Clinical trial NCT02876055
Conditions: Pain, Postoperative
Keywords: Nerve Block/methods Pain, Postoperative/prevention & control Anesthetics, Local/administration & dosage Brachial Plexus/ultrasonography Shoulder Pain/prevention & control
Sponsor: Mayo Clinic
Start date: 2016-11-01; Completion date: 2018-02-01
Enrollment: 125 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Total shoulder arthroplasty (TSA) is considered to be a major surgical procedure resulting in severe postoperative pain, especially in the first 48 hours after surgery. The use of interscalene brachial plexus nerve block remains the cornerstone for analgesia following shoulder surgery; however, with the advent of local infiltration analgesia (LIA), there has been increasing interest in its use for total joint arthroplasty.

Since the benefits of local infiltration analgesia within a comprehensive multi-modal analgesia clinical pathway have yet to be established for total shoulder arthroplasty, the Investigators plan to assess and compare analgesia outcomes between three intervention groups: single shot interscalene brachial plexus block (SISB), continuous interscalene brachial plexus block (CISB), and local infiltration analgesia (LIA).

Detailed description:

Arms: arm 1: An interscalene nerve block will be performed under continuous live ultrasound guidance, obtaining visualization of the roots or trunks of the brachial plexus in between the anterior and middle scalene muscles. 15 to 20 mL of Bupivacaine 0.5% with 1:200,000 Epinephrine will be administered. arm 2: An interscalene nerve block and delivery of a catheter will be performed under continuous live ultrasound guidance, obtaining visualization of the roots or trunks of the brachial plexus in between the anterior and middle scalene muscles.

Initial loading bolus includes 15 to 20 mL of Bupivacaine 0.5% with 1:200,000 Epinephrine. After surgery, the continuous interscalene nerve block catheter will be loaded in the post-anesthesia care unit (PACU) with bupivacaine 0.2% 10 milliliters (mL), and then an infusion will be initiated of bupivacaine 0.2% at 8 to 10 mL per hour. arm 3: The LIA group will utilize weight based dosing of Ropivacaine as part of a "cocktail" solution containing ropivacaine, epinephrine, ketorolac, and normal saline 0.9%. Patients will receive a total volume of 120 mL injected strategically in the periarticular structures by the surgeon. This is a one-time injection. This will occur after implantation of the final prostheses, but prior to closure of the fascia.
Interventions: intervention 1: Single shot interscalene nerve block intervention 2: Continuous interscalene nerve block intervention 3: Local Infiltration Analgesia (LIA)
Intervention descriptions: intervention 1: Peripheral regional anesthesia nerve block - Single shot interscalene nerve block intervention 2: Peripheral regional anesthesia nerve block - continuous catheter interscalene nerve block intervention 3: Injection of local anesthetic into the peri-articular tissues and intra-articular capsule in a systematic approach for orthopedic surgery

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Prospective, randomized 
clinical trial comparing 
analgesic efficacy of single 
injection vs. continuous 
interscalene blocade vs. local 
infiltration analgesia for 
patients undergoing primary 
total shoulder arthroplasty 
 
NCT# 02876055 
 
April 27, 2017 


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Prospective, randomized clinical trial comparing analgesic efficacy of single injection vs. 
continuous interscalene blockade vs. local infiltration analgesia for patients undergoing 
primary total shoulder arthroplasty 
 
 
 
 
 
Regulatory Sponsor: 
Jason K. Panchamia, DO 
Department of Anesthesiology 
Mayo Clinic – Rochester Campus  
507-284-9698 
Study Product: 
 
Protocol Number: (IRBe) 
15-009646 
IND Number: 
 
 
 
 
 
 
Initial version: 
5/5/2016 Version 2.2  
Revised version: 
6/26/2016 Version 2.3 
Revised version: 
7/05/2016 Version 2.4 
Revised version: 
7/28/2016 Version 2.5 
Revised version:     8/19/2016 Version 2.6 
Revised version:  
4/27/2017 Version 2.7 
 
 
 


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Table of Contents 
 
STUDY SUMMARY ................................................................................................................................................... 5 
INTRODUCTION ....................................................................................................................................................... 6 
1.1 
BACKGROUND .................................................................................................................................................. 6 
BACKGROUND AND SIGNIFICANCE .................................................................................................................. 6 
1.2 
INVESTIGATIONAL TECHNIQUE AND AGENTS ................................................................................................... 7 
1.3 
DOSE RATIONALE AND RISK/BENEFITS ............................................................................................................ 8 
2 
STUDY OBJECTIVES ...................................................................................................................................... 9 
3 
STUDY DESIGN .............................................................................................................................................. 10 
3.1 
GENERAL DESIGN .......................................................................................................................................... 10 
3.2 
PRIMARY STUDY ENDPOINTS ......................................................................................................................... 11 
3.3 
SECONDARY STUDY ENDPOINTS .................................................................................................................... 11 
3.4 
PRIMARY SAFETY ENDPOINTS ........................................................................................................................ 12 
4 
SUBJECT SELECTION ENROLLMENT AND WITHDRAWAL ............................................................ 13 
4.1 
INCLUSION CRITERIA ..................................................................................................................................... 13 
4.2 
EXCLUSION CRITERIA .................................................................................................................................... 13 
4.3 
SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING .............................................................................. 14 
4.4 
EARLY WITHDRAWAL OF SUBJECTS ............................................................................................................... 15 
4.4.1 
When and How to Withdraw Subjects .................................................................................................. 15 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects ..................................................................... 15 
5 
STUDY DRUGS ............................................................................................................................................... 16 
5.1 
DESCRIPTION ................................................................................................................................................. 16 
5.2 
TREATMENT REGIMEN ................................................................................................................................... 16 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ....................................................................... 17 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUGS ............................................................................... 17 
5.5 
SUBJECT COMPLIANCE MONITORING ............................................................................................................. 18 
5.6 
PRIOR AND CONCOMITANT THERAPY ............................................................................................................ 18 
5.7 
MASKING/BLINDING OF STUDY...................................................................................................................... 18 
6 
STUDY PROCEDURES .................................................................................................................................. 18 
6.1 
PRE-OPERATIVE PLAN ................................................................................................................................... 18 
6.2 
INTRA-OPERATIVE PLAN ................................................................................................................................ 19 
6.3 
POST-OPERATIVE PLAN ................................................................................................................................. 22 
7 
STATISTICAL PLAN ..................................................................................................................................... 24 
7.1 
SAMPLE SIZE DETERMINATION ...................................................................................................................... 24 
7.2 
STATISTICAL METHODS ................................................................................................................................. 25 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................................... 26 
8 
SAFETY AND ADVERSE EVENTS ............................................................................................................. 26 
8.1 
DEFINITIONS .................................................................................................................................................. 26 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................................. 28 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ............................................... 28 
8.3.1 
Sponsor-Investigator reporting: notifying the Mayo IRB .................................................................... 28 
8.3.2 
Sponsor-Investigator reporting: Notifying the FDA ............................................................................ 29 
8.4 
UNMASKING/UNBLINDING PROCEDURES ....................................................................................................... 29 


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8.5 
STOPPING RULES ............................................................................................................................................ 30 
8.6 
MEDICAL MONITORING.................................................................................................................................. 31 
9 
DATA HANDLING AND RECORD KEEPING .......................................................................................... 31 
9.1 
CONFIDENTIALITY .......................................................................................................................................... 31 
9.2 
SOURCE DOCUMENTS ..................................................................................................................................... 31 
9.3 
RECORDS RETENTION .................................................................................................................................... 32 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ....................................................................... 33 
10.1 
STUDY MONITORING PLAN ....................................................................................................................... 33 
10.2 
AUDITING AND INSPECTING ....................................................................................................................... 33 
11 
ETHICAL CONSIDERATIONS .................................................................................................................... 33 
12 
STUDY FINANCES ......................................................................................................................................... 34 
12.1 
FUNDING SOURCE ..................................................................................................................................... 34 
13 
PUBLICATION PLAN .................................................................................................................................... 34 
14 
REFERENCES ................................................................................................................................................. 34 
 
 
 
 
 
 
 
 


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List of Abbreviations 
 
 
LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
ASA 
American Society of Anesthesiologists 
ASES 
American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form 
CISB 
Continuous Interscalene Nerve Block 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
LANSS Leeds Assessment of Neuropathic Symptoms and Signs 
LAST 
Local Anesthetic Systemic Toxicity 
LIA 
Local Infiltration Analgesia 
NRS 
Numeric Rating Scale 
OBAS 
Overall Benefit of Analgesia Score 
PHI 
Protected Health Information 
PI 
Principal Investigator 
POD 
Postoperative Day 
RASS 
Richmond Agitation-Sedation Scale 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SF-12 
Medical Outcomes Study 12-Item Short Form 
SF-36 
Medical Outcomes Study 36-Item Short Form 
SISB 
Single injection interscalene blockade 
SOP 
Standard Operating Procedure 
TSA 
Total Shoulder Arthroplasty 
 
 
 
 
 
 
 


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Study Summary 
Title 
Prospective, randomized controlled trial comparing analgesic efficacy of single 
injection vs. continuous interscalene blockade vs. local infiltration analgesia for 
patients undergoing primary total shoulder arthroplasty 
Running Title 
SISB vs CISB vs LIA 
Protocol Number 
15-009646  
Phase 
Phase IV 
Methodology 
Single-center, unblinded, randomized control trial with three intervention arms 
Overall Study Duration 
18 Months (time when data collected for last patient) 
Subject Participation 
Duration 
16 weeks 
Single or Multi-Site  
Single Site 
Objectives 
Primary objective is to assess analgesia efficacy between single injection interscalene 
blockade vs. continuous interscalene nerve block vs. local infiltration analgesia for 
patients undergoing primary total shoulder arthroplasty.  Secondary objectives include 
pain scores and opioid consumption at pre-defined time intervals, peripheral nerve 
block complications, length of hospital stay, and postoperative follow up at 12-16 
weeks. 
Number of Subjects 
One hundred and twenty-nine patients will be randomized to one of three 
interventions: single injection interscalene blockade, continuous interscalene nerve 
block, or local infiltration analgesia  
Diagnosis and Main 
Inclusion Criteria 
Patients presenting for unilateral primary total shoulder arthroplasty (includes 
anatomic and reverse total shoulder arthroplasty), who are able to provide to consent, 
older than 18 years of age, and have American Society of Anesthesiologists (ASA) 
physiological status I-III 
Study Product, Dose, 
Route, Regimen 
Ropivacaine weight base dose mixed with epinephrine, ketorolac, and normal saline 
0.9%  injected once in the periarticular structures of the shoulder joint by the surgeon  
Duration of 
Administration 
One time injection 
Reference therapy 
Interscalene brachial plexus block utilizing bupivacaine hydrochloride 
Statistical Methodology 
Randomization of each patient to a study arm will occur in a 1:1:1 allocation utilizing 
randomization schedule which will be created by the Division of Biomedical Statistics 
and Informatics.   Subgroup analysis will be performed evaluating reverse total 
shoulder arthroplasty vs anatomic total shoulder arthroplasty, and patients who 
received allocated treatment per planned protocol  
 
 
 


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Introduction 
 
This document is a clinical research protocol.  The described study will be conducted in 
compliance with the protocol, Good Clinical Practices standards and associated Federal 
regulations, and all applicable institutional research requirements.   
 
