Clinical trial NCT03303794
Conditions: Anesthesia
Keywords: Total Knee arthroplasty bupivacaine anesthesia
Sponsor: Montefiore Medical Center
Start date: 2017-10-25; Completion date: 2018-06-27
Enrollment: 25 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Total knee and hip replacements are some of the most common orthopedic procedures that require aggressive postoperative pain management. This management helps us to improve clinical outcomes such as participation in early physical therapy, hospital discharge, and patient satisfaction. Based on the recent anatomical evidence and the investigator's knowledge of the complexity of the knee joint innervation the investigator proposes a new regional anesthesia technique that provides a complete sensory blockade and better analgesia while preserving the quadriceps strength and avoiding the potential for foot drop caused by inadvertent blockade of the common peroneal nerve.

Detailed description:
This is an assessor-blinded randomized controlled trial evaluating the efficacy of liposomal bupivacaine (Exparel) in patients undergoing Total Knee Arthroplasty. The primary outcome of this study is the proportion of patients "fit to discharge" on postoperative day one. Recently, liposomal bupivacaine (LB) (Exparel) was introduced into clinical practice, using a lipid-based depot (DepoFoam) technology for sustained release of bupivacaine. LB (Exparel) uses this technology to extend the delivery of bupivacaine, a local anesthetic that has been used in clinical practice for decades for peripheral nerve block, spinal, and epidural analgesia and anesthesia. This formulation prolongs the duration of analgesia of bupivacaine for up to 72 hours with a single injection. The study was designed to compare two of our current standard therapies:

1. Adductor Canal Block + Tissue Infiltration (lateral, medial and femoral compartment + posterior capsule tissue infiltration using 0.25% bupivacaine; and
2. Adductor Canal Block + Tissue Infiltration (lateral, medial and femoral compartment + posterior capsule tissue infiltration) using 1:1 mixture of 1.3% LB (Exparel) + 0.5% bupivacaine HCl mixture.

Arms: arm 1: 0.25% bupivacaine in patients undergoing total knee arthroplasty arm 2: 0.25% bupivacaine and 1.3 % liposomal Bupivacaine in patients undergoing total knee arthroplasty
Interventions: intervention 1: Exparel intervention 2: 0.25% bupivacaine
Intervention descriptions: intervention 1: 1.3 % liposomal Bupivacaine in patients undergoing total knee arthroplasty intervention 2: 0.25% bupivacaine in patients undergoing total knee arthroplasty

