaine with epinephrine and using VAS scale more prolonged analgesia than cervical plexus block (BSCB; sex morphine (not reported) the use of levobupivacaine and age not specified) 0.5% alone in patients undergoing thyroid surgery."

1500 Patient procedures where hyaluronidase was incorporated • Pontocaine (224) "At the present time the into the local anesthetic solution various brands of • Pontocaine plus vasopressor (742) (53.68%, range 0-90 y) Onset and duration hyaluronidase are relatively • Pontocaine plus hyaluronidase (20) Moore et al., 1951, of analgesia, expensive. Therefore, if the Not defined The series with hyaluronidase was US61 • Pontocaine plus hyaluronidase and postoperative drug is not being used on an compared to a series of 966 nerve epinephrine (1375) blocks in which pontocaine analgesia experimental basis, the cost in • Pontocaine plus hyaluronidase and comparison to the advantage solutions without hyaluronidase neosynephrine (105) was administered (sex and age not may not justify routine use." specified)

165

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

Spinal block (12386) Epidural block (7286) • Lidocaine (2) "A study of 12,386 spinal • Lidocaine with epinephrine (103) blocks and 7286 epidural • Lidocaine with tetracaine (2) blocks revealed: (1) both technics [sic] to be safe, • Lidocaine with tetracaine and provided the physician epinephrine (6276) administering the block 19672 Patients receiving spinal • Lidocaine with tetracaine and Duration of Moore et al., 1968, carefully evaluates his own Not defined anesthesia or epidural blocks (sex phenylephrine (1) analgesia, US452 capabilities and the patient's and age not specified) • Mepivacaine with epinephrine (15) complications physical status; (2) spinal • Mepivacaine with tetracaine and block to be the more certain of epinephrine (189) the two procedures; and (3) the • Chloroprocaine with epinephrine (11) complications and hazards of • Chloroprocaine with tetracaine and the two technics [sic] to be epinephrine (609) similar." • Propoxycaine with tetracaine and epinephrine (78)

"For intra-abdominal pelvic gynecologic operations using lumbar epidural block and the protocol of this study, 0.75 percent bupivacaine with Onset and maximum 50 Inpatients scheduled to have an Epidural block with: epinephrine 1:200,000 Moore et al., 1974, Double-blind sensory and motor abdominal hysterectomy (0%, age • Bupivacaine and epinephrine (25) produced a significantly higher US288 study anesthesia, quality of not specified) • Etidocaine with epinephrine (25) incidence of satisfactory anesthesia anesthesia for surgical procedures and a longer period of postoperative pain relief than did 1 percent etidocaine with 1:200,000 epinephrine."

166

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"For vaginal delivery using continuous (intermittent) caudal block and the specific protocol of this study, 0.25 and 0.5 percent bupivacaine with Caudal block with epinephrine and: Onset and maximum 60 Inpatients receiving continuous epinephrine 1:200,000 as Moore et al., 1975, • Etidocaine (20) sensory and motor Not defined caudal block for vaginal deliveries compared with 0.5 percent US289 • 0.5% Bupivacaine (20) anesthesia, quality of (0%, age not specified) etidocaine with 1:200,000 anesthesia • 0.25% Bupivacaine (20) epinephrine produced a significantly longer period of pain relief for the parturient and more profound sensory anesthesia."

"The TI technique was faster in onset and resulted in more successful sensory block of all nerves in the first 20 minutes, however the surgical success at All patients received lidocaine mixed with 93 Inpatients with end-stage renal 30 minutes was not statistically Prospective epinephrine followed by ropivacaine via disease scheduled for upper limb significant, although that was Nada et al., 2012, randomized ultrasound-guided supraclavicular brachial Sensory block vascular access surgery under not statistically significant it US290 double-blind plexus block via either: success regional anesthesia (sex and age was clinically significant in study • SI: Single injection (46) not specified) this group of sick patients. • TI: Triple injections (47) Also, Musculocutaneous nerve block was more successful in the TI technique which makes this technique more useful in certain procedures."

167

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"Sural anesthesia assessed at the lateral heel and the lateral 180 Inpatients undergoing aspect of the foot and the fifth reconstructive ankle surgery with toe identified within 4 to 6 sciatic nerve blocks using the minutes demonstrated a similar infragluteal-parabiceps approach Complete sciatic posttest predictive value as Prospective Nader et al., 2010, • Elicited motor response Levobupivacaine and epinephrine after nerve block within anesthesia in the distributions observational US453 (EMR) of inversion (60.2%, obtaining an elicited motor response (180) 25 minutes of of the posterior tibial and study median 49 y [IQR 28-54]) injection peroneal nerves or motor • EMR of plantar flexion movement of the foot at later (52.9%, median 46 y [IQR intervals. In addition, failure to 33-56]) achieve sural anesthesia within 10 minutes was predictive of block failure."

100 Inpatients scheduled for "Potential advantages of the elective ankle or foot surgery modified intertendinous All patients received levobupivacaine with • Group 1 (29.1%, median 48 y approach include more rapid Prospective epinephrine via either: Nader et al., 2009, [IQR 40-58]) onset of anesthesia with an randomized • Classic posterior nerve block (50) Complete block US291 • Group 2 (27.8%, median 55 y evoked motor response of study • Modified intertendinous nerve block [IQR 39-61]) inversion compared to a classic (50) The study did not specify which posterior popliteal sciatic nerve group had which intervention block."

Minimum threshold "Injecting 10 mL of 0.5% current, time to bupivacaine or ropivacaine 139 Inpatients undergoing primary complete block, below the CIEL [common Double-blind, Nader et al., 2013, tricompartmental total knee • Bupivacaine with epinephrine (69) duration of sensory investing extraneural layer] randomized US292 replacement (37%, median 66 y • Ropivacaine with epinephrine (70) and motor block, produces comparable onset and clinical trial [IQR 59-73]) postoperative pain, duration of sensory and motor analgesic blockade as volumes as large requirements as 30 mL."

168

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

436 Outpatients undergoing All patients received the initial sciatic nerve "Blocking the sciatic nerve at a ambulatory surgery under sciatic block: more distal site after a failed nerve block • Sciatic nerve block with Post-operative Nader et al., 2011, subgluteal sciatic nerve block Not defined • Single injection (61%, levobupivacaine and epinephrine (380) neurological US454 does not appear to influence median 42 y [IQR 33-53]) • Supplemental popliteal nerve block symptoms the incidence or duration of • Supplemental popliteal (55%, with lidocaine, levobupivacaine, and neurologic sequelae." median 39 y [IQR 28-47]) epinephrine (56)

Time to first rescue "This study showed superior analgesia, time to analgesia and parental perform blocks, 50 Inpatients scheduled for satisfaction with single-shot intraoperative and Prospective Anderson-Hynes pyeloplasty All patients received ropivacaine with paravertebral block in post-operative Narasimhan et al., randomized, • Caudal block (80%, mean 5.1 epinephrine via either: comparison to single-shot hemodynamics, 2019, India293 blinded clinical y ± 2.6) • Caudal block (25) caudal block for renal post-operative pain trial surgeries in children. However, • Paravertebral block (76%, • Paravertebral block (25) scores, incidence of mean 6.0 y ± 2.6) the block performance in complications, children requires adequate parenteral expertise and practice." satisfaction scores

Scalp block with bupivacaine and lidocaine "Adding either 8 mg with adjuvants of: Total intra-operative dexamethasone or 500 mg Randomized, 40 Inpatients scheduled for awake dexmedetomidine MgSO4 or both to • Epinephrine (10) prospective craniotomy surgeries due to consumption, time to bupivacaine-lidocaine for scalp Nasr et al., 2020, • Epinephrine and dexamethasone (10) double-blinded intracranial mass near eloquent first paracetamol block before awake Egypt294 • Epinephrine and magnesium sulfate controlled areas in the dominant hemisphere requirement, total craniotomy improves (10) study (65%, range 22-48 y) paracetamol performance of the block with • Epinephrine, dexamethasone, and requirement the best results when magnesium sulfate (10) combined."

169

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

Degree of pain relief, duration of 115 Inpatients requiring • Bupivacaine (43) "It is concluded that analgesic effect, Nesheim et al., paracervical block (PCB) for • Bupivacaine with epinephrine (22) bupivacaine without the Not defined time from PCB to 1983, Norway295 obstetrical analgesia (0%, age not • Chloroprocaine (28) addition of adrenalin is the fully dilated cervix, specified) drug of choice for PCB." • Chloroprocaine with epinephrine(22) operative deliveries, fetal complications

78 Inpatients requiring patient- controlled epidural analgesia after "Addition of adrenaline to Ngan Kee et al., elective cesarean section Pain score, pethidine for patient-controlled • Pethidine with epinephrine (40) 1998, Hong Not defined • Epinephrine (0%, mean 30.6 consumption of epidural analgesia does not • Pethidine (38) Kong296 y ± 4.5) pethidine appear to have significant • Plain (0%, mean 32.0 y ± clinical advantages." 4.3)

38 Inpatients receiving postoperative epidural analgesia after Onset of analgesia, "Addition of adrenaline to Ngan Kee et al., Randomized, cesarean section • Pethidine with epinephrine (20) pain scores, 24-hour epidural pethidine has 1997, Hong double-blind • Epinephrine (0%, median • Pethidine (18) consumption of advantages for analgesia after Kong297 study 31.5 y [IQR 27-34.5]) pethidine Caesarean section." • Plain (0%, median 33 y [IQR 30-36])

170

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

“In our study, 40% of the IS group and 20% of the SC group had perceived breathlessness while in the PACU. However, there was no statistically significant difference between the numerical scoring of breathlessness. The SC block has fewer incidences of phrenic nerve palsy but it is associated with generalized sensory and motor blockade. All patients received ropivacaine and In one study, postoperative motor block of the hand was 15 Inpatients undergoing major epinephrine via either: Nicholas et al., Patient satisfaction, not tolerated by some patients. Not defined shoulder surgery (sex and age not • IS Group: Interscalene nerve block (5) 2012, US298 duration of block As well, the SC approach may specified) • SC Group: Supraclavicular nerve theoretically not block lower block (10) roots of the cervical plexus. However, in our study there was no trend towards statistical difference between pain scores and overall satisfaction. Understandably, the findings of this study are limited due to the small sample size. However, preliminary evidence suggests that both block types may be equally sufficient for postoperative pain control following major shoulder surgery."

171

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

59 Inpatients with uremia "Blockade of the scheduled for the creation of an musculocutaneous nerve arteriovenous fistula for developed faster with the hemodialysis in the lateral ante- All patients received mepivacaine with infraclavicular coracoid brachial region epinephrine as a single-injection brachial Loss of sensation, approach than with the axillary Niemi et al., 2007, Not defined • IC approach: Infraclavicular plexus block via either: analgesia, motor approach. The infraclavicular Finland299 brachial plexus (62%, mean • IC approach (29) block coracoid approach may be 63 y ± 13) • AX approach (30) preferable in patients • AX approach: Axillary scheduled for the creation of brachial plexus (73.3%, mean an arteriovenous fistula at the 60 y ± 15) forearm."

"Preoperative oral Double-blind, All patients received IANB with 50 Outpatients receiving inferior administration of IBU Noguera-Gonzalez randomized, mepivacaine and epinephrine before alveolar nerve blocks (IANBs) for significantly improved the et al., 2013, placebo- receiving either: Success of IANB symptomatic irreversible pulpitis efficacy of IANB in patients Mexico300 controlled • Ibuprofen (25) (SIP; 36%, range 18-68 y) with symptomatic irreversible clinical trial • Placebo (25) pulpitis."

172

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"The interscalene block provided complete relief of pain that outlasted its somatic nerve blockade. Likely, the local anesthetic spread included both brachial plexus and stellate ganglion, and therefore it is unknown if the 1 Inpatient with chronic allodynia benefit was derived from Nunez et al., 2016, of the left upper extremity Interscalene block with 2-chloroprocaine Case report Resolution of pain blockade of peripheral or US62 exacerbated by viral illness (0%, and epinephrine (1) autonomic nerves. The 15 y) intervention avoided hospital admission and opioids in this patient for approximately 2 days. There are similar case reports of children with CRPS who had long-term benefit from peripheral nerve catheter infusions for 3-7 days."

"In conclusion, RIEMG [rectified integrated Electromyographic All patients received epidural anesthesia electromyographic recordings] (EMG) with epinephrine and either: measurements could be applied Nydahl et al., Double-blind 27 Volunteers receiving epidural measurements, • Mepivacaine (10) for quantitative assessment of 1989, Sweden301 study anesthesia (100%, range 19-34 y) Isometric muscle • Bupivacaine (9) motor blockade both of the force, Bromage abdominal muscles and of the • Etidocaine (8) scale, Analgesia quadriceps muscle during epidural anaesthesia."

173

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

144 Inpatients whose labor was induced and labored under All patients received combined spinal- regional anesthesia epidural anesthesia with spinal bupivacaine Number of patients • 3 Minutes (0%, mean 31 y ± and fentanyl followed by epidural infusion "Our results suggest that the requesting additional Single-blinded, 5) of ropivacaine, fentanyl, and epinephrine at best timing of epidural Okutomi et al., ropivacaine boluses, randomized • 30 Minutes (0%, mean 32 y ± set times after the spinal injection: infusion following spinal dose 2009, Japan302 total dose of clinical trial 5) • 3 Minutes (36) was within 30 min of spinal ropivacaine needed • 60 Minutes (0%, mean 31 y ± • 30 Minutes (36) induction dose." for labor analgesia 5) • 60 Minutes (36) • 90 Minutes (0%, mean 32 y ± • 90 Minutes (36) 4)

"Use of single-shot PCB [Psoas compartment block] is 40 Inpatients planned to undergo superior to single-shot caudal hip reduction/osteotomy All patients received ropivacaine with Total consumption block regarding length of Omar et al., 2011, Comparative • Caudal block (35%, mean 3 y epinephrine via either: of morphine in the postoperative analgesia and Saudi Arabia303 study ± 1.3) • Caudal block (20) first 24 cumulative dose of morphine • Psoas compartment block • Psoas compartment block (20) postoperative hours in small children undergoing (40%, mean 2.7 y ± 1.4) open hip reduction/osteotomies."

"Nerve stimulator-guided PVB at the level of T1-T6 with ropivacaine represents a suitable alternative to GA for breast cancer surgery. Prospective 40 Inpatients undergoing breast • General anesthesia (20) Success rate, Important benefits of PVB Omran et al., randomized cancer surgery (0%, age not • Paravertebral nerve blockade (PVB) incidence of include reduced surgical stress 2005, Egypt304 study specified) with ropivacaine and epinephrine (20) complications response, as evidenced by lower plasma cortisol and glucose concentrations, superior postoperative analgesia and lower incidence of PONV."

174

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

Block execution 94 Inpatients undergoing minor All patients received femoral and lateral "The anterior approach to time, depth and size knee surgery femoral cutaneous nerve blocks combined sciatic nerve block is of the nerve, needle Ota et al., 2009, • Anterior approach (48.9%, with sciatic nerve blocks with mepivacaine performed as easily and Not defined depth, onset time of Japan305 mean 38 y ± 20) and epinephrine that were administered via: successfully as the posterior sensory and motor • Posterior approach (44.7%, • Anterior approach (47) approach using ultrasound blockade, duration mean 38 y ± 19) • Posterior approach (47) guidance." of block

"We recommend the use of LIA over the use of continuous FNB for pain relief after TKA. However, the combination of • Control group (20) LIA and FNB could be an Visual analogue • Local infiltration anesthesia (LIA) with alternative way of anesthesia Prospective 51 Inpatients undergoing total scale (VAS), Paglia et al., 2020, ropivacaine, epinephrine, and for TKA. Finally, in total knee randomized knee arthroplasty under spinal morphine Italy306 physiological solution (20) arthroplasty, studies are study anesthesia (33%, range 52-91 y) consumption, range required to define the major • Femoral nerve block (FNB) with of motion chirocaine (11) origin of pain, whether it is subcutaneous, capsular, anterior/posterior, to help implement effective treatment."