This document is a protocol for a human research study. This study will be carried out in 
accordance with the applicable United States government regulations and Mayo Clinic research 
policies and procedures.  
 
Use of study medications within this study is not intended to be reported to the FDA in support 
of a new indication for use or to support any other significant change in the labeling for the drug.  
Additionally, use of study medications within this study is not intended to support a significant 
change in the adverting for the product. 
1.1 
Background 
Background and Significance 
 
Uncontrolled postoperative pain can be associated with significant deleterious consequences, 
including elevated stress response, decrease quality of life, increase in morbidity and mortality, 
and the potential for persistent post-surgical pain.1 Total shoulder arthroplasty (TSA) is 
considered to be a major surgical procedure resulting in severe postoperative pain, especially in 
the first 48 hours after surgery.2 Establishing a clinical pathway for total joint arthroplasty, 
utilizing a multi-modal analgesic approach including regional anesthetic techniques, appears to 
improve perioperative outcomes.3 The use of interscalene brachial plexus nerve block remains 
the cornerstone for analgesia following shoulder surgery in comparison to suprascapular nerve 
block, intra-articular injection, and intravenous opioids.4,5 Single injection interscalene blockade 
(SISB) provides adequate pain relief; however, no optimal dose has been identified and the 
duration of action is variable.6 Continuous interscalene nerve block (CISB) provides extended 
analgesia compared to SISB, suggesting its use may be more appropriate for moderate-to-severe 
painful shoulder procedures.7,8 Although analgesia following intra-articular and subacromial 
local anesthetic injections compared to interscalene brachial plexus block has shown to be less 
efficacious, variability includes operator experience, injection technique, medication solution 
with various adjuvants, and surgical procedure.9,10  
 
CISB has the potential to improve analgesia when compared to SISB; however, potential 
problems encountered include technical difficulty of catheter placement, increased procedure 
time, catheter dislodgement, leakage at the site of insertion, and developing an infrastructure to 
support the catheter.   
 
With the advent of local infiltration analgesia (LIA)11, there has been increasing interest in its use 
for total joint arthroplasty.12-14  Theoretical advantages would include comparable pain scores to 
regional anesthesia techniques, while minimizing motor and/or sensory blockade as well as 
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avoid utilizing catheter based regional anesthesia techniques and its potential problems as listed 
above.  LIA is regularly performed for hip and knee surgery, and has been extended to shoulder 
surgery as well.15,16  Currently, there is limited evidence that demonstrates the superiority of 
either technique specifically for TSA.   
 
Since the benefits of local infiltration analgesia within a comprehensive multimodal analgesia 
clinical pathway have yet to be established for total shoulder arthroplasty, differences in the 
analgesia outcomes between these three intervention groups would provide for an evidence-
based clinical pathway that will emerge as a result of this study.  
The primary aim is to investigate the hypothesis that within our current total joint regional 
anesthesia pathway, utilizing multimodal analgesia and regional anesthesia techniques, 
continuous interscalene nerve block provides superior analgesic benefit via the Overall Benefit 
of Analgesic Score (OBAS)17 compared to single injection interscalene blockade and local 
infiltration analgesia on POD 1 for primary total shoulder arthroplasty. 
1.2 
Investigational Technique and Agents 
 
Local infiltration analgesia, developed by Kerr and Kohan, has only recently become a popular 
technique for postoperative analgesic control.11 The proposed technique was developed for knee 
and hip joint replacement; therefore, most of the current literature utilizing local infiltration 
analgesia is for total hip and total knee replacements.12,14,18 There is limited literature utilizing 
local infiltration analgesia for total shoulder arthroplasty, hence the basis for this study.  It is 
known that local infiltration analgesia involves injection of local anesthetic into the peri-articular 
tissues and intra-articular capsule in a systematic approach.  Injection into the peri-articular 
tissue is thoughtfully considered, as injection of medication should be directed at tissues with 
high density of pain receptors.19  The two orthopedic surgeons have discussed with each other 
the peri-articular tissue areas of significance (a priori), which would provide the greatest 
postoperative analgesic control.   
 
The local infiltration analgesia (LIA) group will receive a one-time injection of the “cocktail” 
solution (ropivacaine weight base dose mixed with epinephrine, ketorolac, and normal saline 
0.9%), injected into the periarticular structures by the surgeons.  This will occur after 
implantation of the final prostheses, but prior to closure of the fascia.  All surgeons will complete 
the infiltration following a similar protocol, equally distributing the study medication around the 
glenoid and humerus, subscapularis, deltoid, posterior capsule and subcutaneous tissue. 
 
Bupivacaine and Ropivacaine are amide local anesthetics which inactivates voltage gated sodium 
channels. In nerves, this results in loss of action potential and signal conduction along the nerve 
fiber leading to sensory and/or motor blockade.  Bupivacaine and Ropivacaine are considered to 
be a long acting local anesthetic, and is indicated for multiple uses including local infiltration and 
peripheral nerve block.20,21 
 
 
 


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1.3 
Dose Rationale and Risk/Benefits 
 
Local infiltration analgesia (LIA) involves injecting local anesthetic into the tissues around and 
within areas of the surgical wound, with the intent of providing satisfactory pain control, 
immediate mobilization of the surgical joint, and earlier discharge from the hospital.11  
Additional benefits for utilizing local infiltration analgesia techniques for the management of 
postoperative pain include its simplicity, decreased cost, reduced quadriceps weakness (in total 
knee arthroplasty patients), and reduction in risk of nerve injury following common peripheral 
nerve blocks.12 
 
The use of interscalene brachial plexus nerve block remains the cornerstone for analgesia 
following shoulder surgery in comparison to suprascapular nerve block, intra-articular injection, 
and intravenous opioids. 9,10  Local infiltration analgesia for shoulder surgery, despite showing to 
be less efficacious in terms of pain control, has not shown to be associated with adverse 
events.15,16 Theoretical advantages would include comparable pain scores to regional anesthesia 
techniques, while minimizing motor and/or sensory blockade as well as complications seen with 
interscalene brachial plexus blocks.  Another advantage would be to avoid utilizing catheter 
based regional anesthesia techniques and its potential problems which include difficulty of 
catheter placement, catheter dislodgement, and leakage at insertion site.  The theoretical 
advantages of local infiltration analgesia and the limited studies evaluating its use, particularly 
for total shoulder arthroplasty, are the basis for this study. 
 
A complication associated with LIA would include local anesthetic systemic toxicity (LAST).   
Local anesthetic systemic toxicity is suspected if a patient has acute onset of central nervous 
system changes (tinnitus, metallic taste in mouth, perioral numbness) or cardiovascular changes 
(bradycardia, hypotension, EKG changes).  This complication can occur with an intravascular 
injection, high systemic absorption depending on the vascularity of the site, and doses exceeding 
manufacturer’s recommendation.  LAST can also be seen with peripheral nerve blocks; 
therefore, the risk exists for all three intervention arms.   
 
There are cases of chondrolysis after shoulder surgery following intra-articular infusions of local 
anesthetic.22  This would have no impact on our study population for two reasons: the first 
involves patients undergoing total joint replacement (total shoulder arthroplasty) where the 
cartilage and supporting structures will be replaced with an artificial joint, and the second reason 
involves the use of a single shot peri-articular injection (i.e. no catheters will be placed into the 
surgical site).   
 
The LIA group will utilize weight based dosing of Ropivacaine as part of a “cocktail” solution 
(Table 1), and will receive a total volume of 120 mL injected in the periarticular structures by the 
surgeon. This is a one-time injection.  This will occur after implantation of the final prostheses, 
but prior to closure of the fascia.  All surgeons will complete the infiltration following a similar 
protocol, equally distributing the study medication around the glenoid and humerus, 
subscapularis, deltoid, posterior capsule and subcutaneous tissue.  Medications and dosage of the 
LIA group is as follows: 
 
 


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Table 1: LIA Group 
Drug 
50-74.9kg 
75-99.9 kg 
100-125kg 
Ropivacaine 
200 mg 
300 mg 
400 mg 
Epinephrine 
100 mcg 
200 mcg 
300 mcg 
Ketorolac 
30 mg 
30 mg 
30 mg 
*Normal Saline will be added to bring the total volume to 120 mL 
 
This “cocktail” solution has been used in several studies assessing analgesic efficacy of local 
infiltration analgesia for a variety of orthopedic surgery.11,12,23  It is noted that there currently is 
no standard solution; therefore, the dosages and various adjuvants vary from study to study.  The 
addition of these various adjuvants has shown to possibly provide synergy and improve 
analgesia24,25, and is currently being used by the surgeons at our institution to perform local 
infiltration analgesia. 
 
Volume is required and advocated in studies to adequately target areas of interest; therefore, it is 
not uncommon to see volumes greater than 100 mL for local infiltration analgesia.12,18 
 
All drug products mentioned in this study are FDA approved and commercially available.  All 
products are administered per product prescribing information without further manipulation.   
 