Protocol documents:
Prot_SAP_000.pdf: 
PI: Boleslav Kosharskyy
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Feasibility and Efficacy trial comparing the use of 0.25% bupivacaine alone versus a mixture 
of 0.5% bupivacaine and 1.3 % liposomal Bupivacaine in five compartment infiltration 
technique for patients undergoing total knee arthroplasty; a single blinded randomized trial  
Introduction
Total knee and hip replacements are some of the most common orthopedic procedures that require 
aggressive postoperative pain management. This management helps us to improve clinical outcomes 
such as participation in early physical therapy, hospital discharge, and patient satisfaction.1,2,3 Peripheral 
nerve blocks have been shown to decrease hospital length of stay and provide superior pain control with 
fewer side-effects, as compared with epidural analgesia or patient-controlled opioid therapy.4 However, 
there is a rising concern among clinicians that the benefits of the peripheral nerve blocks come at the 
price of increasing the risk for postoperative falls. 4,5,6,7,8,9, 10, 11, 12.Postoperative falls can occur in as many 
as 1.6% of hospitalized surgical patients.13 
1 Johnson RL, Kopp SL, Hebl JR, Erwin PJ, Mantilla CB. Falls and major orthopaedic surgery with peripheral nerve 
blockade: a systematic review and meta-analysis. Br J Anaesth. 2013 Apr;110(4):518-28. 
2 Hebl JR, Dilger JA, Byer DE, et al. A pre-emptive multimodal pathway featuring peripheral nerve block improves 
perioperative outcomes after major orthopedic surgery. Reg Anesth Pain Med 2008; 33: 510–7
3 Hebl JR, Kopp SL, Ali MH, et al. A comprehensive anesthesia protocol that emphasizes peripheral nerve blockade 
for total knee and total hip arthroplasty. J Bone Joint Surg Am 2005; 87 (Suppl. 2):63–70
4 Ilfeld BM, Le LT, Meyer RS, et al. Ambulatory continuous femoral nerve blocks decrease time to discharge 
readiness after tricompartment total knee arthroplasty: a randomized, triple-masked, placebo-controlled study. 
Anesthesiology 2008; 108: 703–13
5 Feibel RJ, Dervin GF, Kim PR, Beaule PE. Major complications associatedwith femoral nerve catheters for knee 
arthroplasty: a word of caution. J Arthroplasty 2009; 24: 132–7
6 Ilfeld BM, Ball ST, Gearen PF, et al. Ambulatory continuous posterior lumbar plexus nerve blocks after hip 
arthroplasty: a dual-center, randomized, triple-masked, placebo-controlled trial.Anesthesiology 2008; 109: 491–
501
7 Ilfeld BM, Duke KB, Donohue MC. The association between lower extremity continuous peripheral 
nerve blocks and patient falls after knee and hip arthroplasty. Anesth Analg 2010; 111: 1552–4
8 Kandasami M, Kinninmonth AW, Sarungi M, Baines J, Scott NB.,Femoral nerve block for total knee replacement—
a word of,caution. Knee 2009; 16: 98–100
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Falls may occur after orthopedic surgery regardless of the presence of nerve blocks. Prolonged 
quadriceps weakness resulting from lumbar plexus and femoral nerve block may contribute to an 
increased fall risk.7 Previous studies suggest that continuous lumbar plexus blockade may increase the 
rate of postoperative falls in patients undergoing major orthopedic surgery. 4,9-12
Adductor canal blocks have been shown to provide comparable analgesia to femoral nerve block, 
without blocking motor branches of the femoral nerve.14 Consequently, at our institution, we have been 
using continuous adductor canal blockade (ACB) via peripheral nerve catheter to decrease the 
quadriceps weakness found with a femoral nerve block. We combine this strategy with a selective tibial 
nerve block to address posterior knee pain.  However peripheral nerve catheters are prone to 
dislodgement, increased risk of infection and require some degree of training for placement. 
A vast body of literature indicates that the innervation of the knee joint is rather complex with the 
contribution of several branches from the femoral, sciatic and obturator nerves.15,16 Clinically, posterior 
capsule injections17, 18 as well as genicular injections19, 20 are being used successfully for analgesia of the 
knee joint.
9 Klein SM, Nielsen KC, Greengrass RA, Warner DS, Martin A,,Steele SM. Ambulatory discharge after long-acting 
peripheral,nerve blockade: 2382 blocks with ropivacaine. Anesth Analg 2002; 94: 65–70.
10 Muraskin SI, Conrad B, Zheng N, Morey TE, Enneking FK. Falls associated with lower-extremity-nerve blocks: a 
pilot investigation of mechanisms. Reg Anesth Pain Med 2007; 32: 67–72
11 Sharma S, Iorio R, Specht LM, Davies-Lepie S, Healy WL. Complications of femoral nerve block for total knee 
arthroplasty. Clin Orthop Relat Res 2010; 468: 135–40
12 Williams BA, Kentor ML, Bottegal MT. The incidence of falls at home in patients with perineural femoral 
catheters: a retrospective summary of a randomized clinical trial. Anesth Analg 2007; 104: 1002
13 Church S, Robinson TN, Angles EM, Tran ZV, Wallace JI. Postoperative falls in the acute hospital setting: 
characteristics, risk factors, and outcomes in males. Am J Surg 2011; 201: 197–202
14 Kim DH, Lin Y, Goytizolo EA, et al. Adductor Canal Block versus Femoral Nerve Block for Total Knee Arthroplasty. 
Anesthesiology 2014. 120:540-550
15 Kennedy JC, Alexander IJ, Hayes KC; Nerve supply of the human knee and its functional importance. The 