75 Inpatients scheduled for tonsillectomy under general Glossopharyngeal nerve block (GNB) with: anesthesia "GNB is a useful method for • Group R: Ropivacaine with the palliation of post- Prospective, • Group R (60%, mean 36 y ± Pain (VAS), severity Park et al., 2007, epinephrine (25) tonsillectomy pain. An randomized 11) of gag reflex South Korea307 • Group B: Bupivacaine with obtunded gag reflex response study • Group B (64%, mean 34 y ± response epinephrine (25) may be a clinical indicator for 9) • Group C: No GNB (25) analgesia from GNB." • Group C (68%, mean 33 y ± 11)

175

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

72 Inpatients undergoing elective unilateral breast surgery Both groups received PVB injections with a • Anatomical landmark "Ultrasound-guided PVB Randomized, local anesthetic solution containing technique (ALT) provided better anesthesia and Patnaik et al., controlled, ropivacaine, epinephrine, and clonidine via paravertebral block (PVB; Block success rate perioperative analgesia than 2018, India308 observer- 2 different techniques: 0%, mean 42.75 y ± 8.85) the landmark technique for blinded study • ALT (36) • Ultrasound-guided (USG) breast surgery." • USG (36) PVB (0%, mean 49.25 y ± 9.37)

"The anesthetic technic employed was a posterior cervical block which provided anesthesia for an operative procedure over 3 hours in duration. The ability to utilize a regional anesthetic technic greatly facilitated the operative procedure, because it was possible to evaluate temporary occlusion of the carotid artery Paul et al., 1968, 1 Inpatient admitted for a painless Tetracaine with epinephrine via regional Case report Successful block during operation while the US63 mass on his neck (100%, 59 y) posterior cervical block (1) patient was awake. The great value of posterior cervical block for operations upon the carotid artery is well emphasized by demonstration of its efficacy. Subsequent convalescence of the patient following operation has been satisfactory in the 8 months since excision of the aneurysm."

176

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"Epidural analgesia is superior 17 Inpatients with cerebral palsy • LIA with ropivacaine and epinephrine to local infiltration analgesia Randomized Pedersen et al., undergoing unilateral hip (5) for early postoperative pain double-blind Postoperative pain 2016, Denmark309 reconstruction (52.9%, range 3-13 • Placebo (6) management in children with trial y) • Epidural analgesia with bupivacaine (6) cerebral palsy who undergo unilateral hip reconstruction."

"In the present study, the Patients received an axillary brachial plexus musculocutaneous nerve was block with mepivacaine and epinephrine via more often blocked by the either: initial dose of mepivacaine in 50 Inpatients receiving an axillary • Perivascular nerve stimulator technique Pere et al., 1993, the transarterial group (68% vs Not defined brachial plexus block (sex not (25) Successful block Finland310 48% (ns)). Contrary to our specified, range 22-66 y) • Transarterial technique (25) expectations, there were no One patient was operated on twice; he first differences between the groups received a transarterial block and received a in the block of the radial perivascular block 4 months later nerve."

"Patient selection for bilateral 1 Inpatient requiring bilateral ICBs should be carefully Pharmer et al., continuous infraclavicular nerve evaluated, but these blocks can Case report ICB with mepivacaine and epinephrine (1) Analgesia 2017, US64 blocks (ICB) for surgical fixation be successfully and safely used after fracture (0%, 60 y) in certain patients, even in the ambulatory setting."

"Given our patient's fluid restriction and vasopressor requirements we hypothesized that bilateral PVB catheters 1 Inpatient with end-stage cystic would be preferable to TEA. Pinjuv et al., 2016, Bilateral thoracic paravertebral blockade Case report fibrosis presenting for a double Analgesia This case demonstrates that US65 (PVB) with ropivacaine and epinephrine (1) lung transplant (100%, 32 y) bilateral continuous PVB can provide effective analgesia with hemodynamic stability in double-lung transplant patient."

177

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"It is concluded that bilateral • Intercostal block with bupivacaine and 20 Inpatients scheduled to have Effect on the intercostal blocks may inhibit Pither et al., 1988, added epinephrine (10) Not defined cholecystectomy (sex and age not endocrine metabolic the glucose response to surgery UK311 • Epinephrine infiltrated into the specified) response to surgery but have no effect on the intercostal space (10) cortisol response."

• Lidocaine 1% (66) • Lidocaine 1% with epinephrine 1/200,000 (40) "The addition of epinephrine • Lidocaine 1% with epinephrine significantly prolongs the 1/500,000 (14) action of lidocaine. However, a 268 Inpatients receiving Analgesic effect, Double-blind, • Mepivacaine 1% (62) transient uterine inertia occurs Pitkin et al., 1963, paracervical blocks during the first effect on labor, controlled, • Mepivacaine 1% with epinephrine in a significant percentage of US312 stage of labor (0%, age not delivery, clinical trial 1/200,000 (22) patients given epinephrine- specified) complications • Mepivacaine 1.5% (22) containing solutions and the • Tetracaine 0.05% (17) course of labor may thereby be • Normal saline (15) slowed." • Normal saline with epinephrine 1/200,000 (10)

"Both techniques are safe, Time to perform the effective, and with the same 68 Inpatients scheduled for blocks, analgesia, All patients received suprascapular and degree of satisfaction and shoulder arthroscopy surgery opioid consumption, Prospective, axillary nerve block with levobupivacaine acceptability. The selective Pitombo et al., • Interscalene group (38.2%, motor block, randomized and epinephrine via either: blockade of both nerves 2013, Brazil313 mean 55.03 y ± 13.04) cardiovascular study • Interscalene technique (34) showed satisfactory analgesia, • Selective group (47.1%, stability, patient • Selective technique (34) with the advantage of mean 52.21 y ± 15.39) satisfaction and providing motor block acceptability restricted to the shoulder."

178

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"In surgical procedures, epidural analgesia should be Perioperative advantageous for patients who velocity of flow in 38 Inpatients undergoing • General anesthesia (21) are at risk of DTV [sic] either Poikolainen et al., the femoral vein, Not defined retropubic prostatectomy (100%, • Epidural analgesia with butanilicaine because of predisposing 1983, Finland314 postoperative deep age not specified) and epinephrine (17) individual factors or because vein thrombosis the operation carries a high (DVT) risk of thromboembolic complications."

"This study indicates that In each series, one arm received one etidocaine is a reliable local intervention and the other received the other anesthetic for peripheral nerve • Series 1: Etidocaine 0.25% with block. It has a rapid onset of epinephrine (10); Lidocaine 1% with action and, in a 0.5 per cent 10 Volunteers who received Poppers et al., epinephrine (10) Complete analgesia, concentration, produces an Not defined bilateral ulnar-nerve blocks 1974, US316 • Series 2: Etidocaine 0.5% with success of block ulnar-nerve conduction block (100%, range 23-45 y) epinephrine (10); Lidocaine 1% with of moderately long duration. epinephrine (10) Addition of epinephrine, • Series 3: Etidocaine 5% (10); 1:200,000, to the anesthetic Lidocaine 1% (10) solution prolongs its action considerably."

• Etidocaine 0.25% with epinephrine (8) 25 Inpatients in spontaneous labor "Thus etidocaine appears to be • Etidocaine 0.5% (5) Poppers et al., receiving lumbar or caudal Anesthesia, safety an acceptable local anaesthetic Not defined • Etidocaine 0.5% with epinephrine (6) 1975, US315 epidural anesthesia (0%, age not for fetus and neonate for epidural anaesthesia in specified) • Etidocaine 1% (1) obstetrics." • Etidocaine 1% with epinephrine (5)

179

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"Ultrasound-guided BTPV 30 Inpatients with pectus block provides improved excavatum, scheduled for the postoperative analgesia for Prospective, Nuss procedure • Control (15) children undergoing the Nuss Qi et al., 2014, randomized, • Control (86.7%, mean 9.60 y) • BTPV with ropivacaine and Post-operative pain procedure as compared with China317 single-blinded • Bilateral thoracic epinephrine (15) intravenous PCA and study paravertebral (BTPV) block decreases the incidence of 93.3%, mean 6.93 y) postoperative behavioral disturbance."

60 Inpatients undergoing resection for colorectal cancer "The results of this study • Intravenous patient- demonstrated the importance Prospective, controlled analgesia (IV- • IV-PCA with morphine (30) of implementation of TEA as a Radovanovic et randomized, Return of bowel PCA) (60%, mean 64.18 y ± • TEA with levobupivacaine, fentanyl, preferred method for al., 2017, Serbia318 controlled function 9.90) and epinephrine (30) postoperative pain control after clinical study • Thoracic epidural analgesia major open colorectal (TEA; 66.7%, mean 65.88 y surgery." ± 10.00)

180

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"We conclude that paracervical blockade with midazolam sedation and alfentanil analgesia is a promising method for abortion. In a clinical situation it is a challenge for the Co-operation score, anaesthesiologist to titrate and state of wakefulness time the administration of 88 Inpatients undergoing abortion score, A-test, P-test, • General anesthesia (28) alfentanil and midazolam Prospective, • General anesthesia (0%, Maddox-Wing test, Raeder et al., • Regional anesthesia with a paracervical according to the needs of the randomized mean 23 y ± 4.8) Visual Analogue 1992, Norway319 blockade of mepivacaine and individual patient. This may study • Regional anesthesia (0%, Scale (VAS), side- epinephrine (31) provide better results than mean 24 y ± 6.3) effects, need for those reported in this study analgesia, function with a strict mg/kg protocol. If tests either the patient or the gynaecologist rejects regional anaesthesia, general anaesthesia with propofol seems to be an alternative with equally good recovery function."

181

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"This study indicates that the quantity of NaHCO3 needed to alkalize 10 mL of 0.75% ropivacaine at room temperature is 0.012 mEq. 60 Inpatients scheduled to have When the solution contains lower limb surgery • Group 1: Epidural ropivacaine (20) adrenaline 1:200,000 (mg * • Group 1 (60%, mean 32.8 y ± • Group 2: Epidural ropivacaine with mL-1), up to 0.015 mEq of Motor and sensory Ramos et al., 9.6) sodium bicarbonate (20) NaHCO3 may be added. The Not defined onsets, block spread, 2001, Brazil320 • Group 2 (85%, mean 33.1 y ± alkalization of the 0.75% • Group 3: Epidural ropivacaine with duration of block 10.9) epinephrine and sodium bicarbonate ropivacaine solution did not • Group 3 (80%, mean 31.0 y ± (20) cause a reduction of sensory- 10.8) motor onset but did provide a significant increase in the duration of the epidural block with no significant differences between the solutions with and without adrenaline."

1040 Outpatients who had "The addition of • Ropivacaine (220) received an upper or lower dexamethasone to 0.5% Retrospective • Ropivacaine with epinephrine (387) Rasmussen et al., extremity peripheral nerve block Duration of ropivacaine prolongs the database • Ropivacaine with dexamethasone (67) 2013, US455 in an orthopedic outpatient analgesia duration of peripheral nerve analysis surgery center (54.7%, median 45 • Ropivacaine with dexamethasone and blocks of both the upper and y) epinephrine (366) lower extremity."

182

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"In contrast to other reports, this technique provides surgical anesthesia that is adequate for all of the 16 Inpatients scheduled for approaches used for Left interscalene cervical plexus block with Raza et al., implantation of a permanent transvenous pacemaker Not defined mepivacaine, tetracaine, and epinephrine Anesthesia 1991, US456 transvenous cardiac pacemaker implantation, except for (16) (93.8%, mean 65.9 y) placement of a battery in an abdominal pouch. There were no serious complications and/or side effects in any of the patients studies."

• Epidural morphine (22) 49 Inpatients who were scheduled "The addition of epinephrine to Rechtine et al., Double-blind • Epidural morphine with epinephrine for lumbar laminectomy (sex and Anesthesia the morphine solution had no 1984, US321 study (17) age not specified) beneficial effect." • Normal saline (10)

27 Inpatients receiving postpartum • Morphine (12) "The addition of epinephrine to Redick et al., Onset and duration Not defined epidural analgesia (0%, age not • Meperidine (10) meperidine did prolong it's 1980, US322 of analgesia specified) • Meperidine with epinephrine (5) activity."

Onset time, 40 Inpatients scheduled for "In respect of these segmental spread elective upper abdominal surgery • Epidural bupivacaine with epinephrine parameters, no major and duration of Renck et al., 1975, • Bupivacaine (52.6%, mean (19) differences were found Not defined analgesia, systolic Sweden323 68 y ± 13) • Epidural etidocaine with epinephrine between the two solutions blood pressure, heart • Etidocaine (23.8%, mean 52 (21) under the conditions of the rate, peak expiratory y ± 16) study." flow rate

183

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

197 Patients with uncomplicated Adequacy of "In summary, LET gel is at Prospective, laceration of the face or scalp anesthesia before least as effective as LET single-blinded, Resch et al., 1998, • LET gel group (71%, mean • LET gel (92) suturing (using solution for effective topical randomized US9 5.8 y ± 3.5) • LET solution (105) needle), anesthesia for uncomplicated controlled • LET solution group (64%, effectiveness of lacerations of the face and clinical trial mean 5.6 y ± 3.1) anesthesia scalp in children."

"Epidural fentanyl with epinephrine provides adequate 30 Inpatients scheduled for postoperative analgesia, elective cesarean section Onset and duration Double-blind without serious potentiation of Robertson et al., • Fentanyl (0%, mean 30 y ± • Epidural fentanyl (16) of analgesia, pain randomized side effects. The use of a 1985, Canada324 1.8 [SEM]) • Epidural fentanyl plus epinephrine (14) relief (visual analog trial double bolus technique is both • Fentanyl plus epinephrine scale score) time-consuming and (0%, mean 29 y ± 1.0 [SEM]) cumbersome which limits its value for clinical use."

"We recommend that 45 Inpatients presenting for Onset of motor paresthesias to the shoulder be Roch et al., 1992, Interscalene brachial plexus block with Not defined shoulder surgery (sex and age not block, handgrip accepted in performing US457 mepivacaine and epinephrine (45) specified) strength interscalene blocks for patients undergoing shoulder surgery."

• Caudal ropivacaine and epinephrine "CB [Caudal Before] and CA Prospective, Patients scheduled for outpatient prior to incision (not reported) [Caudal After] had lower randomized, Romanu et al., inguinal herniorrhaphy, • Caudal ropivacaine and epinephrine average pain scores than LA double- Postoperative pain 2014, US325 orchiopexy, or orchiectomy (sex after surgery (not reported) [Local Infiltrate] despite blinded, and age not specified) similar amounts of opioid controlled • Ropivacaine infiltrated around surgery site after surgery (not reported) administration.”

184

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"In conclusion, extradural diamorphine provided prolonged analgesia after Caesarean section under subarachnoid anaesthesia. Randomized, • Extradural sodium chloride (15) 45 Inpatients requiring either Duration of Addition of adrenaline had Roulson et al., double-blind • Extradural diamorphine (15) elective or emergency cesarean analgesia, side little effect on the quality or 1993, UK326 controlled section (0%, range 23-45 y) • Extradural diamorphine and effects duration of analgesia in the study epinephrine (15) women studied. Initial subarachnoid rather than extradural block may also increase the duration of postoperative analgesia."