By enrolling in this study there will be no additional risk in the operation or postoperative care as 
these are already established modalities of care, and all acceptable alternatives.  Known risks for 
peripheral nerve blockade include the following: bleeding, infection, and nerve damage. 
 
Since the benefits of local infiltration analgesia within a comprehensive multimodal analgesia 
clinical pathway have yet to be established for total shoulder arthroplasty, differences in the 
analgesia outcomes between these three intervention groups would provide for an evidence-
based clinical pathway that will emerge as a result of this study.  
 
2 Study Objectives 
Primary Objective 
 
We aim to test the hypothesis that patients undergoing total shoulder arthroplasty within a 
clinical pathway utilizing preemptive low-dose opioid and non-opioid medications for 
multimodal analgesia randomized to the continuous interscalene nerve block group will report a 
lower OBAS score on POD 1 (from 9 am to 12 pm) when compared to randomization to the 
single injection interscalene blockade and local infiltration analgesia groups.   
Overall benefit of Analgesic Score (OBAS) is a recently validated tool measuring patient’s 
experience with their postoperative pain regimen.17  This simple 7 question (Q1 to Q7) scoring 
system entails a combination of pain intensity, adverse opioid events, and patient satisfaction.  
Per Lehmann et al, the total OBAS score is calculated via ‘sum items Q1 through Q6 and add [4 
– score from Q7].’17  This score consists of a 29-point scale ranging from 0 (best) to 28 (worst); 
therefore, lower OBAS scores indicate more analgesic benefit.  This will be administered to 
patients on POD 1 by the study team. 
 


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Secondary Objective 
 
Secondary outcomes consist of pain scores via NRS every four hours (if available) since PACU 
admission (pain score recorded to the closest time interval will be acceptable), the use of 
additional opioid medications (measured in morphine equivalents), length of hospital stay 
(number of postoperative days), reason for hospital length of stay > 1 night (i.e., social 
work/disposition, inadequate pain control, nausea/vomiting, other), complications during 
regional anesthesia block placement (inadvertent intravascular injection, inadvertent epidural or 
subarachnoid injection, local anesthetic systemic toxicity and pneumothorax) or during local 
infiltration analgesia  injection (local anesthetic systemic toxicity), catheter-related complications 
(presence of site infection, hematoma, local anesthetic systemic toxicity), inadvertent catheter 
dislodgement, and a postoperative follow up at 12-16 weeks via telephone call or office visit 
evaluating multiple factors including a chronic pain assessment, health-related quality of life, and 
functional outcome specific to shoulder surgery.    
 
Patients reporting a pain score via NRS > 3 at the 12-16 week postoperative period will be asked 
to complete the validated Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) 
during the visit.26,27 The primary purpose of the LANSS scale is to assess nerve damage resulting 
in neuropathic pain. 
 
Health-related quality of life will be assessed with the Medical Outcomes Study 12-Item Short 
Form (SF-12) questionnaire preoperatively and at the 12-16 week postoperative visit or 
telephone call. The SF-12 is a widely used, standardized and validated instrument.28 Briefly, the 
SF-12 is a shorter version of the Medical Outcomes Study 36-Item Short Form (SF-36)29, and 
scores 8 scales (physical functioning, role functioning-physical, bodily pain, general health, 
energy, social functioning, role functioning-emotional, and mental health), with higher scores 
indicating better health.  SF-12 is commonly used as a general health-related quality of life 
measure in shoulder surgery.30-33 
 
American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) is a 
scoring system developed by the Society of the American Shoulder and Elbow Surgeons to 
standardize outcome measures in shoulder and elbow surgery.34 It is widely used in North 
America, and considered a valid and reliable tool.33,35,36  ASES questionnaire will be collected 
pre-operatively and 1 to 1.5 years postoperatively via office visit or telephone call.  Collected 
data will be used in a follow-up study.   
 
3 Study Design 
3.1 
General Design 
 
Single-center, unblinded, randomized control trial with three intervention arms assessing acute 
pain management.  These three arms include: 1) single shot interscalene blockade (SISB group); 
2) continuous interscalene nerve block (CISB group); 3) local infiltration analgesia (LIA group) 
into the periarticular soft tissues at the time of shoulder replacement. 
 
The study will be registered with www.ClinicalTrials.gov 


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After approval by Mayo Clinic IRB, we will work closely with the department of orthopedics at 
Mayo Clinic Hospital, Methodist Campus to enroll patients into the study.  Potential subjects will 
consist of patients who present for elective primary TSA meeting the inclusion and exclusion 
criteria (sections 4.1 and 4.2). Subjects will be approached by study staff for recruitment in 
person and informed consent will be obtained.  Subjects unable to give consent themselves will 
not be approached for participation.  No remuneration will be provided.  All efforts will be made 
to enroll participants regardless of ethnic heritage. No passive recruitment methods (newspapers, 
advertisements, or flyers) will be used.   
 
One hundred and twenty-nine patients are required for this clinical trial.  After baseline values 
are established, data will prospectively be collected during the peri-operative period up to 16 
weeks post-operatively (patient will have follow-up via office visit or telephone call) for the 
purpose of this study.  Data will continue to be collected up to 1.5 years post-operatively, 
particularly the ASES score, and resulting data will plan to be used in a follow-up study.  Data 
will be collected utilizing the institution’s electronic medical record system, and be transferred to 
an electronic research database (REDCap).  
 
3.2 
Primary Study Endpoints 
 
To investigate the hypothesis that within our current total joint regional anesthesia pathway, 
utilizing multimodal analgesia and regional anesthesia techniques, continuous interscalene nerve 
block provides superior analgesic benefit via the Overall Benefit of Analgesic Score (OBAS) 
compared to single injection interscalene blockade and local infiltration analgesia on POD 1 
(defined as 9 am to 12 pm) for primary total shoulder arthroplasty.   
 
3.3 
Secondary Study Endpoints 
 
1. Pain intensity (NRS) assessments prior to post-anesthesia care unit (PACU) discharge, every 
4 hours beginning on arrival to patient room (to the closet time interval), and prior to hospital 
discharge or 12 pm on POD 1 (whichever comes first). 
2. Opioid consumption in daily oral morphine equivalents (OME) – preoperative, 
intraoperative, PACU stay, and total beginning on arrival to patient room until patient 
discharge or up to POD 3 (whichever comes first). 
3. Moderate to severe complications during regional anesthesia block placement (inadvertent 
intravascular injection+, inadvertent epidural or subarachnoid injection, local anesthetic 
systemic toxicity*, and pneumothorax) or during local infiltration analgesia injection (local 
anesthetic systemic toxicity). 
a) +Inadvertent intravascular injection is suspected if a patient experiences sudden loss 
of consciousness, apnea, convulsions, hypotension, respiratory depression, nausea or 
dizziness, or stroke symptomology. 
b) * Local anesthetic systemic toxicity is suspected if a patient has acute onset of central 
nervous system changes (tinnitus, metallic taste in mouth, perioral numbness) or 
cardiovascular changes (bradycardia, hypotension, EKG changes). 


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4. Peripheral nerve block catheter-related complications including presence of site infection 
(tenderness to palpation, erythema, swelling, drainage of pus), hematoma, inadvertent 
catheter dislodgement, and local anesthetic systemic toxicity.  
5. Duration of hospital stay (number of days), in addition to reason for hospital length of stay > 
1 night (i.e., social work/disposition, inadequate pain control, nausea/vomiting, other) 
6. Postoperative follow-up 
a. Telephone encounter or office visit follow up 12 to 16 weeks postoperatively- NRS 
pain scores at rest and with movement of surgical extremity, postoperative neurologic 
changes (persistent numbness, paresthesia, or weakness of surgical extremity), and 
complications or adverse events will be noted.   
7. Questionnaire Forms 
a) SF-12 
i. Collected preoperatively and at the 12-16 week postoperative visit or 
telephone call. 
b) ASES 
i. Collected preoperatively and 1-1.5 year postoperative visit or telephone call 
(data to be used in a follow-up study). 
c) LANSS 
i. Collected at 12-16 week follow-up visit to assess neuropathic pain in patients 
complaining of pain. 
3.4 
Primary Safety Endpoints 
 
These methods are already established procedures in the practice of perioperative pain control 
for a total shoulder arthroplasty.  There is minimal risk of placing a peripheral nerve block.  
Those risks include infection, bleeding, and/or nerve damage.  Patients will be monitored during 
the perioperative period for any adverse events (as defined below and in section 8).  During 
regional anesthesia block placement, trained sedation nurses or anesthesia personnel (staff 
physicians, residents, or nurse anesthetists) will be monitoring patients.  Patients will be 
monitored throughout the procedure utilizing the American Society of Anesthesiologists (ASA) 
standard monitors*, aspirating for blood or cerebral spinal fluid (CSF) prior to administration of 
local anesthetic solution in divided doses, frequent assessment of the patient’s well-being via 
verbal communication, and having emergency medications and airway equipment readily 
available at all times.  Performing this regional block is considered standard in our practice in 
order to provide optimal postoperative analgesia. 
* blood pressure (non-invasive blood pressure cuff cycling every 3 to 5 minutes or 
continuous arterial blood pressure monitoring placed due to clinical judgment of 
covering anesthesiologist), 5 lead EKG, continuous pulse-oximetry, and continuous 
monitoring from operating room anesthesia personnel (if the procedure is performed in 
the operating room) or frequent assessments by nurses who are trained to care for 
patients receiving regional anesthesia blocks (if procedure is performed in block room) 
 
 
Patients undergoing local infiltration analgesia will have their block placed in the operating room 
by the surgeon under general anesthesia.  Per ASA standards, trained anesthesia personnel will 
be directly monitoring the patient at all times during the surgical case, in addition to frequent 


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assessment of vital signs via standard monitors of care, which includes frequent blood pressure 
reading (blood pressure cuff or arterial line), rhythm analysis (5 lead EKG), heart rate (EKG), 
oxygen saturation (pulse-oximetry), temperature, and ventilation via end tidal carbon dioxide 
detection.  Similar to regional block placement, blood pressure monitoring involves the 
following: non-invasive blood pressure cuff cycling every 3 to 5 minutes or continuous arterial 
blood pressure monitoring (placed due to clinical judgment of covering anesthesiologist). 
 
