Clinical trial NCT03887650
Conditions: Post-operative Pain Total Shoulder Arthroplasty Osteoarthritis of the Shoulder Pain Management
Keywords: Brachial Plexus Liposomal Bupivacaine Dexamethasone Interscalene Bupivacaine Shoulder Arthroplasty Regional anesthesia Exparel
Sponsor: Hartford Hospital
Start date: 2019-03-11; Completion date: 2022-03-08
Enrollment: 90 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This will be a single-center, prospective, randomized controlled cross-sectional study comparing interscalene brachial plexus block with liposomal bupivacaine versus bupivacaine with epinephrine and PF dexamethasone in patients undergoing primary shoulder arthroplasty. Primary endpoint will be total opioid consumption in the first three post-operative days.

Detailed description:

Arms: arm 1: 10mL Liposomal Bupivacaine 1.3% (133 mg) mixed with 10mL of 0.5% Bupivacaine (total volume 20mL) in single injection interscalene brachial plexus block arm 2: 20mL 0.5% Bupivacaine with 5 mg PF dexamethasone and 5 mcg epinephrine (total volume 20.5mL) in single injection interscalene brachial plexus block
Interventions: intervention 1: Liposomal Bupivicaine 1.3% intervention 2: Bupivacaine 0.5%
Intervention descriptions: intervention 1: 10mL Liposomal Bupivacaine 1.3% (133 mg) mixed with 10mL of 0.5% Bupivacaine (total volume 20mL) in single injection interscalene brachial plexus block intervention 2: 20mL 0.5% Bupivacaine with 5 mg PF dexamethasone and 5 mcg epinephrine (total volume 20.5mL) in single injection interscalene brachial plexus block

Protocol documents:
Prot_SAP_000.pdf: 
HHC-2018-0231, LIBERATE, 08/25/22
LIBERATE-LIposomal Bupivacaine vERsus Adjuncts in Total shouldErs
Background:
Pain control after orthopedic surgery can be challenging, especially in light of the goals of shortened 
hospital lengths-of-stay, reduced opioid consumption, and increased patient satisfaction. With the 
estimated incidence of new persistent opioid use of 6.5% after surgery in the U.S. 1, reducing opioid 
consumption (and therefore the potential for addiction) has become a major objective in today’s 
healthcare environment. A multimodal analgesic approach that includes non-opioid medications and 
peripheral nerve blockade with local anesthetic is rapidly gaining popularity as a means to accomplish 
this goal. Previous studies have demonstrated that the addition of adjuncts, such as dexamethasone, to 
local anesthetics can prolong peripheral nerve blockade to greater than 24 hours postoperatively 2–4, 5 . It 
has also been shown that adding non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and 
gabapentin to pain control regimens in addition to peripheral nerve blockade decreases opioid 
consumption and hospital length of stay.6
In 2011, the FDA (Food and Drug Administration) approved liposomal bupivacaine (ExparelⓇ), a 
sustained release formulation of bupivacaine, for surgical site infiltration. Liposomal bupivacaine has 
been described as providing prolonged analgesia for up to 72 hours when administered as an infiltrative 
technique. 7 There have been few studies investigating liposomal bupivacaine and its effect on pain relief 
and opioid consumption. The majority of these studies focus on an intraoperative infiltrative technique by 
the surgeon as compared to single injection peripheral nerve blockade with mixed results that trend 
towards a lack of a statistical difference between the two 8;9;10. There are limited studies demonstrating its 
superiority over standard local anesthetics, like bupivacaine, in perineural blocks. 8,9,11–13 Only one study 
thus far has examined the use of liposomal bupivacaine for interscalene peripheral nerve blockade, 12 but it 
was not until April 2018 that liposomal bupivacaine was FDA-approved for use in interscalene peripheral 
nerve blockade. Given the limited amount of evidence comparing liposomal bupivacaine to bupivacaine 
with additives in peripheral nerve blockade, it is unclear whether liposomal bupivacaine can provide 
longer analgesia (as evidenced by time to first opioid) or can reduce opioid consumption as
compared to standard local anesthetic with additives.
In this study, we are seeking to compare our standard approach of a single injection interscalene brachial 
plexus blockade using bupivacaine 20 mL 0.5%, 5 mg dexamethasone, and 5 mcg epinephrine to the 
same volume of a single injection interscalene brachial plexus blockade using liposomal bupivacaine 
mixed with bupivacaine 0.5%. The primary endpoint of the study is the total amount of opioid consumed 
in morphine milligram equivalents (MMEs) by the patient postoperative days 0 through 3 (PODs #0-3) 
for primary total shoulder arthroplasty (TSA) patients, including anatomic and reverse TSA.
Purpose/Aim:
We are seeking to evaluate the effect of liposomal bupivacaine (10ml liposomal bupivacaine 133 mg 
mixed with 10 mL of 0.5% bupivacaine for a total volume of 20 ml of injectate) in a single injection 
interscalene brachial plexus blockade, as compared to our standard approach single injection interscalene 
brachial plexus blockade using bupivacaine 0.5% + 5 mg dexamethasone + 5 mcg epinephrine (20 mL 
volume of injectate).
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/02/2022
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/02/2022


HHC-2018-0231, LIBERATE, 08/25/22
Our primary endpoint is the total opioid consumption postoperative days 0 through 3 (PODs #0-3) after 
TSA, standardized to morphine milligram equivalents (MMEs).
Secondary endpoints include:
●
Time to first opioid medication
●
Pain assessment at post anesthesia care unit (PACU) arrival, PACU discharge, POD #1, POD #2, 
POD #4, and POD #60 using questions from the Modified Brief Pain Inventory (MBPI)
●
Hospitallength-of-stay
●
Assessment of patient overall satisfaction with pain control on a scale from 0 = very dissatisfied 
to 10 = very satisfied.
●
Incidence of distress from block numbness on a scale of 0 to 10 with 0 = not at all and 10 = very 
much (adapted from the Overall Benefit of Analgesia Score)
●
Duration of sensory and motor nerve block while in the hospital
●
Notation of adverse postoperative events or block complications up to 60 days after surgery 
including:
●
Postoperative nausea/vomiting (PONV), as defined by non-prophylactic administration of 
antiemetics during hospital stay within 24 hours post-operation
●
Local anesthetic systemic toxicity (LAST) as defined by any treatment for this condition 
during hospital admission
●
Postoperative neurologic symptoms (PONS) as defined as sensory or motor dysfunction 
in appropriate anatomic distribution of block present at > 4 days post-surgery 14
●
Postoperative ED visit or readmission due to uncontrolled pain within 60 postoperative 
days
●
Bleeding/hematoma at the site of local anesthetic injection that develops prior to 
discharge from the hospital
●
Hospital readmission within 30 days from discharge
Hypothesis:
We hypothesize that using liposomal bupivacaine in interscalene brachial plexus blockade will result in a 
reduced total opioid consumption (in MMEs) during postoperative days 0 through 3, as well as increased 
duration of blockade (represented by time to first analgesic dose).
Study Design:
This will be a single-center, prospective, randomized controlled cross-sectional study comparing the total 
opioid consumption during postoperative days 0 through 3 in two groups of patients undergoing primary 
TSA, both anatomic and reverse. The individuals collecting data will be blinded to the patient’s 
randomization group. Due to the differences in appearance of the medications used, blinding of the 
individual performing the procedure will not be possible as the anesthesiologist will see the medication 
when assessing for intravascular needle placement. IRB approval was obtained.
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/02/2022
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/02/2022


