Prolonging the Interscalene Brachial Plexus Block by Adding Liposomal Bupivacaine or Preservative Free Dexamethasone to Bupivacaine: a Non-inferiority Trial
Phase: PHASE4
Conditions: Shoulder Pain
Sponsor: Hospital for Special Surgery, New York

 
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Prolonging the Interscalene brachial plexus block 
by adding liposomal bupivacaine or preservative 
free dexamethasone to bupivacaine: a non-
inferiority trial  
 
 
FUNDER: 
Department of Anesthesiology 
PROTOCOL NO.: 
2019-0424 
VERSION & DATE: 
 
                  NCT: 
5/28/2021 
04047446 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Protocol Number: 2019-0424  
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ............................................ 2 
PROTOCOL SYNOPSIS ........................................... 3 
1.0 
INTRODUCTION ............................................. 5 
2.0 
OBJECTIVE(S) OF CLINICAL STUDY .......... 6 
3.0 
STUDY HYPOTHESES .................................. 8 
4.0 
STUDY DESIGN ............................................. 8 
4.1 
Endpoints ....................................................................................................................... 8 
4.1.1 
Primary Endpoint ...................................................................................................... 8 
4.1.2 
Secondary Endpoints ................................................................................................ 8 
4.2 
Study Sites ..................................................................................................................... 9 
5.0 
STUDY POPULATION ................................... 9 
5.1 
Number of Subjects ........................................................................................................ 9 
5.2 
Inclusion Criteria............................................................................................................. 9 
5.3 
Exclusion Criteria ........................................................................................................... 9 
6.0 
PROCEDURES ............................................. 10 
6.1 
Intraoperative Protocol ................................................................................................. 10 
6.2 
Postoperative Protocol ................................................................................................. 10 
6.3 
Data Collection ............................................................................................................. 10 
7.0 
STATISTICAL ANALYSIS ............................ 12 
8.0 
ADVERSE EVENT ASSESSMENT .............. 12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Protocol Number: 2019-0424  
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PROTOCOL SYNOPSIS 
Protocol Title: 
Prolonging the Interscalene brachial plexus block by adding 
liposomal bupivacaine or preservative free dexamethasone to 
bupivacaine: a non-inferiority trial 
Protocol Number: 
2019_0424 
Protocol Date: 
5/28/2021 
Sponsor: 
Department of Anesthesiology 
Principal Investigator: 
David Kim, MD 
Objective: 
The intervention being studied is the usage of liposomal 
bupivacaine in conjunction of standard bupivacaine in an 
interscalene block (ISB). It is being compared to standard 
bupivacaine. Does the mixture of liposomal bupivacaine and 
bupivacaine provide extended analgesia in comparison to 
bupivacaine with preservative free dexamethasone? 
Study Design: 
Randomized Controlled Clinical Trial  
Enrollment: 
112 
Subject Criteria: 
 
1. Patients scheduled for elective outpatient arthroscopic 
shoulder surgery  
2. ASA I-III 
3. Ages 18 years or older 
Data Collection: 
Sources: EPIC, Medical Records, and Patient Reported. 
Variables: Demographics, Surgery type, Incidence of adverse 
effects (Horner’s, hoarseness, dyspnea, hiccups), sensory exam 
(alcohol swab), motor exam (handgrip strength: 
present/weak/absent), NRS Pain scores at rest and at 
movement, Patient satisfaction, Opioid Consumption, 
Neuropraxia, Nerve Block Success, Length of PACU stay, Time 
to meet discharge criteria, Post Anesthetic discharge scoring 
system (assessed every 15 min after one hour in PACU, Brief 
Pain Inventory short form, LAST (local anesthetic systemic 
toxicity), Admission for pain.  
Statistical Analysis: 
• 
Alpha level: 0.05 
• 
Beta or power level: 0.8 

 
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• 
Primary outcome variable estimate (mean +/- s.d. for 
continuous outcome, frequency/percentage for 
categorical variable): Mean difference of 1.3 +/- 1.0 
• 
Interim analysis at 50% enrollment mark 
• 
Proposed analysis: T-Test 
• 
Effect size or change expected between groups: 
Noninferior margin of 1.3 
• 
Total sample size required: 102 + 10% (for 
attrition/withdrawal) = 112 
 
 
 

 
Protocol Number: 2019-0424  
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1.0 INTRODUCTION 
 