Patients admitted to the regular nursing floors will have a continuous pulse-oximeter if a 
continuous peripheral nerve block is present.  In addition, vital signs (heart rate, oxygen 
saturation, and blood pressure) will be captured every 4 hours or more frequently if the clinical 
situation dictates in all postoperative orthopedic patients.   
 
Daily follow-up will occur by the inpatient pain service and surgical team.  Adverse events 
and/or complications will be monitored, which includes but not limited to, local anesthetic 
systemic toxicity, neurologic complications, hematoma, bleeding, infection, and wound 
problems.  Nerve damage and assessment is part of the follow-up regarding this study and will 
be followed closely.  In the event an infection was to occur, the PI would be notified, protocol 
would be followed, and investigators of the study would review the incident.   
 
The principal investigator or a designated co-investigator of the study will be notified if a patient 
in the study requires an unanticipated ICU admission.   
 
Please refer to section 8 for detailed explanation for management of adverse events or 
complications.   
 
4 Subject Selection Enrollment and Withdrawal 
4.1 
Inclusion Criteria 
 
1. Adult patients with an American Society of Anesthesiologists (ASA) physiological status 
I-III 
2. Patients presenting for unilateral primary total shoulder arthroplasty (includes anatomic 
and reverse total shoulder arthroplasty). 
3. Patients 18 years of age and older 
4. Able to provide informed consent for him or herself  
4.2 
Exclusion Criteria 
 
1) Chronic pain syndromes such as fibromyalgia or complex regional pain syndrome  
2) Chronic opioid use (>1 mos) with OME >5 mg/day OR acute opioid use (< 1 mos) with 
OME > 30 mg/day. 
3) Body mass index (BMI) > 45 kg/m2 
4) Severe drug allergy* to medications used in this study, including non-steroidal anti-
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• *defined as an immune reaction resulting in shortness of breath, hives, anaphylaxis, 
wheezing, and fever 
5) History of Malignant Hyperthermia.  
6) Major systemic medical problems such as: 
• Pre-existing severe renal disorder defined as glomerular filtration rate (GFR) <50 
units/m2 (if labs are available), currently on dialysis, or highly suspected based on 
history.   
• Severe hepatic disorder defined as current or past diagnosis of acute/subacute 
necrosis of liver, acute hepatic failure, chronic liver disease, cirrhosis (primary 
biliary cirrhosis), chronic hepatitis/toxic hepatitis, liver abscess, hepatic coma, 
hepatorenal syndrome, other disorders of liver 
• Pre-existing medical history of moderate to severe pulmonary disease (obstructive 
and/or restrictive), use of home oxygen, preoperative baseline oxygen saturation < 
94% on room air, FEV 1 < 60% of predicted value (obstructive disease), VC or 
TLC < 70% predicted value (restrictive disease).37   
• History of contralateral hemidiaphragm dysfunction (e.g., paralysis) or phrenic 
nerve injury. 
7) Contraindication to a regional anesthesia technique (e.g., preexisting neuropathy+ in the 
operative extremity, coagulopathy, sepsis, infection at site of injection, uncooperative, 
refusal, anticoagulation medications not held within appropriate time frame*).  
• 
+ pre-existing neuropathy includes sensory and/or motor deficits due to nerve 
insult of surgical extremity, radicular symptoms of surgical extremity, history of 
unresolved brachial plexus injury/brachial plexopathy, and tumors of the brachial 
plexus.  Patients with nerve compression distal to site of surgery, such as history 
of carpal tunnel syndrome or cubital tunnel syndrome, are NOT considered 
contraindications to regional anesthesia. 
• 
*Per ASRA guidelines, Clopidogrel (Plavix) held for at least 7 days, Dabigatran 
(Pradexa) held for at least 5 days, Rivaroxaban (Xarelto)held for at least 3 days, 
Warfarin (Coumadin)held for at least 5 days or recent INR of less than 1.4, 
Enoxaparin (Lovenox) with doses > 1 mg/kg held for close to 24 hours.38 
8) Previous contralateral total shoulder replacement managed with regional anesthetic nerve 
block or periarticular injection/intraarticular injection within the previous 12 months. 
9) Known to be currently pregnant or actively breastfeeding++ 
• 
++ Patients that have a previous history of menopause, hysterectomy, or tubal 
ligation will not be required to perform a pregnancy test.   Female patients that 
do not meet this criterion will be asked to submit a urine sample, and will require 
a negative urine sample in order to proceed with study protocol.  Urine sample be 
collected pre-procedurally.  
10)  Impaired cognition 
4.3 
Subject Recruitment, Enrollment and Screening 
 
After approval by Mayo Clinic IRB, we will work closely with the department of orthopedics at 
Mayo Clinic Hospital, Methodist Campus to enroll patients into the study.  Potential subjects will 
consist of patients who present for elective primary TSA meeting the above inclusion and 
exclusion criteria (section 4.1 and 4.2). Subjects will be approached by study staff for 


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recruitment in person and informed consent will be obtained.  Subjects unable to give consent 
themselves will not be approached for participation.  No remuneration will be provided.  All 
efforts will be made to enroll participants regardless of ethnic heritage. No passive recruitment 
methods (newspapers, advertisements, or flyers) will be used. 
 
Research study coordinators will meet eligible participants at either their preoperative orthopedic 
appointment or the morning of surgery provided they are not the first surgical case of the day. A 
sufficient amount of time will be given to the patient to answer any questions he or she may have 
and to allow the patient to make a well informed decision.   
 
Of note, study staff/clinical research unit, which includes the research study coordinators, is 
composed of RN’s and RRT’s.  Given that this is an institutional initiated study, the study staff is 
able to enroll patients meeting all inclusion/exclusion criteria into the study.   In the event that 
there are any questions or concerns, the study coordinators will contact the PI/Co-PI’s.   
 
Discussion of study participation will be conducted in a private room in the presence of the 
patient's family if he/she so desires.  Information will be provided to the patient without any time 
pressure. Interruptions to this discussion will be minimized by holding this discussion after most 
of the necessary (not study related) preoperative patient care processes are completed. The study 
recruiter will be different from the care team. Patients will be reassured that participation in the 
study does not change in any way their care beyond the random allocation to one of the three 
intervention arms and subsequent data collection. 
4.4 
Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
 
If the patient is unable to comply with the study protocol or they wish to withdraw from the 
study their participation in the study will be terminated.  If the interscalene nerve block catheter 
becomes occluded or is pulled out prematurely, patients will remain in the study as our primary 
analysis will be performed based on the intention to treat. 
 
In order to account for 10% dropout, which includes patients terminated from the study, a total 
sample-size of N=129 (43 per group) is proposed. Follow-up will not be performed for patients 
terminated from the study due to voluntary purposes.   
 
If the patient chooses not to participate he or she will be provided the current perioperative care 
plan in place by the surgeon and will include pain management regardless of participation. 
 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
 
Patients who voluntarily withdraw from the study will have their data collected in the peri-
operative and follow-up periods up to the point of termination.   
 


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Study team will determine if an adverse event occurred (section 8.1 of IND protocol) and will 
assess the relationship to study protocol (including study medications).  If causality is certain, 
probable/likely, or possible as per WHO-UMC causality assessment system39, study team will 
make every attempt to follow up with patient until adverse event is resolved. 
 
Our primary analysis will be performed based on the intention to treat.  A subgroup analysis will 
also be performed on patients who received the allocated treatment as per the planned protocol 
and.   
 
The primary outcome for this study involves assessing its analgesic efficacy compared to other 
standard methods of regional anesthesia acute pain management techniques for patients 
undergoing total shoulder arthroplasty. Survival data will not be assessed in this study; thus, we 
will plan to exclude data after a patient’s termination/withdrawal date.     
 
If the patient chooses not to participate he or she will be provided the current perioperative care 
plan in place by the surgeon and will include pain management regardless of participation. 
5 Study Drugs  
5.1 
Description 
 
Pre-mixed bupivacaine 0.5% with epinephrine1:200,000 is packaged within a clear glass vial, 
containing 150 mg (30 mL) of bupivacaine.  Solution is sterile, and clear and colorless.  
Bupivacaine is readily available and commonly stocked at our institution.  Similarly, ropivacaine 
is a sterile, and clear and colorless solution that is readily available and commonly stocked at our 
institution.   
 
All drug products mentioned in this study are FDA approved and commercially available.  All 
products are administered per product prescribing information without further manipulation.   
5.2 
Treatment Regimen 
 
As mentioned above in section 1.3, the LIA group will utilize weight based dosing of 
Ropivacaine as part of a “cocktail” solution (Table 1), and will receive a total volume of 120 mL 
injected in the periarticular structures by the surgeon. This is a one-time injection.  This will 
occur after implantation of the final prostheses, but prior to closure of the fascia.  All surgeons 
will complete the infiltration following a similar protocol, equally distributing the study 
medication around the glenoid and humerus, subscapularis, deltoid, posterior capsule and 
subcutaneous tissue.  Medications and dosage of the LIA group is as follows: 
 
Table 1: LIA Group 
Drug 
50-74.9kg 
75-99.9 kg 
100-125kg 
Ropivacaine 
200 mg 
300 mg 
400 mg 
Epinephrine 
100 mcg 
200 mcg 
300 mcg 
Ketorolac 
30 mg 
30 mg 
30 mg 
*Normal Saline will be added to bring the total volume to 120 mL 
 


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SISB and CISB groups will utilize pre-mixed bupivacaine 0.5% with epinephrine1:200,000 vial 
for the initial loading bolus.  CISB group will have a continuous catheter attached to a pain pump 
infusing bupivacaine 0.2% when the patient arrives to the PACU. 
 
Table 2 demonstrates the study medication for SISB and CISB groups. 
 