American Journal of Sports Medicine 1982. Vol 10(6) 329-335
16 Franco CD, Buvanendran A, Petersohn JD et al; Innervation of the Anterior Capsule of the Human Knee. Journal 
of Regional Anesthesia and Pain Medicine 2015. Vol 40(4) 363-368
17 B. Krenzel, C. Cook, G. Martin, T. Vail, D. Attarian, M. Bolognesi.  Posterior Capsular Injections of Ropivicaine 
During Total Knee Arthroplasty: A Randomized, Double-Blind, Placebo-Controlled Study.  The Journal of 
Arthroplasty. September 2009, Bol. 24(6): 138-143
18 C. Vlessides M. New Regional Technique Controls Post-TKA Pain. Anesthesiology News. December 2012.
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Recently, liposomal bupivacaine (LB) (Exparel) was introduced into clinical practice, using a lipid-based 
depot (DepoFoam) technology for sustained release of bupivacaine.21 LB (Exparel) uses this technology 
to extend the delivery of bupivacaine, a local anesthetic that has been used in clinical practice for 
decades for peripheral nerve block, spinal, and epidural analgesia and anesthesia. This formulation 
prolongs the duration of analgesia of bupivacaine for up to 72 hours with a single injection. The safety of 
this medication was first studied in animal models.22 It has also been shown to be safe for wound 
infiltration in humans for various surgical procedures.23, 24, 25, 26 Furthermore, there is phase I-III clinical 
trials that have looked at the safety of using liposomal bupivacaine in femoral nerve blocks, intercostal 
nerve block, and ankle nerve blocks. A meta-analysis of these trials did not find increased side effects 
related to the use of LB (Exparel) like neurotoxicity, myotoxicity, or nerve damage.27  However, the FDA 
has not approved Exparel for peripheral nerve blocks.  LB (Exparel) has been used for periarticular 
infiltration during joint replacement surgery both in our institution and in large studies28 without 
adverse events.  At our institution Exparel in combination with Bupivacaine has been used off-label for 
19 C. Franco, A. Buvanendran, J. Petersohn, R. Menzies, L. Menzies.  Innervation of the anterior capsule of the 
human knee: Implication of Radiofrequency Ablation.  Regional Anesthesia and Pain Medicine. Volume 40, Number 
4, JuIy-August 2015
20 C. Egeler, A. Jayakumar, S. Ford.  Motor-sparing knee block-description of a new technique. Anesthesia 2013, 68, 
542-543.
21 Mantripragada S. A lipid based depot (DepoFoam technology) for sustained release drug delivery. Prog Lipid Res. 
2002;41:392–406.
22 Richard BM, Newton P, Ott LR, et al. The safety of EXPAREL® (bupivacaine liposome injectable suspension) 
administered by peripheral nerve block in rabbits and dogs. J Drug Deliv. 2012;2012:962101
23 Golf M, Daniels SE, Onel E. A phase 3, randomized, placebo-controlled trial of DepoFoam(R) bupivacaine 
(extended-release bupivacaine local analgesic) in bunionectomy. Adv Ther. 2011;28:776–788.
24 Haas E, Onel E, Miller H, Ragupathi M, White PF. A double-blind, randomized, active-controlled study for post-
hemorrhoidectomy pain management with liposome bupivacaine, a novel local analgesic formulation. Am Surg. 
2012;78:574–581.
25 Gorfine SR, Onel E, Patou G, Krivokapic ZV. Bupivacaine extended-release liposome injection for prolonged 
postsurgical analgesia in patients undergoing hemorrhoidectomy: a multicenter, randomized, double-blind, 
placebo-controlled trial. Dis Colon Rectum. 2011;54: 1552–1559
26 Bergese SD, Ramamoorthy S, Patou G, Bramlett K, Gorfine SR, Candiotti KA. Efficacy profile of liposome 
bupivacaine, a novel formulation of bupivacaine for postsurgical analgesia. J Pain Res. 2012;5:107–116.
27 Ilfeld BM, Viscusi ER, Hadzic A et al. Safety and Side Effect Profile of Liposome Bupivacaine (Exparel) in Peripheral 
Nerve Blocks. Journal of Regional Anesthesia and Pain Medicine, Vol 40 (5), 572-582. September-October 2015.
28 Emerson RH, Barrington JW, Olugbode O et al. Femoral Nerve Block Versus Long-Acting Wound Infiltration in 
Total Knee Arthroplasty. Orthop 2016 May; 39(3) 449-455
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various regional anesthesia techniques(TAP blocks and intercostal nerve blocks). No serious adverse 
events has been reported with the use of Exparel in regional anesthesia or in local tissue infiltration. 
There are both animal and human studies that describe the safety of LB (Exparel) to be at least 
comparable to that of the other local anesthetics.23,28 LB (Exparel) is FDA approved for surgical site 
infiltration, which is what we propose to accomplish in this study. In this study, we hypothesize that the 
combination of adductor canal block and medial, femoral, lateral compartments with posterior capsule 
tissue infiltration using a mixture of bupivacaine and Exparel will result in better postsurgical analgesia 
after knee replacement surgeries. 
Our proposed study was designed to compare two of our current standard therapies: 
a) ACB + Tissue Infiltration (lateral, medial and femoral compartment + posterior capsule tissue 
infiltration using 0.25% bupivacaine; and
b)ACB + Tissue Infiltration (lateral, medial and femoral compartment + posterior capsule tissue 
infiltration) using 1:1 mixture of 1.3% LB (Exparel)  + 0.5% bupivacaine HCl mixture.  
 