 
Liposomal bupivacaine has chemical properties that indicate that it could provide 
longer block duration that standard bupivacaine. In this study, patients receiving a shoulder 
scope will be enrolled and randomized to receive either liposomal bupivacaine and standard 
bupivacaine or only bupivacaine. Preservative free dexamethasone is a well-studied additive 
that has shown prolongation of the interscalene block (up to 22 hours) and has been well 
adopted as a very common clinical practice. Liposomal Bupivacaine has recently been 
approved by the FDA for interscalene nerve blocks. The study that was used to grant its 
approval compared the liposomal bupivacaine to placebo. There has yet to be a study 
comparing the newly approved additive to a comparable additive. Unlike other studies that 
compared it to placebo or a plain local anesthetic, the goal of this study is to compare 
liposomal bupivacaine to a long acting interscalene block with preservative free 
dexamethasone. Liposomal bupivacaine is being advertised as a single-shot alternative to 
catheters. There have been comparative studies with liposomal bupivacaine infiltration with 
catheters but no comparison to additives such as dexamethasone. 
 
 
Rebound pain is a known phenomenon that led clinicians to seek out blocks that 
would last longer. Williams et al1 demonstrated that by prolonging the block for over 48 
hours for knee surgery, it mitigates the intense rebound pain we witness with shorter acting 
blocks. Abdullah et al2 demonstrated in their meta-analysis that the interscalene block 
provides little benefit for shoulder surgery if the duration is less than 24 hours. There are 
several prospective studies, and reviews supporting preservative-free dexamethasone 
perineural application to prolong the block3,4,5 
 
 
Liposomal bupivacaine (Exparel) has been FDA approved for infiltration use. Just 
recently, it has been approved for the interscalene nerve block. There is only one 
prospective study comparing liposomal bupivacaine mixture to plain bupivacaine with results 
showing modest benefit with regards to worst pain and patient satisfaction after following 
patients over a week6. It is unclear if the effect would be the same if the liposomal 
bupivacaine mixture did not contain any standard bupivacaine. However, the reason the 
authors added standard bupivacaine was the delayed onset of liposomal bupivacaine 
precludes its use as a surgical anesthetic for the study. As the goal of the study was to 
observe the analgesic effect of adding liposomal bupivacaine to the interscalene block, it 
would be a fairer comparison group to measure it against a proven adjuvant like 
dexamethasone. This study will help elucidate liposomal bupivacaine’s analgesic benefit in 
prolonging nerve blocks by comparing it to an effective alternative. The study led to 
liposomal bupivacaine’s FDA approval compared its analgesic properties to placebo7. 
 
 
1. Williams BA, Bottegal MT, Kentor ML, Irrgang JJ, Williams JP. Rebound pain 
scores as a function of femoral nerve block duration after anterior cruciate ligament 
reconstruction: retrospective analysis of a prospective, randomized clinical trial. Reg Anesth 
Pain Med 2007; 266: 516-524. 

 
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2. Abdallah FW1, 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 May;120(5):1114-29. 
 
3. Kirkham K, Jacob-Guillarmod A, Albrecht E, Kirkham K. Optimal Dose of 
Perineural Dexamethasone to Prolong Analgesia After Brachial Plexus Blockade: A 
Systematic Review and Meta-analysis. January 2018. Vol 126. No 1, 270-279 
 
4. Liu J, Richman K, Grodofsky S, Huffman G, Kelly J, Glaser D, Elkassabany N. Is 
there a dose response of dexamethasone as adjuvant for supraclavicular brachial plexus 
nerve block? A prospective randomized doubleblinded clinical study. Journal of Clinical 
Anesthesia. 2015, 27, 237-242 
 
5. Vera P, Pulai I, Tao GC, Manikantan P, Keller B, Connelly NR. Dexamethasone 
with bupivacaine increases duration of analgesia in ultrasound-guided interscalene brachial 
plexus blockade. Eur J Anaesthesiol. 2010 Mar;27(3):285-8. 
 
6. Vandepitte C, Kurosawa M, Witvrouw R, Ludwig A, Bellemans J, Cortez K, 
Vanelderen P, Mesotten D, Leanne I, Heylen M, Van Boxstael S, Golebiewski M, Van del 
Velde M, Knezevic N, Hadzic A. Addition of liposome bupivacaine to bupivacaine HCL 
versus bupivacaine HCL alone for interscalene brachial plexus block in patients having 
major shoulder surgery. RAPM.2017 May/June;42(3): 334-341 
 
7. Patel M, Gadsden J, Bao X, Bendtsen T. Brachial plexus block with liposomal 
bupivacaine for total shoulder arthroplasty or rotator cuff repair: results from a randomized 
controlled trial. Poster presented at: The New York School of Regional Anesthesia 16th 
Annual Fall Symposium; September 23-24, 2017; New York, NY. 
 