Hemodynamic 161 Patients scheduled for variables before and orthopedic surgery with a thigh after tourniquet "Our study shows that the • Group B: Epidural bupivacaine, tourniquet application, need for addition of fentanyl 200 mcg Rucci et al., 1987, Prospective, epinephrine (81) • Group B (75%, mean 35 y ± intraoperative to bupivacaine greatly Italy327 double-blind • Group BF: Epidural bupivacaine, 16) supplemental improves the sensory block in fentanyl, epinephrine (80) • Group BF (80%, mean 35 y ± analgesia, patient- epidural anesthesia." 14) reported tourniquet pain

78 Inpatients receiving spinal anesthesia for unilateral, primary total knee arthroplasty surgery • Combined obturator nerve • OFB with bupivacaine, epinephrine, "Addition of ONB to FTB block (ONB) with femoral clonidine, and dexamethasone (26) Morphine significantly reduced opioid Runge et al., 2016, Randomized triangle block (FTB) (57.7%, • FTB with bupivacaine, epinephrine, consumption during consumption and pain after Denmark328 controlled trial mean 71 y ± 8.0) clonidine, and dexamethasone (23) first 24 TKA compared with a single • FTB alone (56.5%, mean 73 y • LIA with ropivacaine, epinephrine, postoperative hours FTB or LIA, without impaired ± 7.1) and ketorolac (26) ambulation." • Local infiltration analgesia (LIA) (42.3%, mean 70 y ± 8.4)

185

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"The effects of Xylocaine on both sensory and motor nerves All retrobulbar injections contained is more profound than and 120 Patients receiving retrobulbar Russell Jr et al., epinephrine plus: procaine (45); procaine Akinesia of the lasts over twice as long as, the Not defined injection (sex and age not 1954, US329 with hyaluronidase (17); lidocaine (38); or extraocular muscles effects of procaine on these specified) lidocaine with hyaluronidase (20) nerves. The duration of either is increased by adrenalin, but diminished by hyaluronidase."

"Caudal anesthesia was given to a series of patients who constituted 10 per cent of our obstetric deliveries, 87.7 per cent of which were satisfactory 518 Inpatients receiving Caudal anesthesia with initial dose of and resulted in 83 per cent of Russell et al., continuous caudal anesthesia for Anesthesia, side Not defined lidocaine with epinephrine and maintenance the infants delivered having 1964, US458 labor and delivery (0%, age not effects with tetracaine with epinephrine (518) Apgar scores of 8 or greater. specified) These results were based upon a technique of administering a combination of lidocaine and tetracaine which was found to be most satisfactory."

Postoperative "This study demonstrated than headache (VAS), scalp blocks with Randomized, 10 Inpatients scheduled for PCA consumption, levobupivacaine effectively Ryu et al., 2011, placebo- elective craniotomies for • Levobupivacaine with epinephrine (5) hemodynamic relieved postoperative South Korea330 controlled aneurysmal clipping under scalp • Normal saline (5) variabilities, headache and spared study block (sex and age not specified) incidence of PONV postoperative PCA and respiratory consumption without adverse depression events."

186

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

90 Inpatients who underwent unilateral low abdominal surgery • Transversus abdominis plane Postoperative pain (TAP) block (sex not Sahin et al., 2015, All patients received levobupivacaine with scores, total provided, mean 42.50 months Turkey331 Prospective, epinephrine via either: analgesic "Caudal and TAP blocks are ± 23.08) randomized, consumption, time more effective than II/IH nerve • Ilioinguinal/iliohypogastric single-blinded • TAP block (30) of first analgesic blocks in the early Sahin et al., 2017, (II/IH) block (sex not study • II/IH block (30) administration, vital postoperative period." Turkey332 provided, mean 36.40 months • Caudal block (30) parameters, adverse ± 23.98) effects • Caudal block (sex not provided, mean 32.60 months ± 24.98)

"For brachial plexus blocks, epinephrine did not affect the Brachial plexus block with ropivacaine and: duration of analgesia when added to ropivacaine. • No adjuvants (1535) Epinephrine did not enhance 3706 Outpatients who received • Epinephrine (293) the observed increase of block Saied et al., 2017, Observational regional anesthesia at a single • Clonidine (527) duration induced by clonidine Block duration US333 study outpatient surgery center (58.4%, • Clonidine and epinephrine (16) or the combination of mean 44 y ± 17.3) • Dexamethasone (204) clonidine and dexamethasone. • Dexamethasone and epinephrine (303) The most block duration • Dexamethasone and clonidine (790) enhancement was observed • All adjuvants (33) when combination of clonidine and dexamethasone were added to ropivacaine."

187

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

All patients receive test dose of epidural lidocaine, epinephrine; randomized to "Increasing the concentration receive epidural patient-controlled analgesia of fentanyl did not impact the neonates or the outcome of with: Pain on visual labor and delivery. Increasing Sakr et al., 2014, Randomized, 150 Parturients (0%, age not • Bupivacaine, epinephrine, fentanyl 2 analog scale, side the concentration of fentanyl US459 double-blind provided) mcg/mL (not provided) effects, overall significantly decreased the • Bupivacaine, epinephrine, fentanyl 4 patient satisfaction mcg/mL (not provided) bolus volume of study • Bupivacaine, epinephrine, fentanyl 6 solution." mcg/mL (not provided)

“Articaine is more potent and has longer duration of action with better postoperative analgesia and could be 50 Patients requiring surgical Difficulty index for considered as an alternative to extraction of mandibular third Inferior alveolar nerve block with either: extraction, volume, lignocaine in clinical practice. Saralaya et al., Randomized molar onset and duration of With management of 2019, India334 clinical trial • Articaine (40%, mean 25.1 y) • Articaine and epinephrine (25) anesthesia, duration postoperative pain being the • Lidocaine (44%, mean 26.1 • Lidocaine and epinephrine (25) of postoperative critical component of patient y) analgesia care, clinical trials are required to develop long acting local anesthetic with increased postoperative analgesia effect.”

"We conclude that favorable results can be obtained when Randomized, 80 Patients receiving lateral All patients received infraclavicular block Time until readiness either nerve stimulation or controlled, sagittal infraclavicular block with mepivacaine and epinephrine via for surgery, ultrasound guidance is used for Sauter et al., 2008, observer- • Nerve stimulator (60%, mean either: quantified lateral sagittal infraclavicular Norway335 blinded, 52 y ± 13) discomfort during block. Using ultrasound, local comparative • Ultrasound guided (57.5%, • Nerve stimulation (40) block, pain related to anesthetic injection study mean 50 y ± 12) • Ultrasound-guided (40) tourniquet ischemia cranioposterior to the artery appears feasible."

188

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

Randomized "Twenty mL 1% mepivacaine double-blind 151 Inpatients receiving pudendal (plain) is a safe choice for Schierup et al., • Mepivacaine (76) Efficacy of block, and block for vaginal delivery (0%, pudendal block without the 1988, Denmark336 • Mepivacaine with epinephrine (75) Apgar scores prospective age not specified) possible disadvantages of study adding epinephrine."

"LET is an effective alternative to TAC for topical anesthesia during suturing of Signs of pain with 151 Patients with uncomplicated uncomplicated lacerations on Double- needle, adequacy of laceration to the face or scalp the face and scalp in children. Schilling et al., blinded, • LET (78) anesthesia as (66.2%) As a topical anesthetic with 1995, US23 randomized • TAC (73) assessed by • LET (mean 6.4 y ± 3.4) cocaine omitted, LET solution controlled trial physician, duration • TAC (mean 5.9 y ± 3.3) provides an inexpensive of anesthesia alternative that can be used in hospital EDs, clinics, and urgent-care centers."

"The results of this study did not show any significant increase in the duration of postoperative analgesia by adding epinephrine to 30 Inpatients scheduled for ankle ropivacaine for popliteal nerve fusion, subtalar fusion, or a Ultrasound-guided continuous popliteal block. This may be due to the Schoenmakers et combination of both Duration of Randomized nerve block with: intrinsic vasoconstrictive al., 2015, The • Ropivacaine (53.3%, mean 61 postoperative controlled trial • Ropivacaine (15) properties of ropivacaine. The Netherlands337 y ± 7) analgesia • Ropivacaine with epinephrine (15) absence of a significant • Ropivacaine with epinephrine difference can also be the (60%, mean 56 y ± 11) result of a type II error caused by a large variation in the individual TTFR [time to first request for postoperative analgesia]."

189

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"Analgesia was profound and of rapid onset in both groups. Duration of analgesia was greater in the adrenaline group (time to next analgesia 12.51 ± 0.94 h, mean ± SEM), than in the saline group (9.87 ± 0.98 h) (P = 0.057). Analgesia was also more consistent in the 54 Inpatients who underwent adrenaline group, with 77% of cesarean section patients having more than 8 h • Extradural diamorphine (27) Semple et al., Randomized • Group 1 (0%, mean 27 y ± Onset and duration of good analgesia compared • Extradural diamorphine with 1988, UK338 double-blind [SEM] 0.92) of analgesia with 48% in the saline group epinephrine (27) • Group 2 (0%, mean 27.7 y ± (P < 0.05). Plasma morphine [SEM] 0.94) concentrations, measured in 12 patients, were lower, although not significantly so, in the adrenaline group and mean time to peak concentration markedly delayed. No serious side effects were observed, but there was a higher incidence of vomiting in the adrenaline group."

Total volume of "In conclusion, both A2 and Double-blind local anesthetic, 46 Patients who required surgery A4, administered in equal Senes et al., 2015, crossover • Articaine 2% with epinephrine (46) onset and duration of for 2 partially impacted lower volumes, were effective and Brazil339 randomized • Articaine 4% with epinephrine (46) analgesia, quality of third molars (61%, range 18-44 y) safe during lower third molar clinical trial anesthesia, surgery surgery…" difficulty

190

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"Etidocaine was found to be 40 Inpatients scheduled for effective clinically as a local vaginal hysterectomy • Caudal etidocaine with epinephrine Randomized Onset of action, anaesthetic, with a rapid onset Seow et al., 1976, • Etidocaine (0%, mean 55.95 y (20) double-blind muscle relaxation, of action and good muscle Singapore340 ± 10.81) • Caudal lignocaine with epinephrine trial quality of analgesia relaxation, though limited • Lignocaine (0%, mean 53.90 (20) somewhat by the high y ± 12.25) incidence of visceral pain."

"Etidocaine was highly effective for the surgical procedure, with rapid onset of 40 Inpatients scheduled for pelvic action, adequate muscle floor repair • Caudal etidocaine with epinephrine relaxation and longer duration Randomized Onset of action, Seow et al., 1976, • Etidocaine (0%, mean 37.8 y (20) of action. Its use for post- double-blind muscle relaxation, Singapore341 ± 12.70) • Caudal lignocaine with epinephrine operative analgesia may be trial quality of analgesia • Lignocaine (0%, mean 34.6 y (20) hindered by the concomitant ± 8.57) immobilization of the legs. The problem of tachyphylaxis with etidocaine needs further investigation."

45 Patients undergoing arthroscopic surgery "The use of quantitative Single-centre, Interscalene brachial plexus block with: Measurement of sensory testing (QST) enabled • Levobupivacaine (47%, mean prospective, gradual changes in a comparison of the onset, Sermeus et al., 50 y ± 12) randomized, • Levobupivacaine (15) block characteristics intensity, and duration of local 2016, Belgium342 • Levobupivacaine/epinephrine double-blind • Levobupivacaine, epinephrine (15) using quantitative anesthetic (LA) block among (67%, mean 49 y ± 10) study • Ropivacaine (15) sensory testing clinically applied anesthetic • Ropivacaine (60%, mean 56 y drugs." ± 12)

191

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"No difference in intensity between the local anesthetics 30 Patients undergoing shoulder Intensity of tested. A decrease in block arthroscopy surgery quantitative sensory Interscalene brachial plexus block with: intensity, with minimal • Levobupivacaine (30%, mean findings: cold/warm Randomized, changes in pain detection Sermeus et al., 47.9 y ± 14.4) sensation and double-blind, • Levobupivacaine (10) thresholds, was observed in the 2019, Belgium343 • Levobupivacaine/epinephrine cold/heat pain controlled trial • Levobupivacaine, epinephrine (10) roots adjacent to C5, with the (0%, mean 46.5 y ± 12.4) measured by thermal lowest block intensity at C7. A • Ropivacaine (10) quantitative sensory • Ropivacaine (40%, mean 48.7 clinically shorter duration was testing. y ± 8.8) found with 0.75% ropivacaine compared to the other groups."

"Regional anesthesia offers sufficient analgesia during the 84 Patients undergoing total and • Regional anesthesia alone with Postoperative hospital stay for shoulder Shah et al., 2007, hemi-shoulder arthroplasty under interscalene brachial plexus block (73) analgesia, nausea Prospective arthroplasty procedures while US344 interscalene brachial plexus block • Combined regional and general and vomiting, adhering to high patient (38%, mean 65.1 y ± 12.4) anesthesia (11) patient satisfaction comfort and satisfaction, with low complications."

60 Patients undergoing any kind "5% dextrose produces a of orthopedic or plastic surgery on Brachial plexus block with bupivacaine, definite reduction in the Prospective, upper limb lidocaine, adrenaline diluted with: Onset and duration latency of complete sensory as Shah et al., 2014, randomized, • Normal saline (60%, mean of complete motor well as motor blockade with India460 controlled 41.72 y ± 12.95) • Normal saline (30) and sensory block no significant changes in • Dextrose (53%, mean 38.84 y • Dextrose (30) duration of motor and sensory ± 11.49) block."

41 Patients undergoing upper limb Infraclavicular brachial plexus block with: Shah et al., 2011, surgery • Group S: Lidocaine, adrenaline with Time to onset, peak "We conclude that clonidine is India346 Prospective, • Group S (82%, mean 29.36 y saline (11) effect, duration of more efficacious than randomized, ± 7.22) • Group D: Lidocaine, adrenaline with block, postoperative dexamethasone as an adjuvant placebo- • Group D (67%, mean 31.42 y Shah et al., 2015, dexamethasone (12) analgesia to 1.5% lignocaine in brachial controlled ± 8.37) India345 • Group C: Lidocaine, adrenaline with requirement plexus blocks." • Group C (72%, mean 35.61 y clonidine (18) ± 13.89)

192

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

All patients received postoperative epidural "The addition of ondansetron patient-controlled analgesia with fentanyl, Fentanyl, naloxone to our IV-patient controlled ropivacaine, epinephrine; randomized to total doses, side naloxone solution for the 50 Parturients undergoing elective Shah et al., 2012, receive: effects, pain on treatment of post C/S pruritus, Randomized caesarean section (0%, age not US473 • Patient-administered intravenous visual analog scale, reduced the maximum pruritus provided) naloxone (25) itching scores, scores and increased the • Patient-administered intravenous overall satisfaction overall satisfaction from this naloxone with ondansetron (25) pruritus treatment."

"Results of 390 brachial plexus blocks are reported with special reference to comparisons of agents and technics used. Of these blocks 68 per cent were excellent, 13 per cent satisfactory and 17 per cent unsatisfactory.; 2. Expected duration of brachial • Procaine, epinephrine (193 blocks) plexus anesthesia with a procaine and epinephrine • Procaine (23) Results of block, solution is approximately Patients who received brachial • Continuous procaine (9) Shaw et al., 1951, Comparative graded as excellent, ninety minutes.; 3. Addition of plexus blocks for surgical • Procaine, pontocaine, epinephrine US347 study satisfactory or pontocaine to this solution of anesthesia (91%, range 19-48 y) (156) unsatisfactory procaine and epinephrine • Monocaine, epinephrine (8) increases the expected • Monocaine (1) duration of anesthesia to 130 minutes.; 4. A solution of monocaine formate and epinephrine provides rapid, complete brachial plexus anesthesia lasting beyond l 20 minutes.; 5. Continuous brachial plexus anesthesia requires large volumes of solution for excellent results”

193

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"With the limited number of Double-blind, missed blocks obtained in this Inferior alveolar nerve block with: Sheikh et al., randomized, Patients undergoing oral surgery Number of missed study, we were unable to find a • Articaine, epinephrine (not provided) 2014, US348 controlled (sex, age not provided) injections statistically significant • Lidocaine, epinephrine (not provided) clinical trial difference between the two solutions tested as of yet."

"We believe this airway management technique can be advantageous in a patient with 71-year-old female presenting for Spontaneous Shen et al., 2015, Supraclavicular block with ropivacaine, airway anatomy prone to Not defined arteriovenous fistular creation in ventilation and US461 epinephrine obstruction who receives a right arm oxygenation high brachial plexus block and requires deep IV sedation for the surgical procedure."

"Adjuvants may be particularly useful in opioid tolerant patients; the most thoroughly studied adjuvant is ketamine. In a Cochrane review, 27 of 37 trials found that perioperative subanaesthetic dose of Siddapura Bilateral paravertebral catheters injected ketamine reduced rescue 60-year-old male presented for Pain score, ability to Ranganath et al., Case with bupivacaine, infusion of ropivacaine, analgesic requirements or pain Whipple's procedure ambulate 2013, US14 epinephrine intensity, or both. Postoperative pain relief should be carefully tailored in these cases by means of a management plan that notes previous spinal instrumentation and opioid tolerance."