Methods
 This is an assessor-blinded randomized controlled trial evaluating the efficacy of liposomal bupivacaine 
(Exparel) in patients undergoing TKA. Surgeons with appropriate research experience and training will 
be on the research team and will introduce the study to the patients and conduct the informed consent 
process. Patients who are not willing to sign the consent on the day of their surgical visit, the surgeon 
will introduce the study and a copy of the informed consent will be given to the patient to take home to 
make a decision. A member of the research team will follow-up with the patient and will obtain the 
informed consent either during their subsequent surgical visits or on the day of surgery. If the consent is 
obtained on the day of surgery, we will use a private space near the registration for the consenting 
process. No consents will be obtained once the patient is in the ambulatory area.  Additionally, patients 
will also be approached during their informational meeting at Wakefield Medical Center. Patients will be 
given the contact information of the PI to discuss any questions related to the study. 
On the day of surgery, the patients will be randomly assigned either to the Bupivacaine Group or the 
Exparel Group (see below). For each group, the patients will receive the standard of care that is 
practiced in our hospital.  Both groups will receive an adductor canal block which is part of their 
standard care for knee replacement practice in our hospital. In addition to that, the Bupivacaine group 
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will receive the local tissue infiltration of bupivacaine only, and the Exparel group will receive a local 
tissue infiltration using a mixture of Bupivacaine and Exparel. 
All methods described in this research study protocol are used routinely as the standard of care 
practiced in our hospital. The research part of this study protocol is randomly assigning patients to one 
of the two groups. Even though both of these groups are part of the standard of care practiced in our 
hospital, there is always a physician preference in selecting approach received by the patient. 
The primary outcome of this study is the proportion of patients “fit to discharge” on postoperative day 
one.  
Secondary outcomes will include 
1)
Opioid consumption during the first 48 hrs after TKA surgery 
2)
Numeric Pain Rating Scale (NPRS)29,30 pain scores during 48 hrs postoperatively
3)
Discharge destination (home vs. rehab/nursing home)
4)
Change in WOMAC (a form used to assess pain, stiffness and physical function in patients with 
hip/knee osteoarthritis) scores (assessed preoperatively, and postoperatively at two weeks, 
three months and six months
5)
 Percentage of patients with additional  IV pain medications needed
6)
30 day-Post-operative complications 
7)
30-day ED visit 
Inclusion criteria