 
 
This study will aid in validating or invalidating the claim that liposomal bupivacaine 
can effectively provide analgesia in the immediate postoperative period, up to 72 hours. By 
comparing the new, FDA approved local anesthetic to a well-studied cost-effective 
alternative rather than to a placebo, the study will provide new knowledge to the literature. If 
the study shows that exparel is non-inferior to dexamethasone over 72 hours, it will potential 
deter its costly use 
2.0 OBJECTIVE(S) OF CLINICAL STUDY 
 
 
If liposomal bupivacaine does not provide analgesia as adequately as the alternative 
(preservative-free dexamethasone bupivacaine), it will discourage its costly use. Does the 
mixture of liposomal bupivacaine and bupivacaine provide extended analgesia in 
comparison to bupivacaine with preservative free dexamethasone? 
The primary outcome is average NRS pain score at rest over 72 hours (average of 3 24-
hour time point [24, 48, 72 hours]). 
Secondary Outcomes: 
1. NRS pain scores at rest on PACU, POD1, POD2, POD3, POD4, POD7 
2. NRS pain scores with movement in PACU, POD 1, POD2, POD3, POD4, POD7 

 
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3. Brief Pain Inventory short-form in PACU, POD1, POD2, POD3, POD4, POD7 
4. Opioid consumption in PACU, POD1, POD2, POD3, POD4, POD 7 
5. Patient Satisfaction with pain treatment in PACU, POD 1, POD 2, POD 3, POD 4, 
POD 7 
6. Duration of analgesic block via RA phone call 24, 48, 72 hours after block 
placement (or longer if block continues): Patient’s will be asked “Since being 
discharged, when did you first take an analgesic medication for shoulder pain?” and 
“When did your pain relief from the block completely wore off?” 
7. Sensory resolution in PACU, POD1, POD2, POD3, POD4, POD7 (full resolution of 
block will be reported by the patient via RA phone call 24, 48, 72 hours after block 
placement or longer if duration continues, “When did your numbness completely 
resolve and returned to normal?”, will likely be until POD 1, but would continue until 
block resolution) 
8. Motor block resolution in PACU, POD1, POD2, POD3, POD4, POD7 (full 
resolution of block will be reported by the patient via RA phone call 24, 48, 72 hours 
after block placement or longer if block continues, “When did your arm or hand 
weakness resolve and returned to normal?”, will likely be until POD 1, but would 
continue until block resolution) 
9. Success of interscalene block: C5 Dermatome distribution will be assessed in the 
PACU by the anesthesiologist (co-i). Alcohol swab test (2-normal cold sensation, 1-
diminished/dull, 0-absence of cold sensation). Motor test: hand grip (normal-2, weak-
1, absent-0) 
10. Adverse effects: sensory-motor deficits: incidence of paresthesia / neuropraxia: 
persistent tingling, numbness on POD7, if patient reports persistent neuropraxia after 
POD7, will follow up on POD14. If neuropraxia persists, will notify attending 
anesthesiologist and continue to follow until postoperative neurological symptoms 
(PONS) resolve. On POD 7, patients will be asked “on the side where surgery was 
performed, do you have any numbness, tingling, or weakness in the hand or fingers? 
11. If the response to continued numbness/tingling in fingers on POD7 is yes, 
adverse effects will be asked on POD 14. 
12. Incidence of ISB related side effects: Horner’s syndrome, hoarseness, hiccups, 
dyspnea in PACU, POD1-4,7 
13. Time to readiness for PACU discharge (time of PACU admission to time of 
readiness to discharge, measured by Post Anesthetic Discharge Scoring System) 
evaluated every 15 minutes 
 
14. Length of PACU stay (time of PACU admission to PACU discharge) 

 
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3.0 STUDY HYPOTHESES 
 
The prolongation of analgesia provided by adding liposomal bupivacaine to 
bupivacaine is non-inferior to Bupivacaine with preservative free dexamethasone. 
4.0 STUDY DESIGN 
4.1 
Endpoints 
4.1.1 
Primary Endpoint 
• 
The primary outcome is average NRS pain score at rest over 72 hours (average 
of 3 24-hour time point [24, 48, 72 hours]). 
 