Table 2: CISB and SISB Group – Bolus Injection 
Nerve Blocked 
Local Anesthetic 
Concentration 
Volume 
- 
milliliters (mL) 
Adjuvants Added 
Interscalene 
Brachial Plexus – 
CISB and SISB 
Bupivacaine 
0.5% 
15 to 20 mL 
1:200,000 Epinephrine  
 
 
Please refer to section 6.2 for the SISB and CISB groups’ technique and administration of local 
anesthetic. 
5.3 
Method for Assigning Subjects to Treatment Groups 
The treatment allocation will be performed using a randomization schedule which will be created 
by the Division of Biomedical Statistics and Informatics. This randomization schedule will be 
generated using a SAS program (SAS  version 9.3, SAS Institute Inc, Cary NC) with 
randomization performed in blocks of size N=6 to ensure that after every sixth patient is enrolled 
there are an equal number of patients assigned to each of the 3 treatment conditions.  Using this 
randomization schedule, an EXCEL spreadsheet application will be created which will include 
sequentially assigned subject-ID numbers and corresponding treatment assignments. When a 
patient is enrolled they will be assigned the next sequential subject-ID number and a member of 
the anesthesia clinical research unit, who will be different from the care team and are not 
involved in the medical management of the patient, will use the online system to retrieve the 
allocated treatment assignment for this subject-ID. 
5.4 
Preparation and Administration of Study Drugs 
 
Please refer to section 5.2 with regards to treatment regimen and administration of the “cocktail” 
solution for the LIA group.   
 
Pharmacy prepares the weight based dose Ropivacaine, Epinephrine, Ketorolac 30 mg, in 
Normal Saline 0.9% (for a total volume of 120 mL) and provides this to the surgical staff. The 
Department of Pharmacy follows United States Pharmacopeia (USP) <797> preparation 
standards.40 In general, the pharmacy uses environmental engineering controls for air quality of 
the preparation area, personal protective equipment during compounding, and performs 
preparation within laminar flow hoods.  This “cocktail” solution will be dispensed to OR 
personnel during the surgical procedure.   
 
The pre-made “cocktail” solution will be placed in a sterile basin located on the operating room 
table, within the vicinity of the surgeon and operating room technician, who are scrubbed into 
surgery.  Sterility includes a sterile environment such as the operating room, in which a sterile 
field is created utilizing sterile surgical drapes.  Operating room personnel handling the study 


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solution will be in sterile gloves and surgical gowns, hats and masks, and standing close to the 
surgical field.   
 
In the SISB and CISB groups, one vial of pre-mixed bupivacaine 0.5% with 
epinephrine1:200,000 will be obtained from the anesthesia stock room.  Solution is sterile and 
will be poured in a sterile fashion into the sterile nerve block tray.   
5.5 
Subject Compliance Monitoring 
 
Patients receiving treatment will be enrolled in a prospective database.  No other treatment is 
necessary, except the treatment assignment during their scheduled procedure. 
5.6 
Prior and Concomitant Therapy 
 
Patients may receive therapy for any conceivable condition, while enrolled in this trial, as long as 
they meet the inclusion criteria (section 4.1).  Since this clinical trial is assessing analgesia 
efficacy between three different intervention arms, rescue analgesics will be available to all 
patients for uncontrolled pain as this is a standard practice at our institution.   
5.7 
Masking/Blinding of Study  
 
This prospective randomized control trial will be unblinded.  We acknowledge that this unblinded 
study design may be a limitation.  We understand that there may be no way for us to prevent 
participants from being treated differently if the study is unblinded.  They may have a different 
experience dependent upon the intervention biasing their observed outcome.  However, we hope to 
discover the best overall clinical pathway for management of TSA for our patient population. 
 
It would be very difficult to blind patients to the three intervention arms because each intervention 
arm involves a different nerve block technique (interscalene brachial plexus block41 vs local 
infiltration analgesia11).  The SISB and CISB groups involve placing a regional anesthesia 
peripheral nerve block, which is typically done in an awake patient prior to the surgical procedure.  
The LIA group will have their block performed by the surgeon, while the patient is under general 
anesthesia, towards the end of the surgical case just as the surgeon is about to close the fascia. 
 
6 Study Procedures 
6.1 
Pre-Operative Plan 
 
Following informed consent and randomization, study staff will record baseline patient 
demographics (including baseline NRS values for pain at rest, age, weight, gender, ASA physical 
status) from the electronic medical record and/or during the patient interview.   
 
NRS pain scores at rest will be measured at the following time points: arrival to post-anesthesia 
care unit (PACU), prior to PACU discharge, every 4 hours beginning on arrival to patient room. 
Pain scores will be measured until hospital discharge from the time of the initial assessment in 


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the recovery room (PACU). All NRS pain scores will be recorded by registered nurses per 
standard protocol. 
 
Regional Block – Both CISB and SISB: 
 
Based on our current total joint regional anesthesia pathway (MC1156-462rev0115 and 
MC1156-1321rev1015), all patients will be provided (unless contraindicated and at the discretion 
of the attending anesthesiologist) a combination of oral analgesic medications preoperatively: 
1) Tylenol 1 gram – at least 6 hours since last dose 
2) Celecoxib 400 mg – for patients 18-64 years old and CrCl > 50 mL/min (if lab is 
available)  
3)  
  
 
a. Oxycodone (immediate release) 
i. 5-10 mg once for patients 18-64 years old 
4) Scopolamine Transdermal patch:  1.5mg - Apply to skin behind ear for 24 hours for high-
risk patients (history of motion sickness or postoperative nausea vomiting).  This is at the 
discretion of the anesthesiologist. 
 
Local Infiltration Analgesia (LIA): 
1) Tylenol 1 gram – at least 6 hours since last dose 
2) Celecoxib 400 mg – for patients 18-64 years old and CrCl > 50 mL/min (if lab is 
available)  
3)  
  
 
a. Oxycodone (immediate release) 
i. 5-10 mg once for patients 18-64 years old 
4) Scopolamine Transdermal patch:  1.5mg - Apply to skin behind ear for 24 hours for high-
risk patients (Hx: motion sickness or postoperative nausea vomiting).  This is at the 
discretion of the anesthesiologist. 
 
6.2 
Intra-Operative Plan 
General anesthesia (induction with propofol and maintenance with isoflurane inhaled anesthesia 
with or without use of nitrous oxide (N2O) and oxygen combination) with use of endotracheal 
tube, intraoperative monitoring (standard ASA monitoring), and supplemental analgesia.  The 
covering anesthesiologist may also consider sevoflurane or desflurane as the inhalational 
anesthetic.  Additional intraoperative monitoring such as continuous blood pressure via arterial 
line will be at the discretion of the attending anesthesiologist. Each patient will receive 
dexamethasone 8 mg IV42 and granisetron 0.1 mg or ondansetron 4 mg unless contraindicated 
(e.g. brittle diabetes defined as unpredictable and instable blood glucose levels with frequent 
episodes of hypoglycemia and/or ketoacidosis, or severe drug allergy defined as an immune 
reaction resulting in shortness of breath, hives, rash, blisters, anaphylaxis, wheezing, and fever). 
Other medications for nausea prophylaxis will be given at the discretion of the individual 


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anesthesiologist providing intraoperative care (which may include Droperidol 0.625 mg IV or 
Propofol infusion).  
 
Intraoperative opioids will be administered at the discretion of the in-room anesthesia provider 
based on hemodynamic signs of pain such as increased blood pressure or heart rate.  This may 
include but not limited to IV morphine, dilaudid, fentanyl, and ketamine.   
 
All surgeries will be performed by two orthopedic surgeons at Mayo Clinic Hospital, Methodist 
Campus. All patients will receive a unilateral primary total shoulder arthroplasty, either anatomic 
or reverse TSA. 
 
Typically, the decision to perform either an anatomic or reverse TSA is dependent on the function 
and stability of the rotator cuff muscles.  The standard total shoulder arthroplasty involves a metal 
ball replacing the head of the humerus and a plastic implant used to replace the socket of the 
shoulder blade.  In reverse total shoulder arthroplasty, the components are reversed.  Limited 
available studies compare outcomes between standard total shoulder arthroplasty and reverse 
shoulder arthroplasty.  In a recent study by Kiet and colleagues, outcomes between both groups 
were comparable, including pain.43  
 
If patients are randomized to the LIA group, periarticular injection will occur after implantation 
of the final prostheses, but prior to closure of the fascia.  All surgeons will complete the 
infiltration following a similar protocol, equally distributing the study medication around the 
glenoid and humerus, subscapularis, deltoid, posterior capsule and subcutaneous tissue. 
 
Regional Block – Both CISB and SISB: 
 
Preoperatively, patients will be sedated, under the discretion of the anesthesiologist, with 
intravenous midazolam (1-4 mg) and fentanyl (50-200 mcg) for alleviation of anxiety and pain. 
 
 
Patients randomized to either the CISB or SISB group will follow institutional practice in 
accordance to the total joint regional anesthesia pathway (MC1156-462rev0115).  The 
interscalene nerve block will be performed under continuous live ultrasound guidance, obtaining 
visualization of the roots (C5-C6 is ideal) or trunks (Superior Trunk is ideal) of the brachial 
plexus in between the anterior and middle scalene muscles as described by Chan.41 An in plane 
or out of plane approach to needle advancement under live ultrasound guidance will be at the 
discretion of the anesthesiologist.  In cases with poor ultrasound imaging, a combined nerve 
stimulator and ultrasound guidance technique is acceptable.  Appropriate needle placement will 
be verified by injecting normal saline 0.9% and visualizing spread within the interscalene groove 
at the level of the roots/trunks of the brachial plexus.  Local anesthetic may also be used for 
hydrodissection in order to navigate needle placement into the correct position.  The 
proceduralist should attempt to use less than 10 mL (if possible) of saline 0.9% to identify 
correct placement of peripheral nerve block.   
 
Regional Block – SISB 
Once needle position is verified, the initial loading dose of local anesthetic solution to be 
administered is presented in Table 2.   