All patients undergoing a unilateral total knee replacement, due to osteoarthritis or rheumatoid 
arthritis

Aged 40–80 years 

ASA-I-III
29 Ferreira-Valente MA, Palis-Riberio JL, Jensen MP. Validity of four pain intensity rating scale. Pain 2011 Oct; 
152(10) 2399-2404
30 Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. J Clin Nurs. 2005 Aug; 14(7) 
798-804
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Exclusion criteria 

Refusal or absolute medical contraindication to peripheral nerve block

Refusal or absolute medical contraindication to spinal anesthesia

Conversion of spinal anesthesia to general anesthesia after consent is obtained

Inability to cooperate

Allergy to any drug used in the study

Daily intake of opioids (tramadol, morphine, oxycodone, methadone, fentanyl)

Alcohol dependence or use of any illegal drugs within the last month

Inability to perform the mobilization test and Timed-Up-and-Go (TUG) test pre-operatively.
Bupivacaine Group
For the Bupivacaine group, we will provide
1)
Adductor canal block using 15ml of 0.25% bupivacaine. We will perform adductor canal block 
using standard sterile technique and ultrasound guidance as described below. 
2)
Lateral, medial and femoral compartment and posterior capsule infiltration will be performed 
using 40 ml of 0.25% bupivacaine using standard sterile technique and ultrasound guidance 
described below.
Exparel Group
For the Exparel Group, a LB (Exparel) solution (LBS) will be made using 20ml LB (Exparel) 1.3% and 20ml 
bupivacaine HCl 0.5%, resulting in a 1:1 (by volume) mixture of 0.65% LB (Exparel) and 0.25% 
bupivacaine. 
1)
Adductor canal block using 15 ml of  0.25% bupivacaine ( as described above)
2)
Lateral, medial and femoral compartment and posterior capsular tissue infiltration will be 
performed using 40 ml  of 1:1 mixture of 1.3% LB (Exparel) + 0.5% Bupivacaine HCl mixture. 
Technique for performance of Nerve Block
To perform the nerve blocks, a high-frequency linear ultrasound Sonosite probe will be used. For ACB 
the ultrasound probe will be placed in a transverse cross-sectional view in the mid-thigh. The sartorius 
muscle will be identified. Deep to the sartorius muscle, the superficial femoral artery will be identified, 
with the vein just inferior/lateral to the artery. For the control group, a 21g 90mm echogenic needle 
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(StimuQuick, Arrow International Inc, Reading PA) will be inserted lateral to the ultrasound probe, using 
an “in-plane” technique, piercing the sartorius muscle. With the tip of the needle placed just lateral to 
the artery, the local anesthetics described above will be injected into the adductor canal. 
Posterior capsule infiltration will be performed by placing the ultrasound probe in the popliteal fossa, 
identifying the popliteal artery, the fibrous tissue surrounding it, the posterior capsule and the femoral 
condyles. A 21g 90mm echogenic needle(StimuQuick, Arrow International Inc, Reading PA) will be 
inserted using a lateral approach, and the posterior capsule will then be infiltrated with local anesthetic.
The lateral, medial and femoral compartment tissue infiltration are described below:
Superolateral genicular tissue infiltration will be performed by identifying the lateral femoral epicondyle 
with ultrasound; an area 5cm proximal to the epicondyle will be identified, and a 21 gauge 90mm needle 
(StimuQuick, Arrow International Inc, Reading, PA) will be inserted using “out of plane” technique and 
advanced until the bone is contacted. The needle is then withdrawn 1 mm, and the local anesthetic 
injected.
Superomedial tissue infiltration will be performed by identifying the medial femoral epicondyle with 
ultrasound; an area 5cm proximal to the epicondyle will be identified, and a 21 gauge 90mm needle 
(StimuQuick, Arrow International Inc, Reading, PA) will be inserted using “out of plane” technique and 
advanced until the bone is contacted. The needle is then withdrawn 1 mm, and the local anesthetic 
injected.
Pre-patellar femoral infiltration will be performed by identifying the femur on ultrasound 5-7cm 
proximal the patella; a 21 gauge 90mm needle (StimuQuick, Arrow International Inc, Reading, PA) will be 
inserted using “out of plane” technique and advanced until the bone is contacted. The needle is then 
withdrawn 1 mm, and the local anesthetic injected.
Anesthesia and Analgesia
Spinal anesthesia will be performed for all of the procedures in this study, as is standard of care in this 
institution. The dose of the spinal anesthetic will be determined by the intraoperative anesthesiologist, 
as will the sedation administered. Intra-operative fluid therapy will be administered at the discretion of 
the anesthetist, and a femoral tourniquet will be used at the discretion of the surgeon.
Post-operatively, intravenous patient-controlled analgesia (PCA) will be provided with morphine, bolus 1 
mg, lock-out time 6 min and no background infusion. If analgesia is inadequate, patients will receive an 
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additional bolus of 2 mg morphine i.v. until adequate analgesia is obtained. Multimodal Pain 
Management Protocol will be implemented as is standard practice in our institution: see attached.
Moderate to severe nausea or vomiting will be treated as per routine standard of care in the hospital. 
Outcome assessments