Human Subjects:
Inclusion Criteria:
Patients meeting all of the following criteria will be included:
-
Patient age >18 years, with no upperlimit
-
Lack of language barrier
-
Informed consentobtained
-
Presenting for primary total shoulder arthroplasty (TSA), both anatomic and reverse, by a 
specialty-trainedsurgeon
-
American Society of Anesthesiology (ASA) physical status score I- III
Exclusion Criteria:
Patients meeting any of the following criteria will be excluded:
-
Presence of a language barrier
-
Inability to complete telephone and/or paper questionnaire
-
Lack of consent
-
Allergy to local anesthetic
-
Inability of patient to participate in standard multimodal pain regimen (i.e. tylenol, celecoxib, 
ibruprofen, or opiods)
-
Chronic pain syndrome and/or preoperative opioid use > 50 MME per day (including extended- 
release formulations and methadone)15
-
Preoperative consultation to chronic pain service
-
Active medical or recreational use of inhaled/ingested marijuana/cannabinoid products
-
History of (<3 months) or current substance abuse, including any illicit drugs or excessive alcohol 
consumption as defined by the Office of Disease Prevention and Health Promotion (4 or more 
drinks per day or 8 or more drinks per week for women and 5 or more drinks per day or 15 or 
more drinks per week for men)16
-
Baseline peripheral neuropathy of the brachial plexus
-
Contraindication to receiving single shot peripheral nerve blockade; including antithrombotic 
medications as per most recent American Society of Regional Anesthesiology (ASRA) guidelines 
17 , coagulopathy or coagulation disorder, or infection at injection site
-
Severe chronic obstructive pulmonary disease (COPD) or other significant pulmonary disease 
where interscalene nerve block would be contraindicated due to concern for respiratory failure 
from phrenic nerve palsy
-
Weight < 45 kg, given concern for local anesthetic toxicity at dosages given for the study
-
ASA score IV-V
-
Revisionarthroplasty
-
Anatomic abnormality that limits or prevents the patient from receiving an interscalene nerve 
block
-
Pregnant, nursing, or planning to become pregnant during the study or within 1 month after the 
shoulder replacement surgery
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/02/2022
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/02/2022


LIBERATE, 10/24/2019
Post-Enrollment Exclusion:
-
Block failure, as defined by a lack of sensory and motor blockade over incisional areas/shoulder
-
Loss to follow-up after hospital discharge
Procedures/Methods:
The surgeon’s medical executive assistant will notify the research team when a total shoulder 
arthroplasty surgery is booked with the surgeon. During the surgeons’ preoperative visit with the 
potential subject, the surgeon will explain the patient potentially will be approached during their 
PREPARE visit for this study. The research team will screen the potential research subject, and patients 
will be approached and consented for the study in the preoperative PREPARE clinic by a member of the 
research team, with an attending anesthesiologist or regional anesthesia fellow on the acute pain service 
immediately available to answer any questions regarding the study (see consent form).
Details of the procedure are as follows: Prior to any procedure, the patients are checked into the 
preoperative holding area (POHA), surgical consent is reviewed, and the patient’s operative site is marked.
A preoperative assessment of the patient’s motor and sensory function of the operative extremity
will be performed to establish a baseline to compare to postoperative function. Motor function will be 
assessed by shoulder abduction and elbow flexion using the Oxford scale of muscle strength grading 18. 
Sensory function will be assessed on the shoulder by assessing sensation to a pin prick on the shoulder in 
the axillary nerve distribution using the end of a paperclip. The sensory function will be measured using a 
4-point scale (0-3) with 0 = no sensation, 1 = sensation to pressure only, 2 = paresthesia, and 3 = full 
sensation. A peripheral intravenous catheter is inserted and standard monitors, including pulse oximetry, 
blood pressure monitoring every 5 minutes, and 3-lead EKG are applied. Nasal cannula oxygen at 2L/min 
is administered. All patients receive mild sedation with midazolam or propofol prior to peripheral nerve 
blockade. Patients are positioned in a 45-degree semi-upright position with the head turned to the 
contralateral side of surgical site.
Single injection interscalene brachial plexus blockade is performed by one of 3 regional anesthesiologists 
or by one of 3 regional anesthesia fellows under the direct supervision of 6 attending regional 
anesthesiologists. A high-frequency linear ultrasound transducer is used to locate the brachial plexus at 
the level of the nerve roots in the neck (interscalene approach). Ultrasound guidance is utilized to monitor 
the distribution of local anesthetic deposited via a 22G short bevel needle using an in-plane approach. In 
the control group, the local anesthetic solution consists of bupivacaine 0.5% + 5 mg preservative-free 
dexamethasone + 5 mcg epinephrine for a total of 20 mL volume deposited perineurally. The liposomal 
bupivacaine group consists of a total of 133 mg (10 mL) liposomal bupivacaine + 10 mL 0.5% 
bupivacaine (to account for early block coverage) for a total of 20 mL volume deposited perineurally.
Injection of local anesthetic will be achieved with a 10mL syringe under low pressure and with frequent 
aspiration performed to minimize risk of intravascular injection. During the nerve blockade, patients will 
be mildly sedated with intravenous midazolam or propofol with the goal to remain conversive, especially 
with regard to the occurrence of any paresthesias during block placement for safety purposes. Due to the 
difference in physical appearance of the study and control medications, the syringe of medication for 
injection will be held under an opaque towel during the block procedure so the patient remains blinded.
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/02/2022
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/02/2022


After placement of the single injection brachial plexus block and prior to induction of general anesthesia 
in the operating room, the patients will be evaluated for block failure with an assessment of motor and 
sensory function in the same manner performed pre-nerve block. The time of this assessment will be  
recorded to monitor the time from block placement to the time of assessment. At least 15 minutes 
should elapse between block placement and the pre-induction assessment of motor and sensory function.
The patients will be taken to the operating room (OR) for their primary TSA procedures, as performed by 
a specialty-trained shoulder surgeon. A standardized multimodal analgesic regimen for all patients will be 
followed, including preoperative oral acetaminophen 975 mg and celecoxib 200 mg if there are no 
contraindications to these medications. Medications administered preoperatively will be evaluated via 
query of electronic medical record (EMR). Intraoperatively, induction of general anesthesia will be 
achieved using propofol 1-2 mg/kg, fentanyl 1-3mcg/kg, and lidocaine 0.5-1 mg/kg followed by 
paralyzation with rocuronium 0.5-1 mg/kg prior to securing the trachea with endotracheal tube. IV 
fentanyl will be given periodically during the intraoperative course as needed for pain control. IV 
decadron will not be given for prophylaxis of postoperative nausea and vomiting, alternative medication 
will be utilized as deemed appropriate by the attending anesthesiologist. Medications administered 
intraoperatively will be evaluated via query of electronic medical record (EMR). Postoperative analgesia 
in the post-anesthesia care unit (PACU) will consist of intravenous hydromorphone and/or fentanyl as 
needed. Medications administered in the PACU will be evaluated via query of electronic medical record 
(EMR).Postoperative analgesia after PACU discharge and while on the floor will consist of of 
scheduled acetaminophen, scheduled NSAID (celecoxib or ibuprofen), and as-needed opioid medication 
(oxycodone, hydromorphone, or tramadol depending on patient requirements and tolerances).
All patients will be receive an in-person evaluation at the time of post-anesthesia care unit (PACU) 
discharge and on the morning of POD #1 using questionnaires modified from the validated Modified 
Brief Pain Inventory 19 (see attached questionnaires). Patients will receive a sensory and motor exam on 
the operative side in the PACU and on POD#1 prior to discharge. Medications administered during 
admission will be evaluated via query of the electronic medical record (EMR) system. Most patients are 
discharged home in the afternoon of POD #1. They will be discharged home on the standard of care 
pain regimen, which is similar to their in-hospital pain regimen as prescribed by the surgical team.
On POD #2, POD #4 and POD #60, if the patients have been discharged, they will be called via telephone 
and asked questions from a questionnaire regarding overall pain control and the amount of pain 
medications consumed each day. (See the following Questionnaires). Prior to discharge, the patients will 
be given and educated on using a medication diary (see medication diary), by a member of the research 
team, which they will mail back using an addressed, stamped envelope. On the medication diary, patients 
will record the number of opioid pain pills they took POD#1-3. The medication diary will also be used for 
the patients to record their maximum, minimum, and average pain scores for each day using a 0 to 10 
scale. Patients will be asked to read back the information from this diary during phone calls on POD #2 
and POD #4. Patients will be asked the time that they first noticed their block wearing off. During the 
POD #4 phone call, patients are reminded to return their medication diary by mail in the provided 
envelope. In the event that a patient’s medication diary is not received, a research team member will 
attempt to contact the patient up to two times to remind the patient to return the medication diary via mail. 
Patients will be provided with a 24/7 pager number to reach the on-call physician for the acute pain 
service for any questions that might arise after discharge with regard to their peripheral nerve blockade.
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/02/2022
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/02/2022