194

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"Given the ease in performing the nerve block, the historical context of the presacral neurectomy amongst gynecologic surgeons who care Patients with midline pelvic pain, Superior hypogastric nerve block with for chronic pelvic pain, the Sims et al., 2019, Not defined endometriosis, and dysmenorrhea bupivacaine, epinephrine, dexamethasone Not provided progress being made in ERAS US66 (0%, age not provided) (not provided) protocols for gynecologic surgery services, and the extremely promising anecdotal experiencing for our institution, further study of this technique is warranted."

"Solutions of bupivacaine alone and n combination with a second local anesthetic or 45 Primiparas in active labor opioid provided useful • Group 1: Epidural bupivacaine, epidural analgesia in laboring • Group 1 (0%, mean 27.7 y ± Visual analog score, epinephrine (15) parturients. The combination Randomized, 6.7) onset time, duration, Sinatra et al., • Group 2: Epidural bupivacaine, of bupivacaine and fentanyl single-blind • Group 2 (0%, mean 28.7 y ± sensory block, motor 1991, US349 lidocaine, epinephrine (15) offered the longest duration of study 5) block, patient • Group 3: Epidural bupivacaine, analgesia and the lowest • Group 3 (0%, mean 27.7 y ± satisfaction epinephrine with fentanyl (15) frequency of shivering and 7) motor block. The combination of bupivacaine and lidocaine offered little clinical advantage over bupivacaine alone."

195

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

40 Patients undergoing major gynecological surgery Sinclair et al., • Group B (0%, mean 38.4 y ± • Group B: Extradural bupivacaine (10) "Etidocaine 1.5% and 0.75% Sensory and motor 1982, UK350 3.1) • Group BA: Extradural bupivacaine, bupivacaine, both with and Randomized, blockade, time • Group BA (0%, mean 44.9 y adrenaline (10) without adrenaline, are useful double-blind patient first ± 3.5) • Group E: Extradural etidocaine (10) additions to the local Sinclair et al., study complained of pain • Group E (0%, mean 38.2 y ± anaesthetic agents used for 1984, UK351 • Group EA: Extradural etidocaine, after operation 2.4) adrenaline (10) extradural blockade." • Group EA (0%, mean 44.6 y ± 3.3)

30 Patients scheduled for elective "Clonidine added to hand surgery under axillary All patients received brachial plexus block Onset time, time to mepivacaine for brachial brachial plexus anesthesia with mepivacaine, epinephrine: disappearance of plexus block increases the anesthesia, time to duration anesthesia and • Group A (40%, mean 39 y ± Singelyn et al., Randomized, onset of pain, analgesia by a local mode of 5) • Group A: Control (10) 1992, Belgium352 double-blinded maximum action. It also has no effect on • Group B (30%, mean 43 y ± • Group B: Subcutaneous clonidine (10) postoperative pain the onset time of the block or 4) • Group C: Clonidine added to local before intake of on the intensity of the • Group C (60%, mean 51 y ± anesthetic solution (10) analgesic postoperative pain when it 3) appears."

196

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

80 Patients scheduled for elective hand surgery under axillary "This double-blind randomized brachial plexus anesthesia study shows that the minimum • Group A (40%, mean 39 y ± dose of clonidine required to All patients received brachial plexus block 18) prolong significantly the with mepivacaine, epinephrine, with duration of analgesia and • Group B (60%, mean 42 y ± increasing does of clonidine added to the 15) anesthesia after brachial plexus local anesthetic solution: Onset time, time to block with 1% mepivacaine • Group C (60%, mean 46 y ± • Group A: Clonidine 0 mcg/kg (10) return of with epinephrine is, 22) Singelyn et al., Randomized, • Group B: Clonidine 0.1 mcg/kg (10) temperature respectively, 0.1 and 0.5 • Group D (20%, mean 35 y ± 1996, Belgium353 double-blinded • Group C: Clonidine 0.2 mcg/kg (10) sensitivity, mcg/kg. If both durations must 19) • Group D: Clonidine 0.3 mcg/kg (10) postoperative pain be prolonged, we recommend • Group E (50%, mean 39 y ± • Group E: Clonidine 0.4 mcg/kg (10) score the addition of 0.5 mcg/kg 17) • Group F: Clonidine 0.5 mcg/kg (10) clonidine to the local • Group F (50%, mean 43 y ± • Group G: Clonidine 1 mcg/kg (10) anesthetic solution. At this 19) • Group H: Clonidine 1.5 mcg/kg (10) dose, clonidine may be used • Group G (20%, mean 43 y ± without important reported 17) adverse effects even in • Group H (70%, mean 42 y ± outpatients." 14)

"Our study suggests that pretreatment of uncomplicated Pain of lidocaine lacerations at the time of infiltration assessed patient presentation to the by patient or triage desk with LET or 60 Patients presenting for closure guardian on visual EMLA cream results in a Randomized, of uncomplicated lacerations Singer et al., 2001, • LET (29) analog scale and similar reduction in the pain of double-blind (median 8.5 y, range 1-59 y) US29 • EMLA (31) proportion of subsequent injection of clinical trial • LET (76%) lacerations that were lidocaine. Since it is less • EMLA (77%) adequately expensive and not anesthetized to a contraindicated in open needlestick wounds, we believe that LET is the preferred topical anesthetic."

197

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

Pain of lidocaine "Application of topical LET to infiltration assessed simple lacerations in healthy 43 Patients presenting for closure by patient or patients by nurses at the time of uncomplicated lacerations guardian on visual of triage is both feasible and Randomized, Singer et al., 2000, • LET (73%, median 12.5 y, • LET (22) analog scale and efficacious in reducing the double-blind US11 interquartile range 6-34.3) • Placebo: Epinephrine solution (21) proportion of pain of subsequent injection of clinical trial • Placebo (67%, median 13 y, lacerations that were lidocaine. This method may interquartile range 6.5-30.5) adequately also have the potential to anesthetized to a reduce the patient’s ED length needlestick of stay."

"In conclusion, a simple technique is described to perform an ONB using ultrasound guidance. No time 30 Patients scheduled for knee Performance time, is lost in localizing the nerve Preliminary, surgery under general Sinha et al., 2009, Obturator nerve block with ropivacaine, strength of thigh and optimizing the nerve observational anesthesia with nerve block for US462 epinephrine (30) adduction after stimulation current before local study postoperative analgesia (70%, injection anesthetic injection. The mean 50 y ± 16.4) success rate of obturator nerve blockade seems to be comparable to other studies of ONB using nerve stimulation."

198

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"The results of this study indicate that 1.5% etidocaine is an effective local anesthetic for minor surgical procedures in ambulatory patients. Its long duration of action makes it a logical candidate for use in prolonged dental procedures Inferior alveolar nerve block posterior, Surgeon-rated 42 Dental outpatients undergoing such as third molar removal, lingual nerve block, posterior superior quality of anesthesia, surgical removal of impacted third periodontal surgery, or Sisk et al., 1984, Random maxillary nerve block and maxillary intraoperative molars served as subjects at two extensive restorative work. US463 allocation infiltration with etidocaine, epinephrine or bleeding, global separate appointments. (33%, Etidocaine suppresses the lidocaine, epinephrine at first or second evaluation of clinical mean 19.7 y, range 16-24 y) intensity of postoperative pain appointment (42) efficacy alone and in combination with an oral analgesic. The only apparent limitation to its use is the high incidence of bleeding noted. In procedures where hemostasis is not a requirement, this may not be a limitation to its use.

"Patients experienced equal postoperative analgesia, whereas the femoral nerve block group sustained fewer 40 Patients undergoing unilateral • Intrathecal hyperbaric bupivacaine Pain on visual side effects, including nausea, total knee arthroplasty with morphine (20) analog scale, vomiting, and itching. Patients Prospective, Sites et al., 2004, • Intrathecal morphine (45%, • Intrathecal hyperbaric bupivacaine morphine receiving IT morphine were randomized US471 mean 65 y ± 9) with femoral nerve block with consumption, overall less satisfied, clinical study • Femoral nerve block (50%, ropivacaine, clonidine, epinephrine nausea, vomiting, or presumably attributable to IT mean 63 y ± 10) (20) itching opioid-induced adverse effects. Both techniques are insufficient to provide complete postoperative analgesia."

199

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"The aggressive nature of the tumor caused this bad outcome (brain death followed by care 33-year-old Female scheduled for For cesarean section, received epidural withdrawal). We suggest that Skiff et al., 2013, elective cesarean section, followed lidocaine, epinephrine, fentanyl; for Surgical anesthesia, epidural block may still be a Not defined US67 by craniotomy for removal of left postoperative pain, received epidural PCA postoperative pain viable option for parturients frontal lobe tumor with ropivacaine, fentanyl, epinephrine with intracranial tumors and normal ICP [intracranial pressure] admitted for labor and delivery."

Pain on visual "In conclusion extradural analog scale, Skjoldebrand et Healthy women with normal • Extradural pethidine (not provided) pethidine, with or without Randomized, duration of al., 1982, pregnancies (0%, age not • Extradural pethidine, adrenaline (not adrenaline, does not seem to double-blind analgesia, plasma Sweden355 provided) provided) provide a safe alternative to concentration of local anaesthetics in labour." pethidine

"The brachial plexus block is a very satisfactory anesthesia for surgery of the upper extremity in children. It provides excellent relaxation and complete freedom from pain. At the same time it makes it 150 Children receiving brachial possible to avoid the use of Small et al., 1951, Brachial plexus block with procaine, Not defined plexus block (sex not provided, Success of block general anesthesia in US464 tetracaine, epinephrine (150) range 15 months-12 y) circumstances in which general anesthesia is least desirable; e. g., in the outpatient department, after ingestion of food, in the presence of respiratory disease, when traumatic shock is present, and for long operations.”

200

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"We have confirmed that epidural administration of 102 Patients who had a cesarean • Group 1: Epidural saline, diamorphine is superior to section intramuscular diamorphine (21) intramuscular administration, • Group 1 (0%, mean 28.9 y, that the addition of adrenaline • Group 2: Epidural diamorphine 2.5 range 18-39) improves its overall length of mg, adrenaline, intramuscular saline Pain on visual • Group 2 (0%, mean 29.9 y, action and that a dose of 5 mg Randomized (22) analog scale, nausea, Smith et al., 1991, range 19-38) appears to confer no advantage double-blind • Group 3: Epidural diamorphine 5 mg, vomiting, itching, UK356 • Group 3 (0%, mean 31.1 y, over 2.5 mg. Of the dose study adrenaline, intramuscular saline (17) time to next requests range 23-41) regimens we studied, we • Group 4: Epidural diamorphine 5 mg, for analgesia • Group 4 (0%, mean 30.4 y, conclude that epidural intramuscular saline (22) range 24-35) diamorphine 2.5 mg with • Group 5: Epidural diamorphine 2.5 • Group 5 (0%, mean 30.6 y, adrenaline 1/200 000 provides mg, intramuscular saline (20) range 18-39) the optimum choice for postoperative analgesia in this group of patients."

"Adding 0.5 M mannitol to 127.2 mg lidocaine with 50 mcg epinephrine was significantly more effective in achieving a greater percentage Prospective Pain of solution of total pulpal anesthesia than 40 Patients receiving inferior Inferior alveolar nerve block with lidocaine, Smith et al., 2013, randomized, deposition, pain with a 127.2 mg lidocaine with 50 alveolar nerve blocks (42%, epinephrine or lidocaine, epinephrine, US357 single-blind, electric pulp tester, mcg epinephrine formulation average 24 y, range 19-31) mannitol at two separate appointments (40) crossover post-injection survey without mannitol. Injection pain and postinjection pain were not statistically different between the lidocaine/mannitol formulation and the lidocaine formulation without mannitol."

201

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"The time to surgical readiness did not significantly differ when using LAF [lidocaine/adrenaline/fentanyl], 0.75% ropivacaine and 0.5% 90 Parturients undergoing urgent levobupivacaine to extend a caesarean section pre-existing labour analgesic Randomized • Epidural lidocaine, adrenaline, block. A single drug such as • Lidocaine/adrenaline/fentanyl Pain on visual Sng et al., 2008, double-blinded fentanyl (30) ropivacaine or levobupivacaine (0%, mean 30 y ± 5) analog score, Singapore358 controlled • Epidural ropivacaine (30) provided adequate surgical • Ropivacaine (0%, 29 y ± 6) duration of block clinical trial • Epidural levobupivacaine (30) anaesthesia and may reduce • Levobupivacaine (0%, 31 y ± the potential for mistakes in 6) preparing drug mixtures. Ropivacaine 0.75% and 0.5% levobupivacaine are suitable alternatives for extending labour analgesia for urgent caesarean section.”

"This study suggests that administering an epidural bolus in the modified supine position is preferred because of a more equal spread of the 66 Parturients who requested Epidural block with bupivacaine, Extent of sensory local anesthetic solution, less Soetens et al., epidural analgesia epinephrine, fentanyl with patient block, incidence of asymmetrical sensory block 2003, The Not defined • Left lateral (0%, 27 y ± 4) randomized to following positions: bilaterally blocked and better analgesia. This may Netherlands359 • Modified supine (0%, 27 y ± • Left lateral (34) dermatomes, pain on be at the expense of a higher 4.3) • Modified supine (32) visual analog scale incidence of the supine hypotensive syndrome, but this is clinically not detrimental, as it is easily treated by turning the parturient on her side."

202

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"This study demonstrates that the addition of a small dose of Total amount of epinephrine to an infusion of 67 Parturients in active early labor Patients received epidural with loading study solution, levobupivacaine plus Prospective, Soetens et al., • Levobupivacaine/sufentanil/ dose, then patient-controlled infusion or: number of sufentanil intensifies the randomized, 2006, The epinephrine (0%, 28 y ± 4) • Levobupivacaine, sufentanil, parturients who analgesic effects during double-blind Netherlands360 • Levobupivacaine/sufentanil epinephrine (34) received rescue epidural labor analgesia. study (0%, 29 y ± 4) • Levobupivacaine, sufentanil (33) dose, pain on visual However, further study is analog scale required to evaluate its effect on motor blockade and neonatal outcome."

"In conclusion, a motor- sparing block is a feasible analgesic modality for patients 82 Patients scheduled to undergo • Motor-sparing adductor canal block, undergoing primary TKA. In posterior pericapsular injection and the context of background elective primary total knee lateral femoral cutaneous nerve block multimodal analgesia, motor- arthroplasty Sogbein et al., Randomized, with ropivacaine, epinephrine, Duration of sparing blocks provide a • Motor-sparing block (32%, 2017, Canada361 blinded study morphine, ketorolac (41) analgesia significantly longer duration of mean 68 y ± 8) • Periarticular infiltration with analgesia than periarticular • Periarticular infiltration (37%, ropivacaine, epinephrine, morphine, infiltration while preserving mean 63 y ± 9) ketorolac (41) muscle function and not negatively affecting length of stay, satisfaction, side effects, or functional rehabilitation."

203

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"…dexmedetomidine was similar to epinephrine in its 30 Patients scheduled for upper effect on extending the Patients received brachial plexus block limb surgery and brachial plexus duration of nerve block and with: block Sensory block post-operative analgesia. • Group C (control): Mepivacaine (10) duration, motor However, because epinephrine • Group C (80%, mean 48 y ± Song et al., 2014, • Group E: Mepivacaine, epinephrine block duration, time and dexmedetomidine have Randomized 13.7) South Korea362 (10) to sense pain, and opposite effects on heart rate, • Group E (80%, mean 39.5 y ± • Group D: Mepivacaine, onset time were dexmedetomidine is 13.5) dexmedetomidine (10) assessed. considered to be a good • Group D (80%, mean 38 y ± alternative as an adjuvant to 13.4) local anesthesia in patients in whom epinephrine must be used with caution."