The primary end point of the study “fit to discharge” will be assessed using “6 clicks Activity 
Measure for Post-Acute Care (AM-PAC) assessment tool31. The “6-Clicks,” AM-PAC are short 
forms created from the Activity Measure for Post-Acute Care (AM-PAC) instrument, developed 
by researchers at Boston University. The AM-PAC measures three functional domains: basic 
mobility, daily activities, and applied cognition.  The“6-Clicks” AM-PAC instrument assesses basic 
mobility, such as walking and moving from 1 position to another, turning over in bed, climbing 
3-5 steps with railing and sitting down and standing up from a chair. Utilization of “6 clicks AM-
PAC for the purpose of discharge planning, and destination of the patients are well documented 
in published studies32,33. Physical Therapists who will are blinded to the group assessment will be 
conducting the “6 Clicks “ AM-PAC assessment. For assessing the agreement between the 
reviewers, in randomly selected, 25 patients a second reviewer will observe the assessments 
and will score separately. 

Opioid use during the hospital stay will be recorded from the medical charts. All the opioids 
used in the intraoperative and postoperative period will be converted into  IV morphine 
equivalence.  

Pain scores will be collected from the nursing charts, and also research team visiting the patients 
will collect the 24-hour pain score. Pain score will be collected on a Numerical Rating Scale (NRS) 
0 being no pain ad 10 being the worse pain imaginable. 

Other secondary endpoints such as time since first IV rescue medication, post-operative 
complications, ED visit and time to discharge will be collected from medical charts. 
Power and sample size considerations 
31 Haley SM, Coster WJ, Andres PL, et al. Activity outcome measurement for postacute care. Med Care . 2004;42(1 
suppl):I49–I61
32 Jette DU, Stilphen M, Ranganathan VK, Passek SD, Frost FS, Jette AM: AM-PAC “6-Clicks” Functional Assessment 
Scores Predict Acute Care Hospital Discharge Destination. Physical Therapy 2014, 94(9):1252-1261.
33 Menendez ME, Schumacher CS, Ring D, Freiberg AA, Rubash HE, Kwon YM: Does "6-Clicks" Day 1 Postoperative 
Mobility Score Predict Discharge Disposition After Total Hip and Knee Arthroplasties? The Journal of arthroplasty 
2016, 31(9):1916-1920.
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In our clinical audit, we have found that less than 10% of patients are discharged on POD-1, and about 
30% are “fit to discharge.” For the purpose of this study, we assume that use of Liposomal Bupivacaine 
(Exparel) will increase the percentage of patients “ fit to discharge” to 60 percentage on POD-1. With 
0.05 significance level and with 80% power this estimate requires studying 42 patients in each group a 
total of 84 patients. To accommodate for missing study endpoints and potential dropouts, we 
additionally plan to increase the sample size to 90 patients (45 patients in each group).
 Data analysis plan 
Demographic and clinical characteristics (age, gender, type of surgery, medications, ASA status, co- 
morbidities, etc.) baseline AM-PAC scores and  WOMAC scores between two study groups will be 
compared using t-tests or Wilcoxon rank-sum tests for continuous variables and chi-square or Fisher’s 
exact tests for categorical variables. This is to ensure that randomization is appropriately 
implemented.The primary endpoint proportion of patients fit for discharge on POD-1 will be analyzed 
using chi-square or Fisher’s exact test. Mixed models will be used to examine whether effects of study 
treatment on changes in pain scores from baseline vary with time.  Differences in opioid consumption 
and numeric pain rating scale during the first 48 hours post-TKA surgery and discharge times between 
two groups will be examined using t-tests or Wilcoxon rank-sum tests. Differences in discharge 
destination between two groups will be analyzed using chi-square or Fisher’s exact tests. Mixed models 
will be used to examine whether effects of treatment on changes in 6 Clicks AM-PAC scores WOMAC 
vary with time.
Randomization
Patients will be randomly assigned to one of the two groups in 1:1 ratio.  The research office will be 
using an online randomization tool to randomize patients generated to construct a sequence. On 
medical record, the group assignments will be recorded as “study drug.” The key to the randomization 
code will be stored in the research office. In the case of emergency PI and other clinical members will be 
provided with the allocation information. The PI or the designee will inform the IRB and the DSMB 
regarding unblinding the code. The date, time and reason for breaking the blind will be recorded in the 
source document and will be entered in the appropriate section of CRF.
Data Safety Monitoring Board (DSMB)
Data safety monitoring board will be comprised of an anesthesiologist and, a surgeon, and an interim 
statistician. There will be an interim analysis for this study halfway through recruitment. All 
unanticipated serious adverse events will be reported to the DSMB. In the event of unanticipated 
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serious adverse events, a continuation of the study will be at the discretion of DSMB and IRB. In addition 
to the interim analysis, DSMB meetings will be held monthly and in the event of serious adverse events. 
The local injection site will be evaluated for any adverse events during the postoperative period. 
Additionally, the orthopedic physicians will evaluate the sites during their follow up visits.
                              