4.1.2 
Secondary Endpoints 
o 1. NRS pain scores at rest on PACU, POD1, POD2, POD3, POD4, POD7 
o 2. NRS pain scores with movement in PACU, POD 1, POD2, POD3, 
POD4, POD7 
o 3. Brief Pain Inventory short-form in PACU, POD1, POD2, POD3, POD4, 
POD7 
o 4. Opioid consumption in PACU, POD1, POD2, POD3, POD4, POD 7 
o 5. Patient Satisfaction with pain treatment in PACU, POD 1, POD 2, POD 
3, POD 4, POD 7 
o 6. Duration of analgesic block via RA phone call 24, 48, 72 hours after 
block placement (or longer if block continues): Patient’s will be asked 
“Since being discharged, when did you first take an analgesic medication 
for shoulder pain?” and “When did your pain relief from the block 
completely wore off?” 
o 7. Sensory resolution in PACU, POD1, POD2, POD3, POD4, POD7 (full 
resolution of block will be reported by the patient via RA phone call 24, 
48, 72 hours after block placement or longer if duration continues, “When 
did your numbness completely resolve and returned to normal?”, will 
likely be until POD 1, but would continue until block resolution) 
o 8. Motor block resolution in PACU, POD1, POD2, POD3, POD4, POD7 
(full resolution of block will be reported by the patient via RA phone call 
24, 48, 72 hours after block placement or longer if block continues, “When 
did your arm or hand weakness resolve and returned to normal?”, will 
likely be until POD 1, but would continue until block resolution) 
o 9. Success of interscalene block: C5 Dermatome distribution will be 
assessed in the PACU by the anesthesiologist (co-i). Alcohol swab test 
(2-normal cold sensation, 1-diminished/dull, 0-absence of cold sensation). 
Motor test: hand grip (normal-2, weak-1, absent-0) 
o 10. Adverse effects: sensory-motor deficits: incidence of paresthesia / 
neuropraxia: persistent tingling, numbness on POD7, if patient reports 
persistent neuropraxia after POD7, will follow up on POD14. If 
neuropraxia persists, will notify attending anesthesiologist and continue to 

 
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follow until postoperative neurological symptoms (PONS) resolve. On 
POD 7, patients will be asked “on the side where surgery was performed, 
do you have any numbness, tingling, or weakness in the hand or fingers? 
o 11. If the response to continued numbness/tingling in fingers on POD7 is 
yes, adverse effects will be asked on POD 14. 
o 12. Incidence of ISB related side effects: Horner’s syndrome, hoarseness, 
hiccups, dyspnea in PACU, POD1-4,7 
o 13. Time to readiness for PACU discharge (time of PACU admission to 
time of readiness to discharge, measured by Post Anesthetic Discharge 
Scoring System) evaluated every 15 minutes 
o 14. Length of PACU stay (time of PACU admission to PACU discharge) 
 
 
4.2 
Study Sites 
This study will take place at the main campus of the Hospital for Special Surgery (HSS). 
5.0 STUDY POPULATION 
5.1 
Number of Subjects 
112 
5.2 
Inclusion Criteria 
Subjects of either gender will be included if: 
1. Scheduled for elective outpatient arthroscopic shoulder surgery 
2. ASA I-III 
3. Age 18 years or older 
5.3 
Exclusion Criteria 
Subjects will be excluded from the study if: 
• 
History of allergy to local anesthetic, or one of the study medications  
• 
Pre-existing neurological deficits 
• 
Psychiatric or cognitive disorders that prohibit patients from following study 
protocol  
• 
History of drug or alcohol abuse 
• 
Chronic Opioid use (longer than 3 months) 
• 
Chronic pain syndromes 
• 
Infection at the site of injection 
• 
Patients with severe pulmonary disease 
• 
Herniated cervical disc, cervical myelopathy 
• 
Contraindication for general anesthesia and/or interscalene nerve blocks 
• 
Pregnancy 
• 
Open shoulder arthrotomies 
• 
Non-English speakers 

 
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6.0 PROCEDURES 
6.1 
Intraoperative Protocol 
Following sedation, the interscalene block will be done using an ultrasound-guided, in-
plane approach. The anesthesiologist will target below the C5 nerve root. A 22 gauge 1.5-2 
inch needle is advanced in-plane from lateral medial through the middle scalene muscle 
until the needle tip is positioned in the interscalene groove between the C5 and C6 nerve 
roots. Patients will be randomized to two groups: 
 
1. Dexamethasone: 15mL of 0.5% bupivacaine with 4mg of preservative-free 
dexamethasone will be injected 
2. Exparel: 10mL of 133mg liposomal bupivacaine with 5mL of 0.5% bupivacaine 
(15mL total) 
 
Premedication will consist of 2-5mg of Midazolam. After block induction, general anesthesia 
will be performed by administration of propofol (induction doses of 2mg/kg) by the 
anesthesiologist. LMA will be inserted and anesthesia maintained with Propofol infusion and 
Fentanyl (Fentanyl 25-50mcg titrated up to 200mcg) as needed. To avoid PONV, 4mg 
Decadron (Dex group) or 8mg Decadron (Exparel group) will be administered, as well as 
4mg Zofran for both groups. Before the end of surgery, 15-30mg Ketorolac will be given 
(30mg for patients under 65 and over 50kg, 15mg for patients under 65 or under 50kg). 
 