To assess for PONS, at the time of postoperative follow-up with the patient’s orthopedic surgeon, the  patient 
will be asked by the orthopedic team if they have any persistent numbness, tingling, or paresthesias of their 
operative extremity. The patients will also be asked about any of these symptoms during the phone calls in the first 
3 postoperative days, as well as on the POD #60 questionnaire. If the patient reports these symptoms, the patients 
will be asked to describe the location, severity, and type of sensory changes they are experiencing as well as any 
aggravating or alleviating factors.
Baseline demographic data and comorbidities for participants in each group will be collected using the 
EMR system, including: gender, age, body mass index (BMI), ASA class, home medications, and history 
of hypertension (HTN), chronic obstructive pulmonary disease (COPD), hyperlipidemia, diabetes, 
rheumatoid arthritis, and chronic steroid use. Additionally, the EMR will be used to collect information 
on duration of surgery (min), duration of time to perform the block (min), length of PACU stay (min), 
time to discharge home (hrs), time to first dose of opioid medication (hrs), incidence of postoperative 
nausea and vomiting (as defined as receiving one or more antiemetic medications postoperatively in non- 
prophylactic administration) and incidence of complications from peripheral nerve blockade.
Randomization/Blinding:
Randomization will be performed using https://www.randomizer.org in 1:1 fashion. Due to the difference 
in physical appearance of the control and study medications, the anesthesiologist(s) performing the nerve 
block will not be blinded. The individuals collecting study data as well as the patient will be blinded to the 
randomizationassignment.
Risks/Benefits to the Patient:
Patients will be randomized to receiving a single interscalene injection using either (1) bupivacaine 0.5%
+ adjuncts or (2) liposomal bupivacaine + bupivacaine 0.5%. Interscalene single shot peripheral nerve 
blockade is currently part of the standard of care for pain control in the total shoulder arthroplasty 
population at our institution.
Potential Risks:
Potential risks to the patients can be found on the provided consent form. Risks associated with peripheral 
nerve blockade are variable and often secondary to equipment, techniques, and anatomic location.
General risks of peripheral nerve blockade include risk of block failure, bleeding/hematoma formation at 
the site of needle entry, infection, potential allergic reaction to local anesthetic solution, including its 
liposomal, dexamethasone, or stabilization additives, intravascular injection leading to local anesthetic 
systemic toxicity (LAST), and transient or permanent neuropathy.20–23 With regards to the interscalene 
location of the injection, additional risks include the potential for hoarseness,24 dyspnea, 2526 respiratory 
distress and phrenic nerve palsy resulting in hemidiaphragmatic paralysis, 22 10,22,27,28 as well as rare case 
reports of inadvertent injection into the epidural or intrathecal spaces29;30. Additionally, there has also 
been documented hemodynamic instability in patients receiving interscalene blocks who are then in the 
sitting position during surgery31, 32, 33. Patients will be informed of these risks during the consent process.
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/02/2022
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/02/2022


Potential Benefits:
Peripheral nerve blockade has been found to improve postoperative analgesia and decrease opioid 
requirements. Previous studies also suggested that patients who receive a single injection brachial plexus 
blockade for TSA have increased patient satisfaction and increased range of motion. 34 Interscalene 
blockade is the current standard of care for shoulder arthroplasty at our institution. Patients receiving 
liposomal bupivacaine may have a prolonged analgesic effect and take fewer opioid medications than 
those who receive our standard practice of bupivacaine with additives. Patients will be informed of these 
benefits during the consent process.
Adverse Events:
Adverse events that occur during the regional anesthetic procedure will be noted immediately by the 
regional anesthesia team/provider with immediate management. Adverse events which occur during the 
patient’s hospitalization will be reported to the acute pain/regional anesthesia team via a 24/7 paging 
system, which will result in prompt in-person evaluation and management. Adverse events include, but 
are not limited to, bleeding/hematoma at site of needle entry, allergic reaction to local anesthetic 
medication, infection at site of needle entry, transient (or rarely permanent) neurological dysfunction 
including dysesthesia or paresthesia, hemodynamic instability both intraoperatively and postoperatively, 
hoarseness, phrenic nerve palsy, dyspnea, or respiratory distress, or potential inadvertent injection into 
epidural or intrathecal space.
Adverse events or patient concerns that occur up to 60 days post-discharge will be communicated to the 
on-call physician via the 24/7 pager for the acute pain service. This will prompt a return phone call to the 
patient to discuss the concern. If there is a need for urgent in-person patient evaluation, the patient will be 
instructed to come to the emergency department where they will be evaluated by that on-call physician 
upon arrival.
Data Safety and Monitoring Plan:
Risk assessment:
Greater than minimal risk
Personnel responsible for the safety review and its frequency:
The principal investigator will be responsible for monitoring the data, assuring protocol compliance, and 
conducting the safety reviews at the specified frequency, which must be conducted at a minimum of every 
6 months (including when re-approval of the protocol is sought). During the review process, the 
principal investigator (monitor) will evaluate whether the study should continue unchanged, require 
modification/amendment, or close to enrollment. Either the principal investigator or the IRB have the 
authority to stop or suspend the study or require modifications.
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/02/2022
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/02/2022


The risks associated with the current study are deemed greater than minimal for the following reasons:
1.
We do not view the risks associated with the interscalene brachial plexus nerve block procedure 
as minimal risk.
2.
We do not view the risks of sedation for peripheral nerve block procedure as minimal risk.
3.
We do not view the risks associated with peripheral nerve block procedure as minimal risk. 
Although we have assessed the proposed study as one of greater than minimal risk, the potential exists for 
anticipated and/or unanticipated adverse events, serious or otherwise, to occur since it is not possible to 
predict with certainty the absolute risk in any given individual or in advance of first-hand experience with 
the proposed study methods. Therefore, we provide a plan for monitoring the data and safety of the 
proposed study as follows:
Attribution of Adverse Events:
Adverse events will be monitored for each subject participating in the study and attributed to the study 
procedures / design by the principal investigator according to the following categories:
a.
Definite: Adverse event is clearly related to investigational procedures(s)/agent(s)
b. Probable: Adverse event is likely related to investigational procedures(s)/agent(s)
c.
Possible: Adverse event may be related to investigational procedures(s)/agent(s)
d. Unlikely: Adverse event is likely not to be related to the investigational 
procedures(s)/agent(s)
e.
Unrelated: Adverse event is clearly not related to investigational procedures(s)/agent(s)
Plan for Grading Adverse Events:
The following scale will be used in grading the severity of adverse events noted during the study:
1.
Mild adverse event
2.
Moderate adverseevent
3.
Severe adverse event
Plan for Determining Seriousness of Adverse Events:
In addition to grading the adverse event, the PI will determine whether the adverse event meets the 
criteria for a Serious Adverse Event (SAE). An adverse event is considered serious if it results in any of 
the followingoutcomes:
1.
Death
2.
A life-threatening experience in-patient hospitalization or prolongation of existing hospitalization
3.
A persistent or significant disability or incapacity
4.
A congenital anomaly or birth defect
5.
Any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition
An adverse event may be graded as severe but still not meet the criteria for a Serious Adverse Event. 
Similarly, an adverse event may be graded as moderate but still meet the criteria for an SAE. It is
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/02/2022
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/02/2022