"Somatic paravertebral block (SPVB) use in children appears to offer improved postoperative analgesia with fewer side effects than morphine. In light of recent advances in ultrasound and 36 Children undergoing nerve stimulator guidance used Prospective open appendectomy Postoperative • Group I: Somatic paravertebral block during SPVB, the technique Splinter et al., randomized • Group I (56%, mean 10.1 y ± morphine with ropivacaine, epinephrine (18) may indeed become more user- 2010, Canada363 controlled 3) requirements in the • Group II: Control, no block (18) friendly and thus more popular study • Group II (61%, mean 10.6 y ± first 24 hours in the coming years. At 2.9) present, this method is not used often in children; nevertheless, it is a worthwhile simple and effective alternative to provide improved patient recovery patterns in the pediatric population."

204

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"LIA with intra-articular ketorolac and morphine was superior to continuous epidural 99 Patients undergoing total knee analgesia after TKA [total arthroplasty knee arthroplasty] regarding pain scores at rest beyond 24 h • Epidural analgesia (EDA) • EDA: Epidural fentanyl, epinephrine, after surgery, and also knee (33%, mean 65.8 y ± 10.1) bupivacaine infusion (33) Pain on visual function and rehabilitation. • Local infiltration analgesia • LIA: Local infiltration with Prospective, analog scale and Patients were more satisfied (LIA) (39%, mean 67.2 y ± ropivacaine, epinephrine, ketorolac, Spreng et al., randomized, verbal scale at rest during the first 2 days after 8.9) morphine (33) 2010, Norway364 double-blinded and flexion of the operation and could be study • Local infiltration analgesia • LIAiv: Local infiltration with knee, overall patient discharged earlier from the with IV placebo (LIAiv) ropivacaine, epinephrine and satisfaction hospital. Side-effects were (39%, mean 66.5 y ± 11) intravenous ketorolac and morphine more common in patients (33) getting epidural analgesia, and no serious adverse events were seen in the LIA patients. Local administration of ketorolac and morphine had a specific local effect."

"Our preliminary data suggest that methylprednisolone can • Axillary block with mepivacaine, Number of pain pills increase the duration of Surgical patients who required bupivacaine, epinephrine (not used on day of sensory and motor block. Stan et al., 2004, long-acting axillary blockade for provided) surgery and next 2 Pilot study Although we relied on the US68 upper extremity procedures (sex, • Axillary block with mepivacaine, days, duration of patients to determine the age not provided) bupivacaine, epinephrine, sensory and motor duration of their block, the methylprednisolone (not provided) block results from the questionnaires were consistent."

205

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"Our modification of the fascia iliaca compartment block had a statistically significant 44 Patients scheduled for morphine-sparing effect post unilateral total hip arthroplasty • Control: Modified fascia iliaca unilateral THA in the first 24 Randomized, under lumbar subarachnoid block compartment block with saline (22) hours. We hypothesise that the Stevens et al., 24-Hour morphine double-blind • Control (50%, mean 66.8 y ± • Trial: Modified fascia iliaca probable mechanism for this 2007, Australia365 consumption study 9.1) compartment block with bupivacaine, effect is via blockade of the • Trial (68%, mean 68.7 y ± adrenaline, clonidine (22) ilioinguinal, iliohypogastric 9.7) and genitofemoral nerves as well as the femoral, lateral cutaneous and obturator nerves."

Time to analgesia, 40 Patients undergoing lower • Control: epidural 2-chloroprocaine, time to anesthesia, extremity surgery pH adjustment of 2- Randomized, epinephrine (not provided) time to maximum Stevens et al., • Control (sex not provided, chloroprocaine resulted in a double-blind • pH-Adjusted: epidural 2- hypaesthesia, time to 1989, US367 mean 28 y ± 9) decreased latency of epidural study chloroprocaine, epinephrine, sodium regression of • pH-Adjusted (sex not anesthesia. bicarbonate (not provided) maximum provided, mean 33 y ± 8) hypaesthesia

"The addition of dextran to 2- • Paracervical block with 2- CP significantly prolongs the 36 Parturients receiving chloroprocaine, epinephrine (19) Patient-reported Strauss et al., duration of PCB [paracervical Not defined paracervical block during labor • Paracervical block with 2- pain, duration of 1979, US368 block] anesthesia and does not (0%, range 18-34 y) chloroprocaine, epinephrine, dextran pain relief appear to compromise the (17) fetus."

141 Patients scheduled for hand • Group A: Conventional axillary plexus "Ultrasound-guided plexus surgery distal to the elbow block with bupivacaine, epinephrine, Prospective, Number of anaesthesia is markedly more Strub et al., 2011, • Group A (68%, range 17-88 mepivacaine (71) randomized successful anesthetic effective than the blind Switzerland369 y) Group B: Ultrasound-guided axillary study procedures technique when performed by • Group B (66%, range 16-89 plexus block with bupivacaine, a hand surgeon." y) epinephrine, mepivacaine (70)

206

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

99 Patients scheduled to receive "We conclude that the sciatic nerve block as a infragluteal-parabiceps Sukhani et al., component of their anesthesia Sciatic nerve block with levobupivacaine, Rate of complete approach to SNB [sciatic nerve Not defined 2003, US69 management for elective epinephrine (99) block block] is reliable, efficient, reconstructive ankle surgery safe, and well tolerated by (62%, mean 43 y ± 16) patients."

94 Patients undergoing elective • Epidural bupivacaine, adrenaline ± "We feel that epidural Sutherland et al., Prospective lower segment cesarean section lidocaine, adrenaline (47) Incidence of pethidine 25 mg is a useful 1991, UK370 study, random under epidural anesthesia (0%, • Epidural bupivacaine, adrenaline, shivering adjunct to epidural anaesthesia age not provided) pethidine ± lidocaine, adrenaline (47) for elective caesarean section."

"This randomized, active- 100 Patients presenting for breast Randomized, controlled study suggests that surgery subject- Pain score, opioid PVBs [paravertebral blocks] • Erector spinae plane block • Erector spinae plane block with blinded, active- requirements, compared with ESPBs [erector Swisher et al., (0%, median 54.5 y, ropivacaine, epinephrine (50) controlled, antiemetic spinae plane blocks] provide 2020, US371 interquartile range 48-63.8) • Paravertebral block with ropivacaine, parallel-design administration, sleep improvements in short-term • Paravertebral block (0%, epinephrine (50) clinical disturbance perioperative analgesia median 54.5 y, interquartile trial following non-mastectomy range 44-67.8) breast surgery."

"Patient-administered intravenous naloxone All patients received epidural lidocaine, enhanced patient control of fentanyl, epinephrine for surgery and treatment of epidural fentanyl- epidural patient-controlled analgesia with Visual analog pain induced itching and decreased 194 Patients scheduled for elective ropivacaine, fentanyl, epinephrine for scores, itching score, the need for hospital staff Syed et al., 2013, Not defined cesarean section (0%, age not postoperative pain; randomized to receive: overall satisfaction intervention. The greater US465 provided) • Patient-administered intravenous and satisfaction from amount of naloxone used by naloxone (96) naloxone treatment the self-administered group is • Nurse-administered intravenous strongly suggestive of the need naloxone (98) to treat itching in patients who receive epidural-PCA fentanyl for post cesarean section pain."

207

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"Injecting 10 mL of 0.5% Patients received sciatic nerve block, bupivacaine or 0.5% Prospective 139 Patients scheduled for total randomized into 14 groups to receive Sensory and motor ropivacaine below CIEL Szczodry et al., double-blind knee arthroplasty (sex, age not bupivacaine, epinephrine or ropivacaine, block, duration of [common investing extraneural 2013, US372 randomized provided) epinephrine in volumes ranging from 2.5 block layer] produces duration of study mL to 30 mL sensory and motor blockade as volumes as large as 30 ml."

"The usage of epinephrine has 60 Patients admitted for thoracic caused less nausea and easier • Group A: Epidural bupivacaine, Prospective surgery Intraoperative vitals, mobilization. While there was sufentanil during surgery (20) randomized • Group A (sex not provided, postoperative pain a beneficial effect of the Taleska et al., • Group B: Epidural saline during interventional mean 58.6 y ± 4.6) on visual analog reduced intraoperative 2010, surgery (20) clinical • Group B (sex not provided, scale, rate of anesthetic requirements, any Macedonia373 • Group C: Epidural bupivacaine, double-blind mean 60.6 y ± 5.8) postoperative lasting effect of preemptive sufentanil, epinephrine during surgery study • Group C (sex not provided, epidural infusion analgesia did not extend (20) mean 57.9 y ± 3.9) beyond eight hours after the operation."

All patients received brachial plexus block 90 Patients undergoing upper with lidocaine, bupivacaine, epinephrine, extremity surgery randomized to different approaches: • Group A (73%, mean 31.13 y "The axillary brachial plexus • Group A: Transarterial fixation Onset of block, Tamilselvan et al., ± 13.66) block is a safe technique for Not defined technique (30) success rate, extent 1998, India374 • Group B (67%, mean 30.26 y patients undergoing outpatient • Group B: Paresthesia elicitation to of block ± 14.34) upper extremity surgery." localize nerves (30) • Group C (70%, mean 31.41 y • Group C: Use of peripheral nerve ± 9.43) stimulator to localize nerves (30)

208

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"Alkalinization of mepivacaine to near physiologic pH elevates the pCO2 of the Time to sensory and solution and significantly Tetzlaff et al., 39 Patients scheduled for hand All patients received axillary brachial motor onset, decreases the latency to onset 1993, US375 surgery Randomized, plexus block, randomized to: duration of of sensory and motor • Study (37%, mean 53.1 y ± blinded, • Study: Mepivacaine, epinephrine, tourniquet inflation, anesthesia." 9.8) Tetzlaff et al., clinical study sodium bicarbonate (19) time at tourniquet • Control (55%, mean 43.9 ± "Alkalinization of mepivacaine 1994, US376 Control: Mepivacaine, epinephrine (20) pain, number with 6.8) for axillary brachial plexus tourniquet pain anaesthesia may be indicated in cases where use of pneumatic tourniquet for long periods is planned."

Patients received interscalene brachial "Interscalene anesthesia is an 563 Patients who received plexus blocks with: effective anesthetic for elective Tetzlaff et al., interscalene brachial plexus block • Mepivacaine (480) Intraoperative blood shoulder surgery that may Retrospective 1994, US70 for surgical procedures of the • Bupivacaine 0.5% (33) loss decrease intraoperative blood shoulder (sex, age not provided) • Bupivacaine 0.625% (50) loss with a loss complication Epinephrine was added to 496 of the blocks rate."

40 Patients scheduled for elective All patients received brachial plexus block, "Alkalinization of mepivacaine open-shoulder surgery Prospective, randomized to: Motor block as rate improves the quality of motor Tetzlaff et al., • Study (65%, mean 52.5 y ± randomized • Study: mepivacaine, epinephrine, by blinded observer block after interscalene 1995, US377 10.5) trial sodium bicarbonate (20) and surgeon brachial plexus for shoulder • Control (35%, mean 52.9 y ± Control: mepivacaine, epinephrine (20) surgery." 11.6)

"Alkalinization of mepivacaine All patients received interscalene brachial to a pH of near its pKa 40 Patients undergoing elective plexus block, randomized to: Tetzlaff et al., Onset of sensory and increases the speed of onset of Not defined shoulder surgery (sex, age not • Study: mepivacaine, epinephrine, 1990, US378 motor block interscalene block for shoulder provided sodium bicarbonate (20) surgery without affecting the Control: mepivacaine, epinephrine (20) duration of the block."

209

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"This study demonstrated a lower incidence of tourniquet • Group I: Spinal anesthesia with pain with spinal anaesthesia bupivacaine, epinephrine (20) Level of block and than with epidural anaesthesia 60 Patients undergoing orthopedic • Group II: Epidural anesthesia with Tetzlaff et al., time to onset, to the same sensory level. Not defined procedures of the lower extremity mepivacaine, epinephrine (20) 1993, US379 incidence of However, this advantage is (sex, age not provided) • Group III: Epidural anesthesia with tourniquet pain eliminated if the epidural mepivacaine, epinephrine, bicarbonate anaesthetic was performed (20) with an alkalinized local anaesthetic."

"The use of dexmedetomidine 0.5 μg/kg and 1 μg/kg as an adjuvant to lignocaine with Patients received axillary brachial plexus adrenaline (1:200000) in 90 Patients undergoing forearm block with: transarterial axillary brachial surgery plexus block increases the Prospective • Group L (60%, mean 29.27 y duration of sensory, motor • Group L: Lidocaine, epinephrine (30) Onset, quality and Thakur et al., randomized ± 11.6) blockade and decreases as well • Group LD : Lidocaine, epinephrine, duration of sensory 2017, India380 controlled • Group LD (63%, mean 0.5 as delays the requirement of 0.5 dexmedetomidine 0.5 mcg/kg (30) and motor block study 34.27 y ± 15.37) rescue analgesia • Group LD : Lidocaine, epinephrine, • Group LD (70%, mean 1.0 postoperatively without 1.0 dexmedetomidine 1.0 mcg/kg (30) 32.56 y ± 13.26) causing any side effects as compared to control group, maximum benefit being observed with addition of 1 μg/kg dexmedetomidine."

210

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

• Group RB: Axillary brachial plexus block with bupivacaine, lidocaine, "Buprenorphine 2 μg/kg in 67 Patients scheduled for upper epinephrine, buprenorphine and axillary plexus block provides limb surgery intramuscular saline (22) Prospective, Quality and duration significantly prolonged • Group RB (50%, mean 28.36 • Group SB: Axillary brachial plexus randomized, of sensory and motor analgesia with less RA Thakur et al., y ± 4.45) block with bupivacaine, lidocaine, double-blind, block, pain on visual requirement and greater patient 2015, India381 • Group SB (43%, mean 28.22 epinephrine and intramuscular controlled analog scale, satisfaction compared to IM y ± 3.41) buprenorphine (23) study sedation administration. This is highly • Control (59%, mean 26.27 y • Control: Axillary brachial plexus block suggestive of action on ± 3.58) with bupivacaine, lidocaine, peripheral opioid receptors." epinephrine and intramuscular saline (22)

"The duration of analgesia in the clonidine group was prolonged by 45 minutes when compared to adrenaline group Thirty patients were given 20 mL of and was statistically highly 60 Patients who underwent epidural lignocaine with clonidine Thankraj et al., Double-blind Compare duration of significant (p = 0.000). elective surgery of the lower 1:200,000 (preservative free) and the other 1997, India475 study analgesia Clonidine provides a stable abdomen thirty patients were given 20 mL of cardiovascular system with lignocaine with adrenaline 1:200,000. lesser side effects and intraoperative sedation thereby avoiding the need for supplement sedations."

"These findings suggest that All patients received sciatic nerve block in anatomic differences of the Prospective, Patients scheduled to undergo the popliteal fossa with mepivacaine, Procedural time, Thomas et al., nerve have a more important randomized outpatient lower extremity surgery epinephrine and ropivacaine using either onset of sensory and 2011, US382 role in the onset of blockade study (sex, age not provided) nerve stimulation or ultrasound-guidance motor block rather than the medical tool (not provided) utilized to perform the block."

211

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"I recommend the addition of 15 IU hyaluronidase/ml to 2% • Group A: Retrobulbar nerve block lignocaine with adrenaline Thomson et al., 150 Patients undergoing surgery with lidocaine, epinephrine (75) Success or failure of Double-blind 1/100 000 for retro- 1988, for senile cataracts (sex, age not • Group B: Retrobulbar nerve block anesthesia, grade of trial bulbar blocks as an aid to Zimbabwe383 provided) with lidocaine, epinephrine, anesthesia achieving complete ocular hyaluronidase (75) akinesia and anaesthesia in cataract surgery."

There is a "potential for total Tian et al., 2016, 30-year-old female with severe Epidural infusion with bupivacaine, spinal to occur in an infusion Case report N/A US71 preeclampsia in labor epinephrine, fentanyl epidural after a bolus of medication."