6.2 
Postoperative Protocol 
 
Postop medication includes IV acetaminophen (1g IV upon PACU arrival, 750mg if <50kg), 
ketorolac (30mg IV q hours following intraop dose if not yet discharged, 15mg for 65 years 
or older, <50kg). For pain control, tramadol 50mg q 6 hours PRN (mild pain [1-3]); tramadol 
100mg q hours (or 75mg if <50kg) (moderate pain [4-6]; oxycodone 5mg q 3 hours (severe 
pain [7-10]); dilaudid IV for rescue analgesia. Patients will be discharged with Naproxen 
500mg q 12 hours, Percocet 5-325mg 1-2 tabs q 4 hours PRN, and Zofran 8mg q 8 hours. 
6.3 
Data Collection 
The following data will be collected: 
 
Pre-operative/Baseline 
• 
DOB 
• 
Name 
• 
Gender 
• 
Race 
• 
Ethnicity  
• 
Height, weight, BMI 
• 
ASA 
• 
MRN 

 
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• 
Preop NRS 
• 
Preop Sensory tests 
• 
Preop Brief Pain Inventory 
 
 
Surgical procedure (Intra-operative) 
• 
Surgeon and Anesthesiologist  
• 
Surgery start and end 
• 
Length of Surgery  
• 
Anesthesia start and end 
• 
Induction start and end 
• 
Type of Shoulder surgery 
• 
Laterality 
• 
Intraoperative fentanyl and dilaudid use 
 
Post-Operative Day 0 (PACU) 
• 
Vital Signs (systolic bp, diastolic bp, pulse) 
• 
Ambulation (steady gait/no dizziness, requires assistance, unable to 
ambulate/dizziness) 
• 
Nausea and Vomiting 
• 
Pain (NRS) 
• 
Surgical bleeding  
• 
Length of PACU stay (OR to PACU transfer time, PACU discharge 
time) 
 
Post-Operative Day 1 (POD 1) 
• 
NRS 
• 
Brief pain inventory  
• 
Medication Usage 
• 
Block Resolution 
• 
Side Effects 
• 
Satisfaction  
 
Post-Operative Day 2 (POD 2) 
• 
NRS 
• 
Brief pain inventory  
• 
Medication Usage 
• 
Block Resolution 
• 
Side Effects 
• 
Satisfaction  
 
 
 
 
Post-Operative Day 3 (POD 3) 
• 
NRS 
• 
Brief pain inventory  
• 
Medication Usage 
• 
Block Resolution 
• 
Side Effects 
• 
Satisfaction and Blinding  

 
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Post-Operative Day 4 (POD 4)  
 
• 
NRS 
• 
Brief pain inventory  
• 
Medication Usage 
• 
Block Resolution 
• 
Side Effects 
• 
Satisfaction  
 
Post-Operative Day 7 (POD 7) 
• 
NRS 
• 
Brief pain inventory  
• 
Medication Usage 
• 
Side Effects 
• 
Satisfaction  
 
Post-Operative Day 14 (POD 14) 
• 
Side Effects 
  
 
7.0 STATISTICAL ANALYSIS 
• 
Proposed analysis: T-Test 
• 
Interim analysis planned: Yes, at the 50% mark of 56 patients 
• 
Alpha level:  0.05 
• 
Beta or power level: 0.8 
• 
Primary outcome variable estimate (mean +/- s.d. for continuous outcome, 
frequency/percentage for categorical variable): Mean difference of 1.3 +/- 1.0 
• 
Number of groups being compared: 2 
• 
Effect size or change expected between groups:  Noninferior margin of 1.3 
• 
Resulting number per group: 51 
• 
Total sample size required: 102 + 10% (for attrition/withdrawal) = 112 
 
 
 
8.0 ADVERSE EVENT ASSESSMENT 
All Adverse Events (AEs) will be reported in the final study report.