important for the PI to consider the grade of the event as well as its “seriousness” when determining 
whether reporting to the IRB is necessary.
Plan for reporting unanticipated problems involving risks to subjects or others (including adverse 
events) to the IRB:
The principal investigator will report the following types of events to the IRB: 
Any incident, experience or outcome that meets ALL 3 of the following criteria:
1.
Is unexpected (in terms of nature, specificity, severity, or frequency) given (a) the research 
procedures described in the protocol-related documents, such as the IRB-approved protocol and 
informed consent document and (b) the characteristics of the subject population being studied; 
AND
2.
Is related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); AND
3.
Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, legal, or social harm) than was previously known or recognized.
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) may be medical or non- 
medical in nature, and include – but are not limited to – serious, unexpected, and related adverse events. 
Please note that adverse events are reportable to the IRB as UPIRSOs only if they meet all 3 criteria 
listed above.
These UPIRSOs/SAEs will be reported to the HHC IRB in accordance with HHC IRB Policy, using the 
appropriate forms found on the website. All related events involving risk but not meeting the prompt 
reporting requirements described in IRB Policywill be reported to the IRB in summary form at the time of 
continuing review. If appropriate, such summary may be a simple brief statement that events have 
occurred at the expected frequency and level of severity as previously documented.
Plan for reporting adverse events to co-investigators on the study, as appropriate the protocol’s 
research monitor(s), e.g., industrial sponsor, Protocol Review Committee (PRC), DSMBs, study 
sponsors, funding and regulatory agencies, and regulatory and decision-making bodies:
For the current study, the following individuals, funding, and/or regulatory agencies will be notified:
1.   All Co-Investigators listed on the protocol
The principal investigator will conduct a review of all adverse events upon completion of every study 
subject. The principal investigator will evaluate the frequency and severity of the adverse events and 
determine if modifications to the protocol or consent form are required.
Data Use, Collection, Storage and Security:
Data collection and follow-up will be performed by research team physicians, research coordinators, 
assistants, and nurses. The physician(s) will only collect data for patients in which they did not participate 
in the nerve block placement in order to avoid bias. Data collection with regard to baseline demographics 
and surgical information, including type of surgery (anatomic vs reverse) and surgeon will occur via 
query of the EMR system. Patient pain scores and the amount of opioid administered (in
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/02/2022
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/02/2022