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Regional Block – CISB 
Once needle position is verified by ultrasound imaging, a continuous catheter device will be 
placed within the interscalene groove at the level of the roots/trunks of the brachial plexus.  After 
delivery of the catheter, verification of the catheter within the interscalene groove will be 
assessed by again evaluating spread of normal saline 0.9% or local anesthetic within the 
interscalene groove.   
 
The initial loading dose of local anesthetic solution to be administered is presented in Table 2.  
The local anesthetic solution will be bloused through the catheter, and secured into place above 
the clavicle and away from the surgical field.   
 
Brachial plexus block evaluation is as follows: sensory – sensation to cold over the deltoid 
muscle (0= absent or diminished, 1 = at baseline).  Block will be assessed either preoperatively 
(at least 25 minutes after the placement of the block, if presurgical time permits), postoperatively 
in the recovery room, or patients room on POD 0.  This assessment will be charted in the 
electronic anesthesia medical record when it has been completed. 
 
Table 2: CISB and SISB Group – Bolus Injection 
Nerve Blocked 
Local Anesthetic 
Concentration 
Volume 
- 
milliliters (mL) 
Adjuvants Added 
Interscalene 
Brachial Plexus – 
CISB and SISB 
Bupivacaine 
0.5% 
15 to 20 mL 
1:200,000 Epinephrine  
 
Continuous Interscalene Nerve Block (CISB): 
 
The continuous interscalene nerve block catheter will be loaded in the PACU with bupivacaine 
0.2% 10 milliliters (mL), and then an infusion will be initiated of bupivacaine 0.2% at 8 to 10 per 
hour.  Infusion rate will be at the discretion of the pain service and attending anesthesiologist.  
The catheter will be discontinued on POD 1, unless surgeon requests catheter to remain in for a 
longer period of time.    
 
Failed Block – CISB and SISB Group 
 
In the event that a failed block were to occur, defined as intact or baseline sensation to cold over 
the deltoid muscle after 25 minutes since completion of block (pre-op) or pain at the surgical site 
along with intact or baseline sensation to cold over the deltoid muscle (post-op), the patient will 
be managed accordingly at the discretion of the covering anesthesiologist (which may include 
either re-blocking, or utilizing pain medications).  Patient’s will still be involved in the study per 
intention-to-treat analysis.   
 
Local Infiltration Analgesia (LIA): 
 
The LIA group will utilize weight based dosing of Ropivacaine as part of a “cocktail” solution 
(Table 1), and will receive a total volume of 120 mL injected in the periarticular structures by the 
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but prior to closure of the fascia.  All surgeons will complete the infiltration following a similar 
protocol, equally distributing the study medication around the glenoid and humerus, 
subscapularis, deltoid, posterior capsule and subcutaneous tissue.  Medications and dosage of the 
LIA group is as follows: 
 
Table 1: LIA Group 
Drug 
50-74.9kg 
75-99.9 kg 
100-125kg 
Ropivacaine 
200 mg 
300 mg 
400 mg 
Epinephrine 
100 mcg 
200 mcg 
300 mcg 
Ketorolac 
30 mg 
30 mg 
30 mg 
*Normal Saline will be added to bring the total volume to 120 mL 
 
 
Study Site: All surgeries included in this study will be performed at Mayo Clinic Hospital, 
Methodist Campus.  Postoperative care will take place at the same hospital. 
6.3 
Post-Operative Plan 
 
PACU 
 
Pain medications for the PACU are at the discretion of the anesthesiologist.  The following 
medications and doses listed are recommendations and include but not limited to the following: 
1) Fentanyl 25 mcg IV every 2 minutes PRN for pain 4 or greater (maximum 200 mcg) 
2) Hydromorphone 0.2 mg IV every 2 minutes PRN for pain 4 or greater (maximum 2 mg) 
3) Acetaminophen 1000mg PO or IV once for pain (review last dose before administering) 
a. Oral unless RASS < -1 or nausea/ vomiting present 
4) Ketamine 10 mg IV once as needed for pain scores >4 
5) Oxycodone (immediate release) 
a. 5 mg to 10 mg once prior to discharge for pain 4 or greater 
 
  
 
Floor Care 
 
The following will be the post-op pain management protocol for the nursing floors.  This is 
intended to serve as a guide for the primary service or acute pain management team, and can be 
modified or adjusted per the discretion by either team in order to provide optimal care on a case 
by case basis.  Of note, this has been reviewed and approved by Pharmacy (Nathan J. Brinkman, 
Pharm.D., R.Ph. & Laura J. Myhre, Pharm.D., R.Ph.).   
 
TSA Floor Care Analgesic Medications: 
Scheduled Analgesics: 
• Acetaminophen:  1000 mg orally every 6 hours  
 
 
PRN Analgesics: 
• Oxycodone 5 to 10 mg orally every 4 hours PRN. Use 5 mg for pain rated 3 to 5. 
Use 10 mg for pain rated 6 to 10. If after 2 hours of administration pain remains 
greater than 7, please notify primary service to increase frequency to every 3 


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hours.  
 
 
OR        
 
• Hydromorphone 1 to 2 mg orally every 4 hours PRN. Use 1 mg for pain rated 3 
to 5. Use 2 mg for pain rated 6 to 10. If after 2 hours of administration pain 
remains greater than 7, please notify primary service to increase dose. Order if 
patient has a sensitivity or allergy to oxycodone.  
 
 
Breakthrough pain – IV Medications: 
• Fentanyl 25 mcg IV every 30 minutes PRN for pain scores 7 through 10 for 3 
doses. May administer if pain is greater than 6 after scheduled and PRN regimen 
exhausted.  If pain remains greater than 6, notify primary service. 
 
 
Endpoints  
 
Data collection will be obtained based on our primary and secondary endpoints as listed in 
Sections 3.2 and 3.3 
 
 
 
Pre-
operative 
Peri-operative 
Post-operative Follow 
Up 
Study Activity 
Pre-op 
Day 0        
(day of 
surgery) 
Day 
1 
Days 
2-5 
Week  
12-16 
Years 1-1.5* 
Informed Consent 
x 
 
 
Inclusion/Exclusion 
Criteria 
x 
 
 
 
 
 
Pain Scores 
(numeric rating scale) 
x 
x 
x 
x 
x 
 
Patient and Surgical 
Data Collections 
x 
x 
 
 
 
 
OBAS Form  
(primary outcome) 
 
 
x 
 
 
 
SF-12 Form 
x 
 
 
 
x 
 
ASES Form 
x 
 
 
 
 
x 
LANSS 
 
 
 
 
x 
 
Opioid Consumption (up 
to POD 3) 
 
x 
x 
x 
 
 
Length of Hospital Stay 
x 
x 
 
 
Adverse Events 
Monitoring 
 
x 
x 
x 
x 
 
Neurologic 
Complications 
 
x 
x 
x 
x 
 


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Peripheral Nerve Block - 
catheter related 
complications 
 
x 
x 
x 
 
 
Follow up via telephone 
call or office visit 
 
 
 
 
x 
x 
• * Follow-up study as described in Section 2.0 
6.4 
Data Collection 
Primary and Secondary Outcomes 
 
The primary outcome (OBAS on POD 1) will be collected prospectively if possible by 
interviewing patients in their hospital room on POD 1.  The rest of the outcome measures will be 
obtained from DataMart and manual Chart+ record review.  Collected data will be transferred 
into REDCap.   
 
Regional blocks performed on day of surgery will be assessed for loss of sensation over the distal 
deltoid muscle (indicative of appropriate interscalene nerve blockade).  This will be charted in 
Chart+, and results will be retrieved by manual chart review.   
 
Post-operative Follow Up (12-16 Weeks) 
 
The study staff will follow up with study patients 12-16 weeks following their initial shoulder 
surgery.  This will be conducted via office visit or telephone call.  During this encounter, the 
study staff will utilize data collection form.  Collected data includes NRS pain scores at rest and 
with movement of surgical extremity, postoperative neurologic changes (persistent numbness, 
paresthesia, or weakness of surgical extremity), and complications or adverse events.  In 
addition, SF-12 and LANSS questionnaire will also be administered.   
 
7 Statistical Plan 
7.1 
Sample Size Determination 
 
The sample-size for this study was determined in order to provide statistical power of >90% to 
detect a difference of 3 units for the primary endpoint (OBAS on POD1). Based on a previous 
study, we hypothesize that the standard deviation of OBAS will be approximately 3 units.44 
Under this assumption, an effective sample-size of N=39 per group will  provide statistical 
power of >90% to detect a difference between groups of 3 units using a two-sided, alpha=0.017 
(multiple-comparison adjusted for 3 groups), non-parametric test. In addition, for the key 
secondary endpoint of pain (NRS), this sample-size will provide statistical power of 80% to 
detect a difference of 0.75 standard deviations (approximately 2.25 units on the NRS). In order to 
accommodate attrition of approximately 10% (due to canceled surgery, failed block, etc.) we 
propose a total sample-size of N=129 (43 patients per group). 


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7.2 
Statistical Methods 
 
Descriptive Statistics 
 
Baseline characteristics will be summarized using mean and standard deviation for continuous 
variables that have a normal Gaussian distribution, and median and interquartile range for 
continuous variables with a non-normal distribution. Frequencies and percentages will be used to 
summarize categorical baseline characteristics. Baseline characteristics will be compared across 
groups using analysis of variance, or the Kruskal-Wallis test for continuous variables and the chi 
square test for categorical variables. 
 
The primary aim of this study is to assess whether continuous interscalene nerve block provides 
superior analgesic benefit via OBAS compared to single injection interscalene blockade and 
local infiltration analgesia on POD 1 for primary total shoulder arthroplasty.  In order to test this 
hypothesis, the will be compared across groups using ANOVA (or the Kruskal-Wallis test).  
Supplemental pairwise comparisons will be performed using two-tailed tests with alpha=0.017 
(Bonferroni adjusted) used to denote statistical significance.  Similar analyses will be performed 
for secondary endpoints of pain and total additional opioid medications (moeq) until hospital 
discharge.   
NRS pain scores measured at arrival to PACU, PACU discharge, and every 4 hours until time of 
hospital discharge following surgery will be analyzed using repeated measures ANOVA with 
pairwise treatment comparisons performed using linear contrasts.   
 