"Peri- and intraarticular • Group F: Continuous femoral nerve 77 Patients undergoing total knee Opioid consumption, application of analgesics by block with ropivacaine (37) arthroplasty pain on numeric infiltration and bolus injections Toftdahl et al., Randomized • Group I: Peri- and intra-articular • Group F (41%, mean 72 y ± rating scale, can improve early analgesia 2007, Denmark384 clinical trial infiltration and injection with 9) mobilization in and mobilization for patients ropivacaine, ketorolac, epinephrine • Group I (38%, mean 70 y ± 9) postoperative period undergoing TKA [total knee (40) arthroplasty]."

"When ultrasound-guided subgluteal sciatic nerve block is conducted, multiple Sciatic nerve block with mepivacaine, injection of LA to make a Tomozawa et al., Prospective, 86 Patients undergoing knee epinephrine in: Sensory and motor circumferential spread around 2013, Japan385 randomized surgery (sex, age not provided) • Circumferential injections (43) block the sciatic nerve results in a • Non-circumferential injections (43) more rapid onset of sensory and motor blockade as compared with a single injection technique."

212

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"The addition of clonidine to 33 Children undergoing bupivacaine significantly • Treatment: Caudal block with Pain scores, ureteroneocystostomy increases the duration of Double-blind, bupivacaine, epinephrine, clonidine morphine Tripi et al., 2005, • Treatment (11%, mean 59 caudal analgesia and decreases prospective (18) requirements, US386 months ± 30.4) postoperative morphine trial • Control: Caudal block with duration of caudal • Control (20%, mean 67.6 requirements in children bupivacaine, epinephrine (15) analgesia months ± 30.5) undergoing ureteroneocystostomy."

"Our results demonstrate that local infiltration analgesia is • Local infiltration: Femoral nerve block beneficial in reducing length of 83 Patients undergoing primary with ropivacaine, epinephrine and stay and postoperative pain total knee arthroplasty local peri- and intra-articular scores. We recommend local Tripuraneni et al., Consecutive • Local infiltration (93%, infiltration with ropivacaine, ketorolac, Postoperative pain, infiltration analgesia in 2011, U72S series average 65.9 y) epinephrine (40) length of stay conjunction with a single- • Control (91%, average 65.2 • Control: Femoral nerve block with injection femoral nerve block y) ropivacaine, epinephrine, as an alternative for the methylprednisolone (43) multimodal pain control approach in the TKA [total knee arthroplasty] patient."

All patient received single-injection sciatic "This study demonstrates that nerve block with bupivacaine, clonidine, an SACB [single-injection epinephrine and: adductor canal block] utilizing Double- 60 Patients scheduled for primary • Single-injection adductor canal block bupivacaine with multiple blinded, unilateral TKA Movement pain (SACB): Bupivacaine, clonidine, adjuvants provides equivalent Turner et al., randomized, • SACB (70%, mean 68.8 y ± scores at 30 hours dexamethasone, buprenorphine, analgesia to a CACB 2018, US387 controlled, 10) using the numeric epinephrine and postop saline infusion [continuous adductor canal equivalency • CACB (43%, mean 70.9 ± rating scale (NRS) (30) block] up to, and possibly trial 7.9) • Continuous adductor canal block beyond, 30 hours for (CACB): Bupivacaine, epinephrine perioperative analgesia in with postop bupivacaine infusion (30) patients undergoing a TKA."

213

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

85 Patients undergoing a Prospective, unicompartmental knee Adductor canal block with: randomized, arthroplasty "Dexamethasone 4 mg, but not dose- • Dexamethasone 1 mg: Bupivacaine, Block duration 1 mg, prolonged the duration • Dexamethasone 1 mg (53%, Turner et al., dependent, epinephrine, dexamethasone 1 mg (36) determined by serial of an ACB [adductor canal mean 62.8 y ± 8.7) 2018, US388 placebo- • Dexamethasone 4 mg: Bupivacaine, neurologic pinprick block] when measured by • Dexamethasone 4 mg (58%, controlled epinephrine, dexamethasone 4 mg (37) examinations. serial neurologic pinprick mean 63.3 y ± 8.9) equivalency • Control: Bupivacaine, epinephrine (12) exams." trial • Control (25%, mean 59.2 y ± 9.1)

"Large reductions in standard pulmonary function tests Sensory and motor occurred in all patients 30 Patients received interscalene brachial block, minutes after interscalene Prospective, 20 Patients schedule to have Urmey et al., plexus block with either 20 mL or 45 mL of ultrasonography of block with 1.5% mepivacaine randomized elective shoulder surgery (75%, 1993, US389 mepivacaine, epinephrine, sodium the diaphragm, with epinephrine. Reducing the study mean 42 y ± 16.4) bicarbonate pulmonary function volume of local anesthetic testin from 45 mL to 20 mL had little beneficial effect on the adverse effects of interscalene block."

"A single dose of dexamethasone and buprenorphine can provide 60 Patients undergoing upper arm Patients received brachial plexus block good quality postoperative surgeries with: Duration of analgesia lasting for several Vadhanan et al., Randomized, • Group B (60%, mean 37.6 y ± • Group B: Lidocaine, bupivacaine, postoperative hours with minimal adverse 2018, India390 controlled trial 10.6) epinephrine, buprenorphine (30) analgesia on visual effects. Large scale studies • Group D (50%, mean 35.4 y • Group D: Lidocaine, bupivacaine, analog scale with different dosages and ± 9.9) epinephrine, dexamethasone (30) extended follow-up periods might provide further insight regarding their routine usage in daily practice."

214

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"We report a case where we were able to use regional Bilateral saphenous nerve blocks with anesthesia to provide safe and 40-year-old Female with Vaid-Pinyard et ropivacaine, epinephrine and ropivacaine effective acute pain control, Case report nonfreezing cold-induced injury Pain relief al., 2015, US391 infusion through bilateral popliteal sciatic minimize opioid consumption, (immersion foot) nerve catheters and stop cold exposure to allow for healing of cutaneous lesions."

• Combined spinal epidural: Intrathecal bupivacaine, epinephrine, sufentanil "CSE [combined spinal 110 Parturients with term and (55) Pain on visual epidural] analgesia results in Van de Velde et Prospective, pregnancies • Epidural: Epidural bupivacaine, analog scale, excellent pain relief during al., 1999, randomized • Combined spinal epidural epinephrine, sufentanil (55) maternal heart rate labor with immediate Belgium392 comparison (0%, mean 30.1 y ± 1) All patients received patient-controlled and blood pressure gratification as compared to • Epidural (0%, 29 y ± 1) epidural analgesia with bupivacaine, epidural analgesia." epinephrine, sufentanil after initial dose

"CSE for labor pain relief 296 Parturients with • Epidural: Epidural bupivacaine, using 7.5 mcg of intrathecal uncomplicated pregnancies epinephrine, sufentanil (100) sufentanil results in a more Double-blind, • Epidural (0%, median 29 y, • BSE: Intrathecal bupivacaine, Van de Velde et frequent incidence of double interquartile range 27-32) epinephrine, sufentanil (98) Fetal heart rate al., 2004, nonreassuring FHR recordings placebo- • BSE (0%, median 29 y, abnormalities Belgium393 • Sufentanil: Intrathecal sufentanil (98) and uterine hyperactivity but controlled trial interquartile range 27-33) All patients received patient-controlled does not result in serious • Sufentanil (0%, median 29 y, epidural analgesia with bupivacaine, maternal and neonatal interquartile range 26-32) epinephrine, sufentanil after initial dose morbidity."

"Addition of clonidine 75 mcg Prospective, 58 Patients undergoing elective • Group C: Caudal block with to caudally administered local randomized, hemorrhoidectomy bupivacaine, lidocaine, epinephrine, Duration of Van Elstraete et anesthetics significantly double-blind, • Group C (47%, 44.7 y, range clonidine (30) analgesia, degree of al., 2000, prolonged the duration of placebo- 31-65) • Group S: Caudal block with motor block, France394 postoperative analgesia after controlled • Group S (54%, 49.1 y, range bupivacaine, lidocaine, epinephrine, sedation anal surgery in adults, with study 23-92) saline (28) minimal side effects."

215

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

Prospective, 34 Patients undergoing elective Patients received axillary brachial plexus "We failed to demonstrate any Duration of randomized, ambulatory carpal tunnel release block with: prolongation of postoperative Van Elstraete et analgesia, request double-blind, • Group N (39%, mean 54 y ± • Group N: Lidocaine, epinephrine, analgesia when neostigmine al., 2001, for supplementary placebo- 14) neostigmine (18) 500 mcg was added to France395 analgesia, pain on controlled • Group S (38%, mean 56 y ± Group S: Lidocaine, epinephrine, saline lidocaine for axillary brachial visual analog scale study 18) (16) plexus block."

"The 40% prolongation of analgesia achieved in this 107 Parturients who desired study when sufentanil was extradural analgesia for delivery • Group A: Extradural sufentanil 15 added to bupivacaine has Onset of analgesia, • Group A (0%, mean 27 y ± mcg, bupivacaine, adrenaline (37) practical advantages because Van Steenberge et patient evaluation of Double-blind 5.7) • Group B: Extradural sufentanil 7.5 "top-up" injections are al., 1987, efficacy of trial • Group B (0%, mean 26.6 y ± mcg, bupivacaine, adrenaline (36) required less frequently and Belgium396 analgesia, motor 4.7) the dose of bupivacaine is • Group C: Extradural bupivacaine, block at birth • Group C (0%, mean 28.3 y ± adrenaline (34) reduced. This means that 5.3) motor blockade is even less obvious than when 0.125% bupivacaine is used alone."

• Group A: Patient-controlled epidural "Patient-controlled epidural analgesia with bupivacaine, analgesia is an effective, safe Prospective, 59 Parturients who requested Vandermeulen et epinephrine, Quality and duration and acceptable alternative to randomized epidural analgesia al., 1995, sufentanil (29) of analgesia during conventional intermittent and controlled • Group A (0%, mean 28 y ± 4) Belgium397 Group B: Intermittent injections of labor epidural injections for pain study • Group B (0%, mean 29 y ± 4) bupivacaine, epinephrine, sufentanil relief during labor and (30) delivery."

97 Parturients with normal Surgeon-rated "Spinal anaesthesia is a good pregnancy at term undergoing • Group 1: Spinal with bupivacaine (50) Vegfors et al., muscle relaxation, alternative to epidural Randomized cesarean section (0%, age not • Group 2: Epidural with mepivacaine, 1992, Sweden398 patient-rated pain, anaesthesia for elective provided) epinephrine (47) nausea and vomiting caesarean section."

216

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

20 Patients undergoing abdominal surgery Pain at rest, on "The addition of adrenaline Double-blind • Group 1: Epidural sufentanil (10) Verborgh et al., • Group 1 (sex not provided, coughing and with significantly prolonged the randomized • Group 2: Epidural sufentanil, 1988, Belgium399 mean 48 y ± 5) active movement on duration of analgesia provided trial adrenaline (10) • Group 2 (sex not provided, linear analog scale by epidural sufentanil.” mean 49 y ± 4)

"This study demonstrates that levobupivacaine 0.125% and Patients received combined spinal-epidural 75 Parturients in early labor racemic bupivacaine 0.125%, analgesia with: Onset and duration in combination with a small Randomized, • Levobupivacaine (0%, mean Vercauteren et al., • Levobupivacaine: Levobupivacaine, of analgesia, total dose of sufentanil and double-blinded 29 y ± 5) 2001, Belgium400 epinephrine, sufentanil (37) epidural bupivacaine epinephrine, do not differ with study • Bupivacaine (0%, mean 30 y • Bupivacaine: Bupivacaine, epinephrine, administration respect to onset, duration, and ± 5) sufentanil (38) quality of analgesia when used for both intrathecal and epidural labor analgesia."

• Combined spinal-epidural (CSE): "The combined spinal-epidural Intrathecal bupivacaine, sufentanil, technique provided more epidural bupivacaine, epinephrine, effective analgesia during 113 Parturients in active labor at sufentanil (initial dose), then patient- Prospective, Onset of analgesia, labour than epidural analgesia full term pregnancy controlled epidural analgesia with Vernis et al., 2004, blinded, pain on visual alone but offered no other • CSE (0%, mean 27.6 y ± 4.2) bupivacaine, sufentanil (54) France401 randomized analog scale, advantages. It included more • Epidural (0%, mean 28.8 y ± • Epidural: Epidural bupivacaine, study duration of labor adverse effects and this should 4.8) epinephrine, sufentanil (initial dose), be considered before routinely then patient-controlled epidural using the combined spinal- analgesia with bupivacaine, sufentanil epidural technique." (59)

217

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

150 Parturients who requested epidural analgesia for labor Parturients received intermittent epidural "7.5 mcg sufentanil is the • Sufentanil 5 mcg (0%, mean Double-blind, injections of bupivacaine, epinephrine with: optimal dose to add to Vertommen et al., randomized, 28 y ± 4) Onset, duration and intermittent epidural injections • Sufentanil 5 mcg (not provided) 1994, Belgium467 prospective • Sufentanil 7.5 mcg (0%, quality of anesthesia of 10 mi 0.125% bupivacaine • Sufentanil 7.5 mcg (not provided) study mean 28 y ± 4) with adrenaline (1:800 000) for • Sufentanil 10 mcg (not provided) • Sufentanil 10 mcg (0%, mean pain relief in labour." 27 y ± 4)

60 Parturients scheduled for "The epidural injection of elective cesarean section Parturients received epidural bupivacaine, Patient-rated sufentanil added to 0.5% Randomized, anesthesia after bupivacaine with epinephrine • Control (0%, mean 28 y ± 4) epinephrine with: Vertommen et al., double-blind, surgery, duration of improved the quality of • Sufentanil 20 mcg (0%, mean • Control: Saline (20) 1991, Belgium402 prospective postoperative anesthesia during elective 30 y ± 4) • Sufentanil 20 mcg (20) study analgesia, Apgar cesarean section without • Sufentanil 30 mcg (0%, mean • Sufentanil 30 mcg (20) scores jeopardizing the safety of the 27 y ±6) baby."

"The epidural injection of sufentanil added to 0.125% bupivacaine with epinephrine Double-blind, 695 Parturients in labor • Control: Epidural bupivacaine, Onset time, duration (1:800,000) improved the randomized Vertommen et al., • Control (0%, mean 27 y ± 4) epinephrine (347) of analgesia, patient- quality of analgesia during prospective, 1991, Belgium403 • Sufentanil (0%, mean 29 y ± • Sufentanil: Epidural bupivacaine, rated quality of labor and reduced the multi-center 4) epinephrine, sufentanil (348) analgesia incidence of instrumental study deliveries without jeopardizing the safety of the baby or of the mother."

218

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"A group of anaesthetists with regular experience in perivascular axillary block had a frequency of 5.7% of 142 Patients subjected to acute or All patients received axillary block, unintended injection outside elective surgery of the upper randomized to different volumes of the neurovascular sheath, extremity anesthetic solution: causing total failure of blockade. An increase of Vester-Andersen • Group I (sex not provided, • Group I: 20 mL mepivacaine, Sensory and motor injected volume improves et al., 1983, Randomized mean 46 y ± 18) epinephrine (48) block at 30 min analgesia primarily in the area Denmark404 • Group II (sex not provided, • Group II: 40 mL mepivacaine, innervated by the axillary mean 41 y ± 15) epinephrine (48) nerve. The frequency of • Group III (sex not provided, • Group III: 80 mL mepivacaine, analgesia in the mean 44 y ± 17) epinephrine (46) musculocutaneous area was increased with an injected volume of 40 ml, but did not improve with a further increase of volume."

"An increase in the injected amount (200 mg, 400 mg, 600 mg) and concentration (0.5%, All patients received axillary block, 1%, 1.5%) of local anaesthetic 90 Patients subjected to elective randomized to different concentration of did not influence the sensory surgery of the upper extremity mepivacaine: blockade, but a distinct Not defined, • Group 1 (sex not provided, enhancement of the motor Vester-Andersen • Group 1: 40 mL mepivacaine 0.5%, patients mean 50 y ± 18) Sensory and motor blockade was noted. On the et al., 1984, epinephrine (not provided) randomly • Group 2 (sex not provided, blockade at 30 min basis of the results from the Denmark405 • Group 2: 40 mL mepivacaine 1%, allocated mean 39 y ± 17) present and a previous epinephrine (not provided) • Group 3 (sex not provided, investigation, it has been • Group 3: 40 mL mepivacaine 1.5%, mean 41 y ± 18) proved that an increase of the epinephrine (not provided) concentration of local anaesthetic results in an enhancement of the motor blockade."