MMEs) will be obtained via in-person interview and query of the EMR system (during POD #0-1), via 
telephone call/questionnaire (POD #2, POD #4), and through the patient's mailed-in pain diary. If we are 
unable to reach the patient on the first phone call attempt, two additional attempts will be allowed in any 
given day. If the patient is not able to be reached on POD #4, up to 3 attempts will be made on POD #5 in 
order to complete the POD #4 questionnaire. Should the opioid diary not be received in the mail, but the 
patient was able to read all of the data over the phone to us on POD #4 or #5, we will use the data they 
provided over the phone. Should the patient provide all of the data over the phone on POD #4 and then 
mail in the diary, we will default to the medication diary. If patients are unable to be reached via telephone 
during the data collection period (POD #1-5) but return by mail a completed opioid diary, the data
from the diary will be included in the data analysis. Should patients be lost to follow-up prior to 
collecting all of our data, these patients will not be included in the data analysis for our primary endpoint.
Data in one hard-copy format will be stored in a binder associated with each patient which will be kept in 
a double locked office with restricted access to only the individuals involved with data collection and 
analysis. After study conclusion, the binders will be kept in locked office for a period of 6 years. Data 
with all identifying patient information removed will be stored in the secure database REDcap. Access 
will be restricted to members of the research team involved in performing blocks, collecting data, and/or 
analyzing data and granted on a case-by-case basis by the PI. Additionally, IRB approval will be obtained 
and all key personnel (all individuals responsible for the design and conduct of this study) have completed 
CITI Human Subjects Protection Training.
MMEs for the opioids given during the study period will be calculated using an equivalency chart 
obtained from www.cms.gov (see citation below). The formula to calculate MME is as follows: 
Strength per Unit X (Number of Units/ Day) X MME conversion factor = MME/Day. The calculation 
will be repeated for each postoperative day during which data is collected.
Data and Statistical Analysis:
Demographic data amongst both groups will be analyzed after collection. Preliminary analysis will be 
done to determine the distribution of all continuous variables and the appropriateness of parametric data 
analyses. Descriptive data will be produced, mean and standard deviation for continuous variables where 
the assumption of normality ismet, median and interquartile range for continuous variables that are not 
normally distributed as well as ordinal data. Frequencies and proportions will be described for all 
categorical data. The primary analyses will compare the MME of opioids taken postoperatives days 
(PODs #0-3) and the total for the four days. If distributions have been shown to be normal, an 
independent groups t-test will be run; alternatively a Wilcoxon Ranked Sum test will be done if there are 
distribution issues. Similar analyses will be done for reported pain and nausea scores. The time until first 
post-op analgesia, PACU and hospital lengths of stay and the other timing measures are likely to be 
skewed and thus the Wilcoxon Ranked sum test will be used for the analysis. Complication data will be 
analyzed using chi square tests of proportion.  To the extent that the sample size allows, subgroup 
analyses will be done by surgeon, by type of surgery (anatomic vs reverse) and by demographic 
characteristics of the patients to explore if any of these interact with the effects of the block 
medications.
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LIBERATE, 10/24/2019
Power Analysis and Sample Size:
A power calculation was done based on the primary outcome of postoperative days 0-3 use of opioid 
medication. As Exparel was only FDA-approved for use in interscalene peripheral nerve blockade in 
April 2018, we were not able to find empirical data for the comparison proposed in this study. Hannah et 
al compared intraoperative liposomal bupivacaine with single injection interscalene nerve block of 
ropivacaine. While not the same comparison, we felt this would offer good guidance for effect size and 
our power calculation. Hannah et al reported large differences for the use of opioid medication in the two 
groups for postoperative days two and three (comparisons of 112 mg to 37 mg morphine equivalents for 
day 2 and 20 mg versus 5 mg morphine equivalents for day 3). As they unfortunately do not report the 
related standard deviations, the effect sizes were ‘back calculated’ based on their sample size (groups of 
37 and 21) and reported p values (p = .001 and p = .002). This resulted in estimated effect sizes of .84 and
.74 for the two days. To achieve 80% power with an overall significance rate of .05, for an independent 
group t –test, sample sizes of 24 and 30 per group would be needed to detect these large effect sizes.
Although the follow-up period is quite short for the primary endpoint of opiate consumption in 
postoperative days 0 through 3and prior experience has shown excellent record of communicating with 
these patients by telephone for the three day period (length of stay is usually one postoperative day), we 
still feel it is imperative to increase the proposed sample size to account for attrition. Assuming a loss-to- 
follow up rate of 25%, we propose a sample size of 40 patients per arm of the study with the total number 
of 80 participants.
An interim analysis will be done when approximately half (40) of the patients have completed surgery and 
at least POD4 medication data. The timing coincides with the departure of the one surgeon involved from 
HHC. If the continuation is approved and the interim analysis data indicate reason to continue the study, 
one or more different surgeons will be recruited to participate and the sample size adjusted . The interim 
analysis will provide basis for the power calculation to be redone with better empirical evidence on this 
situation rather than extrapolation from similar data. Finally, this timing also coincides with the first IRB 
renewal for the project. A full reporting of all adverse events is included in the continuation and will serve 
as the information for a safety review. These will be reviewed by the IRB prior to the interim analysis 
(plan is for simultaneous review of the continuation and this modification).
The interim analysis will focus on the total post operative MMEs reported for days 1-4 for each day, (days 
0-4) and for the total use of opioids during this period. The time until the first administration of post-op 
analgesia will also be part of this analysis. As described above, each of the analyses will be done using 
either t-tests for independent groups or Wilcoxon Ranked Sum tests; we are anticipating skewed 
distributions for MME and time and thus expect the Wilcoxon statistic to be used. As is standard, a p 
value of .05 will be used to indicate statistical significance for all tests. In order to maintain this type one 
error rate over the entire study, the O’Brien- Fleming method for alpha spending will be used to determine 
the significance levels that will be used for the interim (α= .0054) and final (α= .0492) analyses.
If the continuation of the study is not approved by the IRB, the interim analysis will not be completed as 
the study will be closed.
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LIBERATE, 10/24/2019
If the reported MMEs for the patients who received the liposomal bupivacaine are significantly lower (p<
.0054) than for patients receiving the standard of care, the study will be stopped as having demonstrated a 
significant difference.
If the difference in opioid use between the groups is smaller than what the principal investigator and co- 
investigators determine to be clinically meaningful and/or the redone power calculation indicates the need 
for a sample size that is so large as to not be feasible, the study will be stopped as futile.
The completion of the interim analysis in April, 2020 (detailed report appended) using a total of 40 
patients resulted in findings that showed a difference between the group with the potential for clinical 
relevance but that did not reach the level of statistical significance. The decision was therefore to 
continue the study. A revised sample size calculation was conducted based on the analysis of post- 
operative use of opioids (total for days 1-4) as evidenced in the interim analysis data set. With a 
distribution that did not meet assumptions of normality for use of parametric analysis and included 
several outlier values, the calculation was done using group medians in place of group means and an 
estimate of pooled standard deviation derived from the interquartile range.35 Using these parameters, a 
power calculation suggested 39 patients in each group. This was raised to reflect the relative power of 
independent groups t-test and Wilcoxon Ranked Sum test (the latter equal to .955 of the power of the 
former) and a 10% attrition rate, consistent with the interim data availability for days 1-4.36 The final 
calculation with these adjustments indicates the need for 45 patients in each group to achieve 80% power 
to detect differences equal to or greater than that found in the interim analyses with a significance level 
of .05. Due to the rate of attrition seen in the study during the accrual of the 45 subjects per group, the 
sample size is increased to 55 subjects per group to achieve 90 subjects with full data sets.
Clinical Significance:
We seek to examine whether liposomal bupivacaine injected into the interscalene brachial plexus location 
reduces the total amount of opioid consumed postoperatively, reduces pain scores, or lengthens duration 
of analgesia as compared to the standard use of bupivacaine with adjuncts. Should we find that liposomal 
bupivacaine is able to reduce the amount of opioids consumed postoperatively, it may contribute to a 
decreased risk of chronic opioid addiction. Should liposomal bupivacaine be found to not reduce opioid 
consumption, this also provides useful information regarding analgesic options for patients undergoing 
TSA. This study can also provide valuable information about the cost-benefit analysis of liposomal 
bupivacaine versus our institutional standard of care.
References:
1.
Brummett CM, Waljee JF, Goesling J, Moser S, Lin P, Englesbe MJ, Bohnert ASB, Kheterpal S, 
Nallamothu BK: New Persistent Opioid Use After Minor and Major Surgical Procedures in US 
Adults. JAMA Surg 2017; 152:e170504
2.
Vieira PA, Pulai I, Tsao 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; 27:285–8
3.
Movafegh A, Razazian M, Hajimaohamadi F, Meysamie A: Dexamethasone added to lidocaine 
prolongs axillary brachial plexus blockade. Anesth Analg 2006; 102:263–7
4.
Parrington SJ, O’Donnell D, Chan VWS, Brown-Shreves D, Subramanyam R, Qu M, Brull R: 
Dexamethasone added to mepivacaine prolongs the duration of analgesia after supraclavicular 
brachial plexus blockade. Reg Anesth Pain Med 2010; 35:422–6
5.
Rasmussen SB, Saied NN, Bowens C Jr, Mercaldo ND, Schildcrout JS, Malchow RJ: Duration of
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upper and lower extremity peripheral nerve blockade is prolonged with dexamethasone when added 
to ropivacaine: a retrospective database analysis. Pain Med 2013; 14:1239–47
6.
McLaughlin DC, Cheah JW, Aleshi P, Zhang AL, Ma CB, Feeley BT: Multimodal analgesia 
decreases opioid consumption after shoulder arthroplasty: a prospective cohort study. J Shoulder 
Elbow Surg 2018; 27:686–91
7.
Candiotti K: Liposomal bupivacaine: an innovative nonopioid local analgesic for the management of 
postsurgical pain. Pharmacotherapy 2012; 32:19S – 26S
8.
Abildgaard JT, Lonergan KT, Tolan SJ, Kissenberth MJ, Hawkins RJ, Washburn R, Adams KJ, 
Long CD, Carlisle Shealy E, Motley JR, Tokish JM: Liposomal bupivacaine versus indwelling 
interscalene nerve block for postoperative pain control in shoulder arthroplasty: a prospective 
randomized controlled trial. J Shoulder Elbow Surg 2017; 26:1175–81
9.
Hannan CV, Albrecht MJ, Petersen SA, Srikumaran U: Liposomal Bupivacaine vs Interscalene 
Nerve Block for Pain Control After Shoulder Arthroplasty: A Retrospective Cohort Analysis. Am J 
Orthop 2016; 45:424–30
10.
Wang K, Zhang H-X: Liposomal bupivacaine versus interscalene nerve block for pain control after 
total shoulder arthroplasty: A systematic review and meta-analysis. Int J Surg 2017; 46:61–70
11.
Schroer WC, Diesfeld PG, LeMarr AR, Morton DJ, Reedy ME: Does Extended-Release Liposomal 
Bupivacaine Better Control Pain Than Bupivacaine After Total Knee Arthroplasty (TKA)? A 
Prospective, Randomized Clinical Trial. J Arthroplasty 2015; 30:64–7
12.
Vandepitte C, Kuroda M, Witvrouw R, Anne L, Bellemans J, Corten K, Vanelderen P, Mesotten D, 
Leunen I, Heylen M, Van Boxstael S, Golebiewski M, Van de Velde M, Knezevic NN, Hadzic A: 
Addition of Liposome Bupivacaine to Bupivacaine HCl Versus Bupivacaine HCl Alone for 
Interscalene Brachial Plexus Block in Patients Having Major Shoulder Surgery. Reg Anesth Pain 
Med 2017; 42:334–41
13.
Sabesan VJ, Shahriar R, Petersen-Fitts GR, Whaley JD, Bou-Akl T, Sweet M, Milia M: A 
prospective randomized controlled trial to identify the optimal postoperative pain management in 
shoulder arthroplasty: liposomal bupivacaine versus continuous interscalene catheter. J Shoulder 
Elbow Surg 2017; 26:1810–7
14.
Sites BD, Taenzer AH, Herrick MD, Gilloon C, Antonakakis J, Richins J, Beach ML: Incidence of 
local anesthetic systemic toxicity and postoperative neurologic symptoms associated with 12,668 
ultrasound-guided nerve blocks: an analysis from a prospective clinical registry. Reg Anesth Pain 
Med 2012; 37:478–82
15.
CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016. MMWR Recomm 
Rep 2016; 65
16.
2015-2020 Dietary Guidelines - health.gov at
<https://health.gov/dietaryguidelines/2015/guidelines/>
17.
Horlocker TT, Vandermeuelen E, Kopp SL, Gogarten W, Leffert LR, Benzon HT: Regional 
Anesthesia in the Patient Receiving Antithrombotic or Thrombolytic Therapy. Reg Anesth Pain Med 
2018; 43:263–309
18.
Kendall FP, McCreary EK, Provance PG, Rodgers M, Romani W: Muscles: Testing and Function, 
with Posture and Pain.2014
19. Mendoza T, Mayne T, Rublee D, Cleeland C: Reliability and validity of a modified Brief Pain 
Inventory short form in patients with osteoarthritis. Eur J Pain 2006; 10:353–61
20.
Adhikary SD, Armstrong K, Chin KJ: Perineural entrapment of an interscalene stimulating catheter. 
Anaesth Intensive Care 2012; 40:527–30
21.
Barutell C, Vidal F, Raich M, Montero A: A neurological complication following interscalene 
brachial plexus block. Anaesthesia 1980; 35:365–7
22.
Ediale KR, Myung CR, Neuman GG: Prolonged hemidiaphragmatic paralysis following interscalene 
brachial plexus block. J Clin Anesth 2004; 16:573–5
23.
Lenters TR, Davies J, Matsen FA 3rd: The types and severity of complications associated with 