Postoperative complications will be compared across groups using the chi-square test and 
hospital length of stay (number of postoperative days) will be compared across treatment groups 
using the Kruskal-Wallis test with supplemental pairwise comparisons performed using the rank 
sum test. Similar analyses will be performed for additional endpoints collected at the 12-16 week 
follow-up visit including NRS pain scores and SF-12 scales.  
 
Our primary analysis will be performed based on the intention to treat.  All calculated p-values 
will be two sided. For the overall analyses comparing across all 3 treatment groups 
simultaneously p-values less than 0.05 will be considered statistically significant. For 
supplemental pairwise treatment group comparisons p-values less than 0.017 (Bonferroni 
adjusted) will be considered statistically significant. The statistical analysis will be performed 
using SAS version 9.4 (SAS Institute Inc., Cary, North Carolina, United States). 
 
Handling of Missing Data 
 
All Subjects enrolled according to the entry criteria will be eligible for evaluation, regardless of 
the sequence of treatment that ensues.  
 
Management of dropouts and missing data will depend on their frequency and the nature of the 
outcome measure.  Analysis of the distribution of prognostic factors between subjects with data 
and those without data will be reviewed for significance to assess selection bias.  Adjustments 
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completely.  An endpoint analysis (last observation carry forward), as described by 
Friedman45 will be used for success rate assessments.  
 
Outlier values will be evaluated for their validity; all data will be included unless judged to be 
invalid.     
 
7.3 
Subject Population(s) for Analysis 
 
Our primary analysis will be performed based on the intention to treat.  Therefore, any subject 
randomized into the study, regardless of whether they received study drug, will be included in 
the primary analysis.  A subgroup analysis will also be performed on patients who received the 
allocated treatment as per the planned protocol, and patients undergoing reverse vs anatomic 
primary TSA.   
 
8 Safety and Adverse Events 
8.1 
Definitions 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets the following three criteria:  
• Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for the 
subject or others (including individuals who are not research subjects). These include: (1) 
death; (2) life threatening adverse experience; (3) hospitalization - inpatient, new, or 
prolonged; (4) disability/incapacity - persistent or significant; (5) birth defect/anomaly; (6) 
breach of confidentiality and (7) other problems, events, or new information (i.e. 
publications, DSMB reports, interim findings, product labeling change) that in the opinion 
of the local investigator may adversely affect the rights, safety, or welfare of the subjects 
or others, or substantially compromise the research data, AND 
• Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, consent document, not listed in the 
Investigator’s Brochure, or not part of an underlying disease. A problem or event is 
"unanticipated" when it was unforeseeable at the time of its occurrence. A problem or 
event is "unanticipated" when it occurs at an increased frequency or at an increased 
severity than expected, AND 
• Related: A problem or event is "related" if it is possibly related to the research procedures. 
 
Non-UPIRTSO 
 
A reportable event that does not meet the Mayo Clinic IRB's definition of a UPIRTSO. 
 
Adverse Event 
An untoward or undesirable experience associated with the use of a medical product (i.e. drug, 
device, biologic) in a patient or research subject. 


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Serious Adverse Event 
Adverse events are classified as serious or non-serious.  Serious problems/events can be well 
defined and include; 
• death 
• life threatening adverse experience 
• hospitalization 
• inpatient, new, or prolonged; disability/incapacity 
• persistent or significant birth defect/anomaly 
 
And/or per protocol may be problems/events that in the opinion of the sponsor-investigator 
may have adversely affected the rights, safety, or welfare of the subjects or others, or 
substantially compromised the research data. 
 
All adverse events that do not meet any of the criteria for serious, should be regarded as non-
serious adverse events.  
 
Adverse Event Reporting Period 
For this study, the study treatment follow-up period is defined as 7 weeks following the last 
administration of study treatment.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
may be recorded as an adverse event if the frequency, intensity, or the character of the condition 
worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  Throughout the study, any new clinically significant findings/abnormalities that meet 
the definition of an adverse event must also be recorded and documented as an adverse event.  
 
Adverse Event Causality 
We understand the importance pharmacovigilance, and the significance of establishing a 
relationship between study drug and adverse events.  Causality assessment or algorithms are 
available to assist with evaluating the likelihood or relationship between study drug and adverse 
event.  We will utilize the WHO-UMC causality assessment system to assess adverse event 
causality. 39 
 
Post-study Adverse Event 
Unresolved adverse events related to the study medication/procedure will be followed by the 
PI/Co-PI’s until the events are resolved, the subject is lost to follow-up, or the adverse event is 
otherwise explained 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
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this protocol.  Any condition responsible for surgery should be documented as an adverse event 
if the condition meets the criteria for an adverse event.  
 
• Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported 
as an adverse event in the following circumstances: Hospitalization or prolonged 
hospitalization for diagnostic or elective surgical procedures for a preexisting condition.  
Surgery should not be reported as an outcome of an adverse event if the purpose of the 
surgery was elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
 
8.2 
Recording of Adverse Events 
The study team will seek information on adverse events by specific questioning and, as 
appropriate, by examination.  This will occur on daily follow up inpatient encounters as well as 
telephone or office visit encounters around 12-16 weeks post-procedure.  Information on all 
adverse events will be recorded in the electronic medical record and also in the appropriate 
adverse event worksheet.  Related signs, symptoms, and abnormal diagnostic, laboratory or 
procedure results will be recorded as well.  PI/Co-PI’s will be notified of the adverse events. 
 
The clinical course of each adverse event will be followed until resolution, stabilization, or until 
it has been determined that the study treatment or participation is not the probable cause.  Serious 
adverse events that are still ongoing at the end of the study period will be followed, as stated 
above.  Any serious adverse event that occurs after the study period and is considered related to 
the study treatment or study participation will be recorded and reported. 
8.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
 
When an adverse event has been identified, the study team will take appropriated action 
necessary to protect the study participant and then complete the Study Adverse Event Worksheet 
and log.  The sponsor-investigator will evaluate the event and determine the necessary follow-up 
and reporting required.   
 
Serious adverse events will be evaluated and reported per institutional policy and regulatory 
requirements.   
8.3.1 Sponsor-Investigator reporting: notifying the Mayo IRB 
 
Information collected on the adverse event worksheet (and entered in the research database):  
• Subject’s name:  
• Medical record number:  
• Disease/histology (if applicable):  
• The date the adverse event occurred:  
• Description of the adverse event:  
• Relationship of the adverse event to the research (drug, procedure, or intervention):  


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• If the adverse event was expected:  
• If any intervention was necessary:  
• Resolution: (was the incident resolved spontaneously, or after discontinuing treatment) 
• Date of Resolution:  
 
The sponsor-investigator will review all adverse event reports to determine if specific reports 
need to be made to the IRB and FDA.  The sponsor-investigator will review the adverse event 
worksheet and only directly related SAEs/UPIRTSOs will be reported to the IRB.  
 
For NON-UPIRTSOs, the investigator reports problems or events that do NOT meet the criteria 
of an UPIRTSO to the Mayo Clinic IRB in summary format at the time of the next continuing 
review. 
 
 
8.3.2 Sponsor-Investigator reporting: Notifying the FDA 
 
Any applicable IND regulations will be followed related to reporting to the FDA of all 
unexpected, serious suspected adverse reactions according to the required IND Safety Reporting 
timelines, formats and requirements. 
 
Unexpected fatal or life threatening suspected adverse reactions where there is evidence to 
suggest a causal relationship between the study drug/placebo and the adverse event, will be 
reported as a serious suspected adverse reaction.  This will be reported to the FDA on FDA Form 
3500A, no later than 7 calendar days after the sponsor-investigator’s initial receipt of the 
information about the event. 
 
Other unexpected serious suspected adverse reactions where there is evidence to suggest a causal 
relationship between the study drug/placebo and the adverse event, will be reported as a serious 
suspected adverse reaction.  This will be reported to the FDA on FDA Form 3500A, no later than 
15 calendar days after the sponsor-investigator’s initial receipt of the information about the 
event. 
 
Any clinically important increase in the rate of serious suspected adverse reactions over those 
listed in the protocol or product insert will be reported as a serious suspected adverse reaction.  
This will be reported to the FDA on FDA Form 3500A no later than 15 calendar days after the 
sponsor-investigator’s initial receipt of the information about the event. 
 
Findings from other studies in human or animals that suggest a significant risk in humans 
exposed to the drug will be reported.  This will be reported to the FDA on FDA Form 3500A, no 
later than 15 calendar days after the sponsor-investigators initial receipt of the information about 
the event. 
 
8.4 
Unmasking/Unblinding Procedures 
 


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This study is an unblinded study.   
8.5 
Stopping Rules  
 
Adverse events and serious adverse events, as defined in Section 8.1 of IND protocol, will be 
monitored by the study team for patient safety.  Known serious adverse events associated with 
interscalene nerve blocks (SISB and CISB groups) include inadvertent intravascular injection+, 
local anesthetic systemic toxicity (LAST)*, inadvertent epidural or subarachnoid injection, and 
pneumothorax.   Additionally, patients will be monitored throughout the procedure utilizing 
standard ASA monitors, aspirating for heme or cerebral spinal fluid (CSF) prior to administration 
of local anesthetic solution in divided doses, frequent assessment of the patient’s well-being via 
verbal communication, and having emergency medications and airway equipment readily 
available at all times.  Performing this regional block is considered standard in our practice and 
these methods are already established procedures in the practice of perioperative pain control for 
a total shoulder arthroplasty.4,5  
 
Serious adverse event associated with local infiltration analgesia (LIA group) is local anesthetic 
systemic toxicity (LAST).   
+ Inadvertent intravascular injection is suspected if a patient experiences sudden loss of 
consciousness, apnea, convulsions, hypotension, respiratory depression, or stroke 
symptomology. 
* Local anesthetic systemic toxicity is suspected if a patient has acute onset of central 
nervous system changes (tinnitus, metallic taste in mouth, perioral numbness) or 
cardiovascular changes (bradycardia, hypotension, EKG changes). 
 