219

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"An increase in volume extends the area of analgesia in the proximal direction. The incidence of analgesia in the All patients received axillary block, area innervated by the randomized to different volumes of musculocutaneous nerve is anesthetic solution: reduced if the injected volume Not defined, Vester-Andersen 90 Patients subjected to elective • Group I: 40 mL mepivacaine, Sensory and motor is less than 40 ml. An increase patients et al., 1984, surgery of the hand or forearm epinephrine (30) blockade at 20, 30 in concentration intensifies the randomly Denmark406 (71%, median 52 y, range 21-78) • Group 2: 50 mL mepivacaine, and 40 min motor blockade. An increase in allocated epinephrine (30) amount (mg) has no influence • Group 3: 60 mL mepivacaine, on the sensory or motor epinephrine (30) blockade - but a combined increase in volume and amount (mg) improves “the quality” of the sensory blockade of incomplete blockades."

"The effect of a supplementary perivascular dose of local All patients received axillary block with 50 anaesthetic could be judged as mL mepivacaine, epinephrine; patients with acceptable with regard to block failure at 20 minutes or incomplete intensifying an insufficient block at 30 minutes were randomly sensory blockade, but that it allocated to: was incapable of extending the • Supplementary: Additional injection of Not defined, blockade into areas which Vester-Andersen 229 Patients subjected to elective 20 mL mepivacaine, epinephrine (54) patients Sensory and motor were totally unblocked after et al., 1986, surgery of the upper extremity • Control: No supplementary injection randomly blockade the primary injection. On the Denmark407 (64%, not provided) (175)* allocated basis of a previous and the

present investigation, we have *Number of control patients includes suggested practical, simple patients with complete block at 20 and 30 guidelines which might help minutes and those with block failure or the anaesthetist in deciding on incomplete block who were allocated to no his course of action when supplementary injection faced with an inadequate axillary blockade."

220

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"Although caudal morphine 60 Pediatric patients undergoing may result in more sustained ureteral reimplantation Pain on Face, Legs, initial analgesia, caudal (ureteroneocystostomy) All patients received caudal block with Activity, Cry, clonidine combined with Random, Consolability nurse-controlled analgesia • Clonidine (15%, mean 42 ropivacaine, epinephrine and: Vetter et al., 2007, double-blind (FLACC) pain scale, appears to provide comparable months ± 20) • Clonidine (20) US408 prospective time to first analgesia with fewer side • Hydromorphone (5%, mean • Hydromorphone (20) study morphine dose, total effects. Based on these results, 46 months ± 22) • Morphine (20) amount of morphine the use of caudal clonidine • Morphine (15%, mean 41 in first 24 hours may be superior to caudal months ± 21) opioids after pediatric ureteral reimplantation."

Pain on verbal Patients received interscalene brachial 88 Patients scheduled for shoulder analog score, "The addition of plexus block with either: arthroscopy amount of dexamethasone to a Prospective, • Dexamethasone: Bupivacaine, Vieira et al., 2010, • Dexamethasone (59%, mean postoperative bupivacaine–epinephrine– randomized, epinephrine, clonidine, dexamethasone US409 51 y ± 10) analgesics required, clonidine interscalene block double-blind (44) • Control (75%, mean 48 y ± patient satisfaction prolongs sensory block and • Control: Bupivacaine, epinephrine, 12) with pain reduces opioid use." clonidine, saline (44) management

Patients randomized to receive: • Modified adductor canal block with "Pain scores, narcotic Randomized ropivacaine, epinephrine, morphine, consumption and Vijayashankar et 82 Patients scheduled for elective Time to first rescue equivalence ketorolac (not provided) physiotherapy outcomes are al., 2016, US410 TKA (sex, age not provided) analgesia trial • Periarticular infiltration with comparable between the two ropivacaine, epinephrine, morphine, modalities." ketorolac (not provided)

221

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"Supplemental IPACK [infiltration of local anesthetic between the popliteal artery All patients received either femoral nerve or and capsule of the knee] in adductor canal block/catheter with regional analgesia techniques 19 Patients who underwent Total morphine Vitter et al., 2017, Retrospective ropivacaine and epinephrine; 11 patients for patients undergoing ACL anterior cruciate ligament repair equivalents US73 study also received local infiltration of [anterior cruciate ligament] (sex, age not provided) consumption ropivacaine and epinephrine between the repair reduces total MEC popliteal artery and capsule of the knee [morphine equivalents consumption] and ambulatory surgery center discharge times."

"Addition of Tramadol to 60 Patients presenting for upper lignocaine resulted in early Patients received brachial plexus block limb surgery onset and prolonged duration with: of motor and sensory block as • Group I (85%, mean 36.2 y ± • Group I: Lidocaine, adrenaline (20) compared to group-I and III. Wakhlo et al., 7.62) Duration of sensory Randomized • Group II: Lidocaine, adrenaline, However addition of 2009, India411 • Group II (70%, mean 38.6 y block and pain relief tramadol (20) butorphanol to lignocaine ± 13.1) • Group III: Lidocaine, adrenaline, though has no effect on the • Group III (85%, mean 33.1 y butorphanol (20) onset and duration of block yet ± 10.8) it results in prolonged duration of post-operative pain relief."

"Continuous epidural block was used in the treatment of 15 Continuous epidural with procaine, patients who are believed to Walker et al., 15 Patients with pancreatitis (sex, epinephrine or lidocaine, epinephrine have had pancreatitis. Relief of Not defined Pain relief 1953, US74 age not provided) (number of patients who received each symptoms and apparently a combination not provided) favorable effect on the course of the disease was obtained in each instance."

222

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"Single-shot ACB [adductor canal block] combined with PCI [posterior capsular infiltration] can more effectively reduce postoperative pain after TKA 90 Patients undergoing unilateral • ACB + PCI: Adductor canal block and Postoperative pain Prospective, [total knee arthroplasty] primary total knee arthroplasty posterior capsular infiltration with as assessed by the Wang et al., 2019, double-blind, compared with local PIA • ACB + PCI (33%, mean 64.8 ropivacaine, epinephrine (45) visual analog scale China412 randomized [periarticular infiltration y ± 7) • PIA: Periarticular infiltration analgesia and consumption of controlled analgesia], without increasing • PIA (27%, mean 64 y ± 6.7) with ropivacaine, epinephrine (45) morphine the risk of complications. Based on these results, we propose that perioperative multimodal analgesia procedures for TKA patients should be further explored."

"In our study, there was a significant association between 1000 Patients undergoing postepidural backache and Prospective, hemorrhoidectomy • Group I: Epidural lidocaine, multiple attempts at epidural Wang et al., 1997, randomized, • Group I (60%, mean 33.7 y ± epinephrine (500) Incidence of post- needle insertion. In summary, China413 double-blind 16.2) • Group II: Epidural lidocaine, epidural backache epidural dexamethasone study • Group II (57%, mean 31.9 y epinephrine, dexamethasone (500) reduced the incidence and ± 17.5) severity of postepidural backache."

223

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"Rib cage expansion continues to contribute to tidal volume during high EA [epidural anesthesia] in most subjects, even when most of the muscles of the rib cage are paralyzed; the mean phasic electrical Respiratory muscle activity of unblocked Patients received either epidural lidocaine, activity, chest wall respiratory muscles such as Warner et al., 6 Healthy persons (83%, range 26- Not defined epinephrine (2) or etidocaine, epinephrine configuration, scalenes does not increase in 1996, US466 42 y) (4) functional residual response to rib cage muscle capacity paralysis produced by EA, and high EA increases the functional residual capacity, an increase produced in most participants by a caudal motion of the diaphragm and a decrease in interthoracic blood volume."

"Further confirmation of nerve catheter placement was obtained with patient experiencing significant pain control/VAS [visual analog score] score improvement before proceeding to the Continuous lateral sciatic catheter with Pain on visual Washington et al., 21-year-old male with injuries due operating room as well as Case report ropivacaine, epinephrine for initial dose, analog scale, 2011, US75 to improvised explosive device continued pain control both in ropivacaine for infusion narcotic use the PACU [post-anesthesia care unit] and for 6 days postoperative to include a repeat more extensive procedure until his departure for definitive management back in the United States."

224

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"The mean onset of action was 10.8 minutes for bupivacaine 104 Patients undergoing • Extradural bupivacaine, adrenaline and 14.5 minutes for Watt et al., 1970, gynecological or general (53) Onset and duration amethocaine. The duration of Randomized UK414 abdominal surgery (sex, age not • Extradural amethocaine, adrenaline of analgesia action, taken as the need for a provided) (51) post-operative opiate, was 423 minutes for bupivacaine and 334 minutes for amethocaine."

Postoperative pain scores, interval All patients received preoperative sciatic between initial 41 Patients undergoing total knee nerve block with bupivacaine, epinephrine; ropivacaine injection replacement randomized to receive preoperative femoral "Epinephrine does not Not defined, and first patient- Weber et al., 2001, • Ropivacaine, epinephrine nerve block and postoperative patient- influence the duration of random controlled analgesia Switzerland415 (29%, mean 75 y ± 6) controlled analgesia via femoral catheter analgesia of the ropivacaine allocation injection, interval • Ropivacaine (20%, mean 70 with: concentrations investigated." between first and y ± 9) • Ropivacaine, epinephrine (21) second patient- • Ropivacaine, saline (20) controlled analgesia injections

All patients received postoperative epidural analgesia initially with lidocaine, then randomized to top-ups with (number who “The optimum concentration received each not provided): of fentanyl with adrenaline in this trial was 2.5 mcg/ml but Randomized, 20 Patients scheduled for elective • Fentanyl 2.5 mcg/mL Onset time, time to Welchew et al., this concentration may still be double-blind upper abdominal surgery (80%, • Fentanyl 5 mcg/mL peak effect, duration 1983, UK416 a little too high as the upper study mean 46.3 y, range 23-65) • Fentanyl 10 mcg/mL of analgesia • Fentanyl 20 mcg/mL inflexion point on the shifted • Fentanyl 2.5 mcg/mL, epinephrine dose response curve was not • Fentanyl 5 mcg/mL, epinephrine demonstrated." • Fentanyl 10 mcg/mL, epinephrine

225

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"It remains unclear how much of the pain following complex All patients had saphenous and subgluteal ankle surgery is subserved by Prospective, sciatic catheters placed, which were initially the saphenous innervation. double-blind, 29 Patients undergoing major dosed with bupivacaine, epinephrine, Weller et al., Pain score at 48 High variability in pain scores randomized, ankle surgery (sex, age not clonidine; randomized to receive saphenous 2017, US417 hours and opioid use may have placebo- provided) infusion: masked any potential controlled trial • Saline (14) improvement due to • Ropivacaine (15) continuous saphenous nerve blockade."

30 Children undergoing Time to first rescue Patients randomized to receive caudal block outpatient surgical procedures analgesia, number of Prospective, with: "There were no differences in below the umbilicus patients requiring Wheeler et al., randomized, • Group C: Clonidine, bupivacaine, demographics, investigated • Group C (sex not provided, rescue analgesia at 2005, US418 double-blind epinephrine (15) parameters, or adverse effects mean 4.9 y ± 2.2) 4, 6, 8, 12 and 24 study Group NC: Bupivacaine, epinephrine between groups." • Group NC (sex not provided, hours after caudal (15) mean 4.1 y ± 1.6) block

"LAT gel appears to be a safe and effective means of providing anesthesia for the repair of simple finger Adequacy of 67 Children with a simple finger lacerations in children. It White et al., 2004, Prospective anesthesia, digital laceration requiring repair (66%, Topical application of LAT gel to wound appears particularly effective US33 case series ischemia, pain on mean 11.9 y) on the dorsal surface of the visual analog scale finger. LAT gel may provide a painless and effective alternative to infiltration anesthesia.'

226

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"A 1% diphenhydramine Subjects randomly received each of three solution should be used solutions in an inferior alveolar nerve block cautiously for the inferior alveolar nerve block. The Prospective, at three separate appointments: Willett et al., 30 Healthy adults (77%, average combination lidocaine, randomized, • Lidocaine, epinephrine Pain levels 2008, US419 26 y, range 20-29) diphenhydramine solution was crossover • Diphenhydramine, epinephrine irritating post-injection and • Lidocaine, epinephrine, was not as effective as a diphenhydramine lidocaine solution for pulpal anesthesia."

"The current study indicates Double-blind, 50 Patients undergoing surgery Brachial plexus block with: Onset and duration that motor block outlasts Winnie et al., randomized under brachial plexus anesthesia • Lidocaine, epinephrine (not provided) of sensory and motor sensory block, not only with 1984, US420 study (sex, age not provided) • Etidocaine, epinephrine (not provided) blockade etidocaine, but with all of the amide local anesthetic agents."

"A single-shot USG-PVB [ultrasound-guided paravertebral block] appears to 66 Patients undergoing be a safe and effective thoracoscopic lobectomy • Paravertebral block (PVB): Incidence of Randomized, technique to reduce the Wu et al., 2018, • PVB (65%, mean 58.2 y ± ropivacaine, epinephrine (34) postoperative controlled incidences of POSVT China431 7.8) • Intercostal nerve blocks (ICNB): supraventricular study [postoperative supraventricular • ICNB (59%, mean 56.5 y ± ropivacaine, epinephrine (32) tachycardia tachycardia] and atrial 8.3) fibrillation in patients undergoing thoracoscopic pulmonary resection."

227

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"TEA [thoracic epidural 28 Patients who underwent open analgesia] with bupivacaine and the addition of fentanyl Pooled renal surgery and epinephrine appear to analysis of • Bupivacaine (0%, median 61 Postoperative continuous thoracic epidural Difference in decrease MUCP [maximum open y, interquartile range 55-71) analgesia with: maximum urethral Wuethrich et al., urethral closure pressure] at observational • Bupivacaine, fentanyl (0%, • Bupivacaine (7) closure pressure at 2013, rest in women. The addition of study and median 63 y, interquartile • Bupivacaine, fentanyl (8) rest before and Switzerland421 fentanyl alone to bupivacaine double-blind range 55-70) during thoracic • Bupivacaine, fentanyl, epinephrine may reduce this effect. Thus, randomized epidural analgesia • Bupivacaine, fentanyl, (13) the TEA effect on urethral trial epinephrine (0%, median 65 function seems to depend on y, interquartile range 48-77) the drug mixture administered."

All patients received popliteal nerve block "No clinical benefit was 56 Patients scheduled for foot or with bupivacaine, epinephrine, clonidine; Number of hours obtained from perioperative Randomized, ankle surgery randomized to receive pre- and patient reported administration of pregabalin Yadeau et al., double-blind, • Placebo (36%, mean 61 y ± postoperative oral: moderate-severe (100 mg preoperative, then 50 422 2012, US placebo- 12) • Placebo (28) pain on numerical mg every 12 hrs) as part of a controlled trial • Pregabalin (39%, mean 60 y • Pregabalin (28) rating scale during multimodal postoperative ± 9) first 24 hours analgesic regimen following foot and ankle surgery."

"We report the first successful use of Pecs blocks to provide effective chest wall analgesia for a patient undergoing 78-year-old Male underwent minimally invasive cardiac Yalamuri et al., mitral valve repair via right Ultrasound-guided pectoral nerve blocks surgery with thoracotomy. We Case report Pain control 2017, US76 anterior thoracotomy for severe with ropivacaine, epinephrine believe that these blocks may mitral regurgitation provide an important nonopioid option for the management of pain during recovery from minimally invasive cardiac surgery."