interscalene brachial plexus block anesthesia: local and national evidence. J Shoulder Elbow Surg
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2007; 16:379–87
24.
Shakespeare TJ, Tsui BCH: Intermittent hoarseness with continuous interscalene brachial plexus 
catheter infusion due to deficient carotid sheath. Acta Anaesthesiol Scand 2013; 57:1085–6
25.
Tsui BCH, Dillane D: Reducing and Washing Off Local Anesthetic for Continuous Interscalene 
Block. Reg Anesth Pain Med 2014; 39:175–6
26.
Chidiac EJ, Kaddoum R, Peterson SA: Patient survey of continuous interscalene analgesia at home 
after shoulder surgery. Middle East J Anaesthesiol 2009; 20:213–8
27.
Ip VHY, Tsui BCH: Continuous interscalene block: the good, the bad and the refined spread. Acta 
Anaesthesiol Scand 2012; 56:526–30
28.
Plit ML, Chhajed PN, Macdonald P, Cole IE, Harrison GA: Bilateral vocal cord palsy following 
interscalene brachial plexus nerve block. Anaesth Intensive Care 2002; 30:499–501
29.
Yanovski B, Gaitini L, Volodarski D, Ben-David B: Catastrophic complication of an interscalene 
catheter for continuous peripheral nerve block analgesia. Anaesthesia 2012; 67:1166–9
30.
Fredrickson M, Harrop-Griffiths W: Death by regional block: can the analgesic benefits ever 
outweigh the risks? Anaesthesia 2012; 67:1071–5
31.
D’Alessio JG, Weller RS, Rosenblum M: Activation of the Bezold-Jarisch Reflex in the Sitting 
Position for Shoulder Arthroscopy Using Interscalene Block. Anesthesia & Analgesia 1995; 
80:1158–62
32.
Liguori GA, Kahn RL, Gordon J, Gordon MA, Urban MK: The use of metoprolol and glycopyrrolate 
to prevent hypotensive/bradycardic events during shoulder arthroscopy in the sitting position under 
interscalene block. Anesth Analg 1998; 87:1320–5
33.
Sia S, Sarro F, Lepri A, Bartoli AM: The Effect of Exogenous Epinephrine on the Incidence of 
Hypotensive/Bradycardic Events During Shoulder Surgery in the Sitting Position During 
Interscalene Block. Anesthesia & Analgesia 2003; 97:583–8
34.
Ilfeld BM, Wright TW, Enneking FK, Morey TE: Joint range of motion after total shoulder 
arthroplasty with and without a continuous interscalene nerve block: a retrospective, case-control 
study. Reg Anesth Pain Med 2005; 30:429–33
35. Cochrane Handbook for Systematic Reviews of Interventions (Julian P.T. Higgins and Sally Green 
(Eds).Chichester, West Sussex ; Hoboken NJ :John Wiley & Sons, 2008.
36.
Siegel S and Castellan Jr. NJ (2000) Nonparametric Statistics for the Behavioral Sciences. Second 
Edition. McGraw Hill, Sydney. ISBN0-07-100326-6 p. 95
Citations added
13
Informed Consent for Research:
(Please see attached document)
Medication Diary:
(Please see attached document)
Morphine Milligram Equivalent Reference:
https://www.cms.gov/Medicare/Prescription-Drug- 
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Coverage/PrescriptionDrugCovContra/Downloads/Opioid-Morphine-EQ-Conversion-Factors-Aug- 
2017.pdf
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Questionnaires:
PACU discharge questionnaire:
1.
On the pain scale from 0 to 10 where 0 is no pain and 10 is the worst pain you can imagine, how 
would you rate your current pain?
Response:  
2.
Are you experiencing any discomfort? And if so, where, and how would you describe the 
discomfort?
Response:  
3.
On a scale from 0 to 10 with 0 being not distressing at all and 10 being very distressing, 
following your surgery, how distressing do you find the numbness of your arm to be?
Response:  
POD #1 morning in-hospital questionnaire:
1.
On the pain scale from 0 to 10 with 0 being no pain at all and 10 being the worst pain you can 
imagine, what is the HIGHEST level of pain that you experienced since leaving the recovery 
room?
Response:  
2.
On the pain scale from 0 to 10 with 0 being no pain at all and 10 being the worst pain you can 
imagine, what is the LOWEST level of pain that you experienced since leaving the recovery 
room?
Response:  
3.
On the pain scalefrom 0 to 10 with 0 being no pain at all and 10 being the worst pain you can 
imagine, what is the AVERAGE level of pain that you experienced since leaving the recovery 
room?
Response:  
4.
Have you noticed your nerve block starting to wear off, and if so, do you recall the time that it 
started wearing off?
Response:  
Prompt for POD #2 phone call questionnaire:
Hello, this is 
calling from the Hartford Hospital Bone and Joint Institute. I am calling regarding 
the research study on the nerve block you had for your shoulder surgery. I have a few questions to ask 
you. These questions should take approximately 5 minutes to answer. If you have your medication diary 
available, please get it as it will help in answering some of these questions.
1.
For the day following your surgery, yesterday, on a scale from 0 to 10 with 0 being no pain at all 
and 10 being the worst pain you can imagine, what was the highest level of pain that you 
experienced?
Response: 
2.
For the day following your surgery, yesterday, on a scale from 0 to 10 with 0 being no pain at all 
and 10 being the worst pain you can imagine, what was the lowest level of pain that you
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experienced?
Response: 
3.
For the day following your surgery, yesterday, on a scale from 0 to 10 with 0 being no pain at all 
and 10 being the worst pain you can imagine, what was the average level of pain that you 
experienced?
Response: 
4.
For the day following your surgery, yesterday, which pain medications did you take and how 
many did you take. Please reference your medication diary.
Response:  
5.
On a scale from 0 to 10 with 0 being not distressing at all and 10 being very distressing, 
following your surgery, how distressing did you find the numbness of your arm to be?
Response:  
6.
Following your surgery, have you experienced any of the following? Rash, swelling, or 
inflammation at the site of the nerve block, bruising at the site of the nerve block, bleeding at the 
site of the nerve block, ringing in your ears, numbness or tingling of your lips, or nausea and/or 
vomiting. Additionally, have you had to go to the emergency department at all since leaving the 
hospital, and if so, what did you go to the emergency department for?
Response:  
7.
If you did not already notice your nerve block wearing off when we saw you on the last the day 
after your surgery, have you since noticed your nerve block starting to wear off, and if so, do you 
recall the time that it started wearing off?
Response:  
These are all the questions I have for you today. We will be calling you again in 2 days to ask you some 
more questions regarding your nerve block. Thank you so much for your time answering these questions. 
Thank you and have a great day.
Prompt for POD #4 phone call questionnaire:
Hello, this is 
calling from the Hartford Hospital Bone and Joint Institute. I am calling regarding 
the research study on the nerve block you had for your shoulder surgery. I have a few more questions to 
ask you. There are a few more questions to answer compared to the previous time we called 2 days ago, 
however these questions should still only take approximately 5 minutes to answer. If you have your 
medication diary available, please get it as it will help in answering some of these questions.
1.
For the second day after your surgery, 2 days ago, on a scale from 0 to 10 with 0 being no pain 
at all and 10 being the worst pain you can imagine, what was the highest level of pain that you 
experienced?
Response:  
2.
For the second day after your surgery, 2 days ago, on a scale from 0 to 10 with 0 being no pain 
at all and 10 being the worst pain you can imagine, what was the lowest level of pain that you 
experienced?
Response:  
3.
For the second day after your surgery, 2 days ago, on a scale from 0 to 10 with 0 being no pain 
at all and 10 being the worst pain you can imagine, what was the average level of pain that you
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experienced?
Response:  
4.
For the second day after your surgery, 2 days ago, which pain medications did you take and how 
many did you take. Please reference your medication diary.
Response:  
5.
For the third day after your surgery, yesterday, on a scale from 0 to 10 with 0 being no pain at all 
and 10 being the worst pain you can imagine, what was the highest level of pain that you 
experienced?
Response:  
6.
For the third day after your surgery, yesterday, on a scale from 0 to 10 with 0 being no pain at all 
and 10 being the worst pain you can imagine, what was the lowest level of pain that you 
experienced?
Response:  
7.
For the third day after your surgery, yesterday, on a scale from 0 to 10 with 0 being no pain at all 
and 10 being the worst pain you can imagine, what was the average level of pain that you 
experienced?
Response:  
8.
For the third day after your surgery, yesterday, which pain medications did you take and how 
many did you take. Please reference your medication diary.
Response:  
9.
Since your last phone call from us 2 days ago, have you experienced any of the following? Rash, 
swelling, or inflammation at the site of the nerve block, bruising at the site of the nerve block, 
bleeding at the site of the nerve block, ringing in your ears, numbness or tingling of your lips, or 
nausea and/or vomiting. Additionally, have you had to go to the emergency department at all 
since leaving the hospital, and if so, what did you go to the emergency department for?
Response:  
10. If you did not already noticed your nerve block wearing off since we called you 2 days ago, have 
you since noticed your nerve block starting to wear off, and if so, do you recall the time that it 
started wearing off?
Response:  
11. On a scale from 0 to 10 with 0 being completely dissatisfied and 10 being completely satisfied, 
how satisfied are you with your overall pain control after surgery?
Response:  
Thank you again for answering these questions. Please remember to place your medication diary in the 
pre-addressed and stamped envelope provided to you and mail it back to the hospital as soon as you can. 
Thank you again for answering these questions and participating in the research study. Will be calling 
you in approximately 2 months to see how you have been. Have a great day.
Prompt for POD #60 phone call questionnaire:
Hello, this is 
calling from the Hartford Hospital Bone and Joint Institute. I am calling regarding 
the research study on the nerve block you had for your shoulder surgery. I have a few more questions to
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ask you. These questions should still only take approximately 5 minutes to answer.
1.
On the shoulder on which you had surgery 2 months ago, on a scale from 0 to 10 with 0 being no 
pain at all and 10 being the worst pain you can imagine, what was the highest level of pain that 
youexperienced?
Response:  
2.
On the shoulder on which you had surgery 2 months ago, on a scale from 0 to 10 with 0 being no 
pain at all and 10 being the worst pain you can imagine, what was the lowest level of pain that 
youexperienced?
Response:  
3.
On the shoulder on which you had surgery 2 months ago, on a scale from 0 to 10 with 0 being no 
pain at all and 10 being the worst pain you can imagine, what was the average level of pain that 
youexperienced?
Response:  
4.
“How well are you doing with your recovery compared to what you expected on a scale of 0-10 
with 10 being the best score and 1 being the worst score.”
Response:  
5.
Are you currently taking pain medications for pain in the shoulder that was operated on 2 months 
ago? Which medications are you taking? How many are you taking?
Response:  
6.
Since your last phone call from us 2 months ago, have you experienced any of the following? 
Rash, swelling, or inflammation at the site of the nerve block, bruising at the site of the nerve 
block, bleeding at the site of the nerve block, ringing in your ears, numbness or tingling of your 
lips, or nausea and/or vomiting. Additionally, have you had to go to the emergency department at 
all since leaving the hospital, and if so, what did you go to the emergency department for?
Response:  
7.
Has the arm that received the nerve block and surgery returned to normal sensation? 
Response:  
8.
On a scale from 0 to 10 with 0 being completely dissatisfied and 10 being completely satisfied, 
how satisfied are you with your overall pain control after surgery?
Response:  
Thank you again for answering these questions and participating in the research study. Have a great day.
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/02/2022
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ICF_001.pdf: 
Page:
1 of 6
PI:
Finkel
IRB #:
HHC-2018-0231
Version:
June 8, 2020
IRB Use Only.
Informed Consent for Research
Principal Investigator: 
Kevin Finkel, MD
Anesthesia 
(860)972-5978
You have been asked to participate in the research study, LIBERATE: LIpososmal Bupivacaine vERsus 
Adjuncts in Total shouldErs. You are being asked to take part in this study because you are undergoing a 
shoulder joint replacement.  
The Hartford HealthCare Institutional Review Board (IRB) has reviewed the information in this consent 
document and has given approval for the study doctor to do the study.  An IRB is an independent committee 
established to help protect the rights of research subjects.  This does not mean the IRB has approved your 
participation in the study.  You must think about the information in this consent document for yourself.  You 
must then decide if you want to be in the study.
A.  The Purpose and procedures of this research
A.1.  What is the purpose of this research?
The purpose of this study is to compare two different numbing medicines for use in shoulder nerve block for 
patients undergoing shoulder surgery.  We plan to  compare them by tracking the amount of opioid pain 
medications taken after surgery and asking questions about your pain control. 
Pain control after shoulder surgery often requires multiple types of pain treatment, referred to as a “multimodal” 
pain control. Injecting numbing medication near the site of the nerves that affect the shoulder helps with pain 
control both during and after surgery. We will be comparing our usual numbing medications (called 
bupivacaine) to a similar numbing medication that may be longer-acting (called liposomal bupivacaine).  The 
goal is to determine if the liposomal bupivacaine causes a longer-lasting numbing block- and less pain after 
surgery.
A.2.  What procedures are involved with participation in this research study?
All patients who have shoulder replacement surgery will be considered for a shoulder nerve block. If the 
anesthesia doctors think that the shoulder nerve block would be safe for you after speaking with you about your 
medical problems and medications, you will be offered the block with one of the two numbing medications will 
be chosen by chance. You will be assigned to one of the two groups by chance (like the flip of a coin): neither 
you nor the doctor that interviews you about your pain will be able to decide to which group you are part of. 
This is called “randomization.” 
 