LAST is a known serious adverse event with any local anesthetic administration.  Preventive 
measures include high degree of suspicion, vital sign monitoring (blood pressure, EKG, oxygen 
saturation), using an appropriate dose of local anesthetic, injecting local anesthetic in divided 
dose, aspirating prior to injection of medication looking for heme, consider using epinephrine in 
solution as a vascular marker, being prepared to treat a LAST event immediately (checklist, 
external defibrillator, resuscitate medications, emergency airway equipment), and having lipid 
emulsion therapy readily available (standard of care).46  We acknowledge that despite the rarity 
of these serious adverse events, the potential still exists.   
 
Study stopping criteria includes: 
 
CISB and SISB groups: 
a) The study will stop if 5% of subjects in either group experience inadvertent 
intravascular injection, inadvertent epidural or subarachnoid injection, and 
pneumothorax.  
b) The study will stop if 5% of subjects in either group experience LAST. 
 
LIA group 


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a) The study will stop if 5% of subjects experience LAST. 
 
We acknowledge that unanticipated adverse events may arise during this study.   
 
CISB, SISB, and LIA groups: 
a) The study will stop if 5% of subjects in any group (4 patients) experience an 
unanticipated serious adverse event (as defined in section 8.1 of IND protocol). 
 
If the study is stopped for any of the reasons listed above, a root cause analysis will be performed 
to determine cause of adverse event and relationship to study protocol.  The study team will 
formulate an appropriate plan of action to ensure patient safety. Such a plan may include, but is 
not limited to, protocol modifications, immediate termination of accrual, and adjustments in 
management of previously enrolled participants continuing to undergo study interventions. 
 
8.6 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site.  This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan (see section 10  “Study Monitoring, Auditing, and Inspecting”).  Medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 
 
9 Data Handling and Record Keeping 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (long term survival status that 
the subject is alive) at the end of their scheduled study period. 
9.2 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents.  Examples of these original documents and data records 


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include: hospital records, clinical and office charts, laboratory notes case report forms, and 
recorded data from automated instruments 
 
Data Management 
 
A study case report form (CRF)/data collection form will be established and utilized by the study 
team to record outcome measures.  The data will then be transferred to an electronic research 
database (REDCap).   Data from the electronic research database will be utilized for primary and 
secondary analysis.   
 
Data Security and Confidentiality 
 
All patient information will be de-identified and kept in secure locations where only authorized 
study personnel can have access. All computers are password protected and secured behind 
institution firewall.  Case report forms will be maintained, in a secure location within the 
institution campus.  
 
Data Quality Assurance 
 
All data will be entered by appropriately trained personnel.  This is a single site study.   Data will 
be collected manually and electronically abstracted through the use of our EMR and our OR 
database/ICU database.  Data collected will be manually entered into the RedCap system for 
electronic data storage and analysis.  
 
Every 50 of subject study data will be cross-referenced for accuracy. 
 
Data Clarification Process 
 
Incomplete, or erroneous data will be corrected by analyzing the patient’s electronic record. 
 
9.3 
Records Retention 
 
The sponsor-investigator will maintain records and essential documents related to the conduct of 
the study.  These will include subject case histories and regulatory documents.  Records will be 
maintained according to regulatory and institutional requirements.   
 
In order to constitute evidence with respect to product safety or regulatory or legal compliance, 
the Investigator agrees to retain study-related documents in a location that is secure and to which 
access can be gained if required.  The following documents must be archived: the Investigator’s 
File containing all required GCP documents, including signed Informed Consent Forms and 
Subject-related materials, and CRFs.   
 
With respect to coding case report forms and subject identification code list, as described in 
section 5.3, patients will be randomized using a randomization schedule.  Using this 
randomization schedule, an EXCEL spreadsheet application will be created which will include 
sequentially assigned subject-ID numbers and corresponding treatment assignments.  All case 


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report forms utilize this subject-ID numbers.  Case report forms are maintained in a de-identified 
manner by including subject ID, subject’s initials, and dates of pertinent study involvement.    
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
A data and safety monitoring plan will be incorporated within the protocol.  The goal of the data 
and safety monitoring plan is to make adequate provision to monitor the data collected to ensure 
the safety of subjects, and that adequate provisions to protect the privacy of subjects and the 
confidentiality of the data are maintained (45 CFR 46.111). The investigator will allocate 
adequate time for such monitoring activities.  The Investigator will also ensure that the monitor 
or other compliance or quality assurance reviewer is given access to all the study-related 
documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has 
adequate space to conduct the monitoring visit. 
 
Studies being conducted under an IND may be monitored during the conduct of the trial by staff 
from the Mayo Clinic Office of Research Regulatory Support.  Clinical trial monitoring may 
include review of the study documents and data generated throughout the duration of the study to 
help ensure the validity and integrity of the data along with the protection of human research 
subjects.  This will assist sponsor-investigators in complying with Food and Drug Administration 
regulations. 
 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
sponsor, and government regulatory agencies, of all study related documents (e.g. source 
documents, regulatory documents, data collection instruments, study data etc.).  The investigator 
will ensure the capability for inspections of applicable study-related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance offices. 
11 Ethical Considerations 
This study is to be conducted according to United States government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted local Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 
study.  The decision of the IRB concerning the conduct of the study will be made in writing to 
the sponsor-investigator before commencement of this study. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  This consent form will be submitted with the protocol for review and approval by the IRB 
for the study.  The formal consent of a subject, using the Approved IRB consent form, must be 


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obtained before that subject undergoes any study procedure.  The consent form must be signed 
by the subject or the subject’s legally authorized representative, and the individual obtaining the 
informed consent. 
12 Study Finances 
12.1 Funding Source 
 
Funding will be obtained internally through the institution from the Department of Orthopedic 
Surgery at Mayo Clinic Hospital, Methodist Campus.  The funds will be used to support the use 
of an anesthesia clinical research unit (ACRU) to recruit patients, collect data, and monitor for 
adverse events.  This will also fund a statistician to analyze data.  
 
13 Publication Plan 
 
Subsequent to trial closure, data will be analyzed, and a manuscript will be submitted to the 
appropriate journal, after consensus among all the investigators.  No funding agency is involved 
with this study.   
 
The study will be registered with www.ClinicalTrials.gov 
 
We plan on conducting a follow up study in accordance to this trial.  Data collected for the 
follow up study includes ASES scores (Section 2.0). 
 
14 References 
 
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Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet. 
2006;367(9522):1618-1625. 
2. 
Ullah H, Samad K, Khan FA. Continuous interscalene brachial plexus block versus parenteral 
analgesia for postoperative pain relief after major shoulder surgery. The Cochrane database of 
systematic reviews. 2014;2:CD007080. 
3. 
Johnson RL, Duncan CM, Hebl JR. Clinical Pathways for Total Joint Arthroplasty: Essential 
Components for Success. Advances in Anesthesia.29(1):149-171. 
4. 
Sulaiman L, Macfarlane RJ, Waseem M. Current concepts in anaesthesia for shoulder surgery. 
Open Orthop J. 2013;7:323-328. 
5. 
Bowens C, Jr., Sripada R. Regional blockade of the shoulder: approaches and outcomes. 
Anesthesiol Res Pract. 2012;2012:971963. 
6. 
Abdallah FW, Halpern SH, Aoyama K, Brull R. Will the Real Benefits of Single-Shot Interscalene 
Block Please Stand Up? A Systematic Review and Meta-Analysis. Anesth Analg. 2015. 
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Mariano ER, Afra R, Loland VJ, et al. Continuous interscalene brachial plexus block via an 
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Kean J, Wigderowitz CA, Coventry DM. Continuous interscalene infusion and single injection 
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Contreras-Dominguez V, Carbonell-Bellolio P, Sanzana ES, Ojeda-Greciet A, Orrego-Santos R. 
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Fontana C, Di Donato A, Di Giacomo G, et al. Postoperative analgesia for arthroscopic shoulder 
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Kerr DR, Kohan L. Local infiltration analgesia: a technique for the control of acute postoperative 
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12. 
Spangehl MJ, Clarke HD, Hentz JG, Misra L, Blocher JL, Seamans DP. The Chitranjan Ranawat 
Award: Periarticular injections and femoral & sciatic blocks provide similar pain relief after TKA: a 
randomized clinical trial. Clin Orthop Relat Res. 2015;473(1):45-53. 
13. 
Jiang J, Teng Y, Fan Z, Khan MS, Cui Z, Xia Y. The efficacy of periarticular multimodal drug 
injection for postoperative pain management in total knee or hip arthroplasty. J Arthroplasty. 
2013;28(10):1882-1887. 
14. 
Domb BG, Gupta A, Hammarstedt JE, Stake CE, Sharp K, Redmond JM. The effect of liposomal 
bupivacaine injection during total hip arthroplasty: a controlled cohort study. BMC Musculoskelet 
Disord. 2014;15:310. 
15. 
Bjornholdt KT, Jensen JM, Bendtsen TF, Soballe K, Nikolajsen L. Local infiltration analgesia 
versus continuous interscalene brachial plexus block for shoulder replacement pain: a 
randomized clinical trial. Eur J Orthop Surg Traumatol. 2015. 
16. 
Costantino F. Local Anaesthesia Efficacy as Postoperative Analgesia for Open Shoulder 
Instability Surgery: A Prospective Randomised Controlled Study. Journal of Anesthesia & Clinical 
Research. 2012. 
17. 
Lehmann N, Joshi GP, Dirkmann D, et al. Development and longitudinal validation of the overall 
benefit of analgesia score: a simple multi-dimensional quality assessment instrument. Br J 
Anaesth. 2010;105(4):511-518. 
18. 
Busch CA, Shore BJ, Bhandari R, et al. Efficacy of periarticular multimodal drug injection in total 
knee arthroplasty. A randomized trial. The Journal of bone and joint surgery American volume. 
2006;88(5):959-963. 
19. 
Guild GN, 3rd, Galindo RP, Marino J, Cushner FD, Scuderi GR. Periarticular regional analgesia in 
total knee arthroplasty: a review of the neuroanatomy and injection technique. Orthop Clin North 
Am. 2015;46(1):1-8. 
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