228

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

"When ultrasound-guided subgluteal sciatic nerve block Yamamoto et al., 90 Patients scheduled for knee Patients randomized to receive subgluteal is conducted, multiple 2012, Japan424 Prospective, surgery sciatic nerve block with mepivacaine, injections of local anesthetic to randomized, • Group M (44%, mean 32 y ± epinephrine following techniques: Sensory and motor make a circumferential spread double-blind 14) • Group M: Multiple injections to create blockade Yamamoto et al., around the sciatic nerve study • Group S (51%, mean 37 y ± circumferential spread (43) 2014, Japan423 improve the rate of sensory 16) • Group S: Single injection (43) and motor blocks compared with a single injection.”

30 Patients undergoing elective "The combination of orthopedic, urological, or lower Patients randomized to receive extradural bupivacaine and ketamine for Onset of anesthesia, Randomized, abdominal surgery anesthesia with: extradural anesthesia may be Yanli et al., 1996, duration of double-blind • Bupivacaine (73%, mean • Bupivacaine, epinephrine (15) useful if the onset time and the Turkey425 postoperative study 37.9 y ± 16.2) • Bupivacaine, epinephrine, ketamine anesthetic level are important analgesia • Bupivacaine, ketamine (80%, (15) as may be the case for an mean 39 y ± 14.5) urgent procedure."

Patients randomized to receive epidural with: • Bupivacaine 0.125% (15) Pain on visual "The combination of • Bupivacaine 0.125%, epinephrine (15) analog scale, bupivacaine 0.125% with duration of adrenaline 1.25 Yau et al., 1990, Double-blind 90 Parturients in established labor • Bupivacaine 0.125%, epinephrine, analgesia, mcg/ml and fentanyl 50 mcg China426 comparison (0%, mean 27.4 y ± 4.5) fentanyl (15) • Bupivacaine 0.25% (15) maximum % gives good pain relief and is a • Bupivacaine 0.25%, epinephrine (15) reduction in pain suitable choice for obstetric score epidural analgesia." • Bupivacaine 0.25%, epinephrine, fentanyl (15)

229

Author, Year, Patient Population Primary Outcome Study Typea Intervention/Comparator (# of patients)b Authors’ Conclusions Country (% male, age) Measure

All patients received epidural labor "SA [spinal anesthesia] may 323 Parturients undergoing analgesia with ropivacaine, fentanyl, prior lower the failure rate of pain- cesarean section to surgery randomized to: free surgery, as well as the Prospective, Yoon et al., 2017, • Epidural (0%, mean 33.8 y ± • Epidural surgical anesthesia: lidocaine, Comparison of rate rescue analgesic requirement randomized South Korea427 3.5) fentanyl, epinephrine, sodium of pain-free surgery during intrapartum CS controlled trial • Spinal (0%, mean 34.3 y ± bicarbonate (163) [cesarean section] compared 3.4) Spinal surgical anesthesia: hyperbaric with ESA [epidural surgical bupivacaine, fentanyl (160) anesthesia]."

"A single dose of 4 mg epidural morphine sulfate, as compared with the same dose given intramuscularly, provided more profound and • Group A: Epidural saline, prolonged analgesia after Youngstrom et al., intramuscular morphine (12) cesarean section, through the 1982, US 428 • Group B: Epidural morphine, Post-operative pain onset of effect was delayed. Controlled, 42 Parturients undergoing intramuscular saline (12) levels, plasma The mean peak plasma double-blind caesarean section (0%, age not • Group C: Epidural morphine with concentration of concentration of morphine Yu et al., 1980, study provided) epinephrine, intramuscular saline (11) morphine base was significantly lower US429 • Group D: Epidural morphine, no after epidural morphine than intramuscular injection (7) after intramuscular morphine. Addition of epinephrine to epidural solutions did not significantly influence either analgesia or plasma morphine concentration."

"Adding epinephrine to QLB2 At the end of surgery, all patients received Chronological [quadratus lumborum block 2] 20 Parturients at term undergoing quadratus lumborum block 2 with: Zanfini et al., changes in venous lowered the peak of venous Not defined cesarean section under spinal • Ropivacaine alone (not provided) 2019, Italy430 local anesthetic ropivacaine concentration; this anesthesia (0%, age not provided) • Ropivacaine, epinephrine (not concentration could increase safety of block provided) in the obstetric population."

230

Abbreviations: FNB, femoral nerve block; IM, intramuscular; IV, intravascular; LET, lidocaine-epinephrine-tetracaine; LIA, local infiltration analgesia; PCA, patient-controlled analgesia; PCEA, patient-controlled epidural analgesia; VAS, visual analog scale; TAC, tetracaine-adrenaline-cocaine; THA, total hip arthroplasty; TKA, total knee arthroplasty. aAs defined by authors. bEpinephrine is also spelled as adrenaline or adrenalin; for accuracy, the substance name that the study authors used is presented in this table. Most studies did not specify the salt form, so bitartrate is not included unless the study specified use of this salt form.

231

Appendix 3.1. Single-agent survey instrument for medical associations

Welcome. We want to understand your clinical use of compounded epinephrine. Your feedback will help the Food and Drug Administration (FDA) develop a list of drugs that can be used in compounding by 503B outsourcing facilities. Your anonymous responses will be shared with the FDA. The time required to complete this survey is approximately 10-15 minutes. If you have additional questions or concerns about this study, please email: [email protected]. If you have questions about your rights as a research subject, please contact HRPO at 410-760-5037 or [email protected]. Thank you, Dr. Ashlee Mattingly Principal Investigator The University of Maryland School of Pharmacy An agency may not conduct or sponsor, and a person is not required to respond to a collection of information unless it displays a currently valid OMB control number. OMB Control No. 0910-0871 Expiration date: June 30, 2022

232

1. How familiar are you with the following terms?

Very familiar Somewhat familiar Not familiar Compounded drugs (medications prepared to o o o meet a patient-specific need)

503A Compounding pharmacy (a pharmacy that prepares compounded o o o medications prescribed by practitioners to meet a patient-specific need)

503B Outsourcing facility (a facility that compounds larger quantities without o o o the receipt of a patient- specific prescription)

2. Do you prescribe or administer epinephrine to your patients?

o Yes o No

3. Which salt form of epinephrine do you use?

o Epinephrine bitartrate o Epinephrine hydrochloride o Unsure o Other (please describe)

4. Do you prescribe or administer epinephrine by any of the following dosage forms and/or routes of administration? (check all that apply)

o Inhaled nasal spray o Injectable solution (epidural, perineural, intracaudal) o Topical cream o None of the above

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5. I prescribe or administer epinephrine for the following conditions or diseases: (check all that apply)

o Asthma o Anaphylaxis, hypersensitivity reaction o Bradycardia o Cardiac arrhythmias and/or arrest o Coagulation disorder o Excessive uterine contraction o Hypotension o Laryngotracheobrochitis o Local anesthetic o Mucosal or nasal congestion o Shock o Surgical bleeding o Other (please explain) ______

6. I use compounded epinephrine because: (check all that apply)

o Commercial products are not available in the dosage form, strength, or combination I need. (please explain) ______o Patient allergies prevent me from using commercially available products. (please explain) ______o Patient conditions prevent me from using commercially available products. (please explain) ______o There are no commercially available products containing epinephrine. o Other (please explain) ______

7. Do you stock non-patient-specific compounded epinephrine at your practice?

o Yes o No o I'm not sure

8. I obtain compounded epinephrine from the following: (check all that apply)

o Compound myself at my practice o Have the product compounded by an in-house pharmacy o Purchase, or have a patient purchase, from a compounding pharmacy o Purchase, or have a patient purchase, from an outsourcing facility o Other (please explain) ______

9. What is your practice setting? (check all that apply)

o Physician office/private practice o Outpatient clinic o Hospital/health system o Academic medical center o Emergency room o Operating room o Other (please describe) ______

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10. What degree do you hold? (check all that apply)

o Doctor of Medicine (MD) o Doctor of Osteopathic Medicine (DO) o Doctor of Medicine in Dentistry (DMD/DDS) o Doctor of Pharmacy (PharmD) or Bachelor of Science in Pharmacy (BS Pharm) o Naturopathic Doctor (ND) o Nurse Practitioner (NP) o Physician Assistant (PA) o Other (please describe) ______

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Appendix 3.2. Lidocaine / epinephrine / tetracaine survey instrument for medical associations

Welcome. We want to understand your clinical use of compounded lidocaine / epinephrine / tetracaine (LET). Your feedback will help the Food and Drug Administration (FDA) develop a list of drugs that can be used in compounding by 503B outsourcing facilities. Your anonymous responses will be shared with the FDA. The time required to complete this survey is approximately 10-15 minutes. If you have additional questions or concerns about this study, please email: [email protected]. If you have questions about your rights as a research subject, please contact HRPO at 410-760-5037 or [email protected]. Thank you, Dr. Ashlee Mattingly Principal Investigator The University of Maryland School of Pharmacy An agency may not conduct or sponsor, and a person is not required to respond to a collection of information unless it displays a currently valid OMB control number. OMB Control No. 0910-0871 Expiration date: June 30, 2022

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1. How familiar are you with the following terms?

Very familiar Somewhat familiar Not familiar Compounded drugs (medications prepared to o o o meet a patient-specific need)

503A Compounding pharmacy (a pharmacy that prepares compounded o o o medications prescribed by practitioners to meet a patient-specific need)

503B Outsourcing facility (a facility that compounds larger quantities without o o o the receipt of a patient- specific prescription)

2. Do you prescribe or administer lidocaine / epinephrine / tetracaine (LET) to your patients?

o Yes o No

3. Which salt form of epinephrine do you use?

o Epinephrine bitartrate o Epinephrine hydrochloride o Unsure o Other (please describe)

4. Do you prescribe or administer lidocaine / epinephrine / tetracaine (LET) by any of the following dosage forms and/or routes of administration? (check all that apply)

o Topical gel o Topical spray o None of the above

5. I prescribe or administer lidocaine / epinephrine / tetracaine (LET)the following conditions or diseases: (check all that apply)

o Local anesthesia o Other (please explain) ______

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6. I use compounded lidocaine / epinephrine / tetracaine (LET): (check all that apply)

7. Do you stock non-patient-specific compounded lidocaine / epinephrine / tetracaine (LET) your practice?

o Yes o No o I'm not sure

8. I obtain compounded epinephrine from the following: (check all that apply)

9. What is your practice setting? (check all that apply)

o Physician office/private practice o Outpatient clinic o Hospital/health system o Academic medical center o Emergency room o Operating room o Other (please describe) ______

10. What degree do you hold? (check all that apply)

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Appendix 3.3. Survey instrument for Ambulatory Surgery Center Association

Welcome. We want to understand your clinical use of compounded drugs. Your feedback will help the Food and Drug Administration (FDA) develop a list of drugs that can be used in bulk compounding by 503B outsourcing facilities. Your anonymous responses will be shared with the FDA. The time required to complete this survey is approximately 10-15 minutes. If you have additional questions or concerns about this study, please email: [email protected]. If you have questions about your rights as a research subject, please contact HRPO at 410-760-5037 or [email protected]. Thank you, Dr. Ashlee Mattingly Principal Investigator The University of Maryland School of Pharmacy An agency may not conduct or sponsor, and a person is not required to respond to a collection of information unless it displays a currently valid OMB control number. OMB Control No. 0910-0871 Expiration date: June 30, 2022

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1. How familiar are you with the following terms? Very familiar Somewhat familiar Not familiar Compounded drugs (medications prepared to o o o meet a patient-specific need)

503A Compounding pharmacy (a pharmacy that prepares compounded o o o medications prescribed by practitioners to meet a patient-specific need)

503B Outsourcing facility (a facility that compounds larger quantities without o o o the receipt of a patient- specific prescription)

2. Do you utilize a 503B outsourcing facility to acquire compounded drugs? o Yes. If yes, why? ______o No. If no, why not? ______

3. Do you obtain any of the following products from a 503B outsourcing facility? (check all that apply) o I do not obtain any compounded drugs from 503B outsourcing facilities o Amitriptyline / Ketoprofen / Oxymetazoline o Budesonide o Calcium gluconate o Droperidol o Epinephrine o Epinephrine for ophthalmic administration o Epinephrine / Lidocaine for ophthalmic administration o Epinephrine / Bupivacaine / Fentanyl o Fentanyl o Flurbiprofen o Flurbiprofen for ophthalmic administration o Hydromorphone o Ipamorelin o Ketoprofen / Nifedipine o Lidocaine / Epinephrine / Tetracaine HCl o Meperidine o Morphine o Naloxone o Neomycin o Phentolamine o Promethazine o Remifentanil

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o Sufentanil o Tramadol o None of the above

4. What type of specialty procedures are performed in your facility? (check all that apply) o Dental o Dermatology o Endoscopy o Neurosurgery o Obstetrics/gynecology o Ophthalmology o Otolaryngology o Orthopedics o Pain o Plastics o Podiatry o Other (please describe) ______

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Appendix 4. Survey distribution to professional associations

Agreed/Declined, Specialty Associationa Reason for Declining

American Academy of Allergy, Asthma, and Immunology Declined – survey not Allergy/Immunology (AAAI) approved

American Society of Regional Anesthesia and Pain Medicine Declined – failed to (ASRA) respond

Declined – failed to Anesthesia Society for Ambulatory Anesthesia (SAMBA) respond

Declined – failed to Society for Neuroscience in Anesthesiology and Critical Care respond

Declined – failed to Critical Care Critical Care Societies Collaborative respond

Declined – provided Academy of General Dentistry (AGD) interview referrals Dentistry & Oral Medicine Declined – failed to American Dental Association (ADA) respond

American Academy of Dermatology (AAD) Agreed Dermatology Declined – not American Osteopathic College of Dermatology (AOCD) interested

The Endocrine Society (ENDO) Agreed Endocrinology Pediatric Endocrine Society Agreed

Declined – failed to American Gastroenterological Association (AGA) respond Gastroenterology Declined – did not Obesity Medicine Association (OMA) have anyone to contribute to research

Declined – does not Hematology American Society of Hematology (ASH) distribute surveys

Declined – failed to Infectious Disease American Academy of HIV Medicine (AAHIVM) respond

Declined – failed to Medicine American Medical Association (AMA) respond

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American Association of Naturopathic Physicians (AANP) Agreed Naturopathy The Oncology Association of Naturopathic Physicians Agreed (OncANP)

American College of Clinical Pharmacists: Nephrology Agreed Practice Network Nephrology Declined – provided American Society of Nephrology interview referrals

American Society for Parenteral and Enteral Nutrition Declined – provided Nutrition (ASPEN) interview referrals

Declined – failed to American Gynecological and Obstetrical Society (AGOS) Obstetrics and respond Gynecology Nurse Practitioners in Women’s Health Agreed

Ophthalmology American Academy of Ophthalmology (AAO) Agreed

American Academy of Otolaryngology-Head and Neck Declined – survey not Otolaryngology Surgery (AAO-HNS) approved

Declined – survey not American Academy of Pain Medicine (AAPM) approved Pain Management Declined – failed to American Academy of Physical Medicine and Rehabilitation respond

Pediatrics and American Academy of Pediatrics (AAP) Agreed Neonatology

Declined – failed to Primary Care American College of Physicians (ACP) respond

Declined – failed to American Academy of Clinical Psychiatrists respond Psychiatry Declined – failed to American Association for Geriatric Psychiatry respond

Rheumatology American College of Rheumatology (ACR) Agreed

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Ambulatory Surgery Center Association (ASCA) Agreed

Declined – no interest American Academy of Orthopaedic Surgeons (AAOS) in participation from members

Declined – only send American Association of Hip and Knee Surgeons (AAHKS) surveys from members

American College of Surgeons (ACS) Agreed

American Society for Metabolic and Bariatric Surgery Declined – only send (AMBS) surveys from members

Declined – failed to Surgery The Association of Bone and Joint Surgeons respond

Declined – failed to Physician Assistants in Orthopaedic Surgery respond

Society of American Gastrointestinal and Endoscopic Surgeons Declined – failed to (SAGES) respond

Declined – policy limits number of surveys per year and Society of Gynecologic Surgeons (SGS) do not have a method to identify if any of the SGS members are using ipamorelin

Declined – failed to Toxicology American Academy of Environmental Medicine (AAEM) respond

Urology Sexual Medicine Society of North America (SMSNA) Agreed aAssociations that declined in Year 1 were not contacted in Year 2.

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