We plan to follow your progress during the surgery and in the recovery room. 
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/08/2021
IRB EXPIRATION DATE: 09/07/2022


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IRB #:
HHC-2018-0231
Version:
June 8, 2020
IRB Use Only.
Informed Consent for Research
On the day of your surgery, after you are checked into the POHA (preoperative holding area), you will undergo 
an assessment of motor and sensory function prior to placement of the block. At least 15 minutes after 
placement of the block, prior to the start of your general anesthesia, you will undergo another assessment of 
motor and sensory function. 
After surgery you will have two in-person evaluations where you will be asked questions regarding the quality 
of the block and pain scores. The first one will occur at time of discharge from the PACU (post-anesthesia care 
unit) and the second will occur the morning of POD#1 (postoperative day number one). The morning of POD#1 
you will also undergo an assessment of motor and sensory function.
Prior to discharge you will be given a medication diary and instructions on completing it, along with hospital 
discharge instructions from your surgeon. Your discharge summary will include instructions on how to take 
your prescribed medications, including your opioid pain medications. 
When you are ready to go home from the hospital, your surgeon will provide you with prescriptions for pain 
medication, along with instructions on how to take your prescribed medications, including your opioid pain 
medications. The discharge instructions and any medications provided are part of your surgeon’s standard 
practice. Our research team will provide you with a small diary to record your pain levels and the pain medicine 
you take at home for three days. We would then contact you by telephone and ask a series of questions three 
additional times: two days after surgery, four days after surgery, and sixty days after surgery. We expect each 
call will take approximately 5-10 minutes. . After your call on postoperative day 4, you will be reminded to 
send back your medication dairy in the self-addressed stamped envelope previously provided to you.
A.3.  Which of these procedures is experimental?  
Both numbing medications that will be used are approved by the US Food and Drug Administration (FDA) for 
use in shoulder nerve blocks. However, the collection of clinical data and comparing them is considered 
experimental.
A.4.  Where will participation take place?
This procedure will take place at the Bone and Joint Institute located at 32 Seymour Street, Hartford, CT 06106.
A.5.  How long will participation last? 
The study will last for approximately 1 year, but your participation will last 60 days. 
B.
The possible risks, discomforts and side effects of the procedures are 
described below, including safeguards to be used for your protection.
If you choose to participate in this study you are at risk for the following side effects that may be due to the 
procedure:
   Reversible and less serious side effects (occurring 1-10% of the time):
-
Block Failure (it does not work to help with postoperative pain control) 
-
Drooping of the eyelid
-
Constriction of the pupil 
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/08/2021
IRB EXPIRATION DATE: 09/07/2022


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PI:
Finkel
IRB #:
HHC-2018-0231
Version:
June 8, 2020
IRB Use Only.
Informed Consent for Research
-
Vocal cord paralysis (hoarseness)
-
Discomfort/pain at injection site 
   Rare (occurring less than 1% of the time):
-
Hematoma (bruising and swelling at the site of injection)
-
Intra-arterial or intravenous injection (Injection into an artery or vein)
-
Seizure
-
Allergic reaction to any medication used 
-
Difficulty Swallowing
-
Neuralgia (Nerve Pain) 
-
Nerve Damage
-
Epidural spread of the local anesthetic
-
Intrathecal (spinal) spread of the local anesthetic
-
Pneumothorax (collapsed lung) 
-
Infection over the site of the needle 
You should discuss these with the researcher and/or your regular doctor. There may be other side effects that we 
cannot predict at this time. Other medicines will be given to make the side effects less serious and less 
uncomfortable. Many of the side effects go away shortly, after the shoulder nerve block is stopped, but in some 
cases side effects can be serious or long lasting or permanent.
C.
There are possible benefits to you or others to be expected from your 
participation in this research.
With both types of numbing medicines injected around the nerve roots you should experience less pain after 
surgery and usually require fewer pain pills during the first several hours after surgery. If you receive the 
liposomal bupivacaine, the numbing medicine may last longer to help control your pain and decrease the 
amount of pain pills you need. There may or may not be a direct benefit to you as a result of taking part in this 
study. However, what is learned in this study may help in controlling pain after total shoulder arthroplasty and 
may advance scientific knowledge.
D.
There are alternatives to participation in this study that you should 
consider.
You do not have to be in this study to receive treatment for your condition. Instead of being in this research 
study, you can choose not to participate. Of note, the standard practice at our institution is for every patient 
having shoulder surgery to receive a shoulder nerve block with numbing medicine.  
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/08/2021
IRB EXPIRATION DATE: 09/07/2022


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PI:
Finkel
IRB #:
HHC-2018-0231
Version:
June 8, 2020
IRB Use Only.
Informed Consent for Research
E.
Who can you call if you have questions about this study? 
You do not have to sign this consent form until all the questions you have at this time are answered.  The 
investigator is willing to answer any questions you may have about the study procedures.  Below is a list of 
contacts if you should have any questions about the study.
Questions about:
Contact
Phone #
the research, research-related treatments, or 
a research related injury
Kevin Finkel, MD
(860)972-5978
your rights as a research participant
An IRB Representative
(860) 972-2893
the research in general
Director of Research
(860) 972-2893
a confidential issue that you would like to 
discuss with someone not associated with 
research
Patient Advocates
(860) 972-1100
F.
Your participation in the research is voluntary.
You may refuse to participate, withdraw your consent, and discontinue participation in the research at any time.  
You may do so without penalty, or loss of benefits to which you are otherwise entitled.  Your decision whether 
to participate will not affect your future medical care at Harford HealthCare.  Participating in this study is 
voluntary.  Your regular care and your relationship with your study doctor and the study staff will not be 
affected.  You may leave the study simply by notifying your study doctor.  
G. 
You will not receive financial compensation for your participation in this 
research.
H.
Your confidentiality will be guarded to the greatest extent possible.  
Hartford HealthCare will protect all the information about you and your part in this study, just as is done for all 
patients at Hartford HealthCare.  Your records will be maintained in accordance with applicable state and 
federal laws.  However, private identifiable information about you may be used or disclosed for purposes of this 
research project as described in the study’s authorization form.  
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/08/2021
IRB EXPIRATION DATE: 09/07/2022


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IRB #:
HHC-2018-0231
Version:
June 8, 2020
IRB Use Only.
Informed Consent for Research
Records of your participation in this study will be held confidential to the extent permitted by the applicable 
laws and regulations, and consistent with the Health Insurance Portability and Accountability Act (“HIPAA”) 
Authorization that you will be asked to sign.  The study doctor, the sponsor or persons working on behalf of the 
sponsor, and under certain circumstances, the United States Food and Drug Administration (FDA), as well as 
governmental agencies in other countries where the study drug may be considered for approval and the Ethics 
Committee/Institutional Review Board (IRB) will be able to inspect and copy confidential study specific 
records which identify you by name.  Therefore, absolute confidentiality cannot be guaranteed.  If the results of 
this study are published or presented at meetings, you will not be identified
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law.  
This Web site will not include information that can identify you.  At most, the Website will include a summary 
of the results.  You can search this Web site at any time. The NCT identifier for this study is NCT03887650.
I.
What happens if you are injured as a direct result of your participation in 
this research project? 
In the event that you are injured as a direct result of taking part in this research, you will receive help in the 
following way:
If you have medical insurance, Hartford HealthCare will collect fees for medical treatment at Hartford 
HealthCare from your insurance company.  If you are not fully covered by insurance or uninsured, Hartford 
HealthCare will cover these expenses.  
There is no plan for Hartford HealthCare to pay for your medical expenses at other hospitals or for pain and 
suffering, travel, lost wages, or other indirect costs of taking part in this research.  You do not waive any of your 
legal rights by signing this informed consent document. 
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/08/2021
IRB EXPIRATION DATE: 09/07/2022


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IRB Approval Dates
PI:
Finkel
Approval:
IRB #:
HHC-2018-0231
Valid Through:
Version:
June 8, 2020
IRB Signature:
Informed Consent for Research
J.
Signatures
You will be given a copy of this informed consent document to keep.  By signing below, it means that you have 
read it, that you voluntarily agree to participate in this research, LIBERATE: LIpososmal Bupivacaine vERsus 
Adjuncts in Total shouldErs
, and that you consent to the performance of the procedures listed above.
______________________________________________________
Participant’s Signature
Printed Name
Date
_________________________________________________________________________________________
Person Obtaining Participant’s Signature
Printed Name
Date
______________________________________________________
Witness signature
Printed Name
Date
(A witness is the person observing the explanation of the above information to the participant.  A witness to the 
informed consent process is optional unless presented orally.)
HHC-IRB
IRB NUMBER: HHC-2018-0231
IRB APPROVAL DATE: 09/08/2021
IRB EXPIRATION DATE: 09/07/2022