Data Management  
 All study data will be collected and entered into the computer database. Each subject will be assigned 
to a random number code, and the key is linking the code and the subject identifier will be stored in a 
locked cabinet. The computer database will be password protected and will be kept on the Montefiore 
drive. The research manager is responsible for auditing the consistency of the data transcribed from the 
paper CRF to the computer. A protocol violation log will be maintained and all protocol violations will be 
reported to the IRB and DSMB. The planned interim analysis (half way through the recruitment) will be 
mainly focused on the adverse events, rather than the efficacy of the procedure.
Human safety 
LB (Exparel) is a local anesthetic, that uses DepoFoam technology to extend the delivery of bupivacaine, 
a local anesthetic that has been used in clinical practice for decades. Depofoam technology has been 
used as an extended delivery system for other drugs. 
All nerve blocks performed in this study is part of the standard of care at our hospital. Risks associated 
with these blocks bleeding, infection, and damage to surrounding structures including the nerve. 
Furthermore, local anesthetics, which are routinely used for peripheral nerve blocks, carry the risk of 
local anesthetic toxicity, neurotoxicity, and allergic reactions. During the  consenting clinical process for 
performing nerve blocks, these risks are being communicated with the patients.
Although bleeding complications from peripheral nerve blocks with continuous catheters have been 
described in patients that receive anticoagulation,34 multiple studies since then have not shown any 
incidences of bleeding more serious than ecchymosis and bruising at the injection site.35,36 
34 Bickler P, Brandes J, Lee M, et al. Bleeding complications from femoral and sciatic nerve catheters in patients 
receiving low molecular weight heparin. Anesth Analg 2006;103:1036 –7
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Transient neurologic deficits after femoral nerve blocks are estimated to be 3.4 in 1,000 patients while 
the incidence of permanent nerve injury after any peripheral nerve block is extremely low with only one 
reported case from a review of 16 studies incorporating data from over 34,000 peripheral nerve blocks.
37
Local anesthetic toxicity is rare but can occur as serious complications of local tissue infiltration. As is the 
standard protocol at all the areas where tissue infiltration is performed, we will follow standard 
precautions for preventing intravascular injection of local anesthetic (US guidance, aspiration before 
injection), as well as have equipment for resuscitation immediately available (lipid emulsion, code cart). 
The liver metabolizes local anesthetics such as bupivacaine, and as a result, these drugs will be used 
cautiously in patients with active liver diseases38. 
There is a risk of infection associated with local tissue infiltration. Reactions at the injection site may 
include swelling, tenderness, and warmth, discharge from the surgical site, and fever and chills which 
may develop a few hours after the injection and can last up to two days.3940 All local injections 
performed in this study will use sterile procedures to reduce the possible risk of infection.  
There is also a risk of delay in rehabilitation outcome measures.  Some postoperative complications 
include prolonged stiffness, persistent pain and diminished function.41 Physical acitivities targeted 
towards regaining muscle strength will be performed in the rehabilitation period and we will do our best 
to ensure a succesful recovery for each patient. These patients are constantly being evaluated by 
physical therapists in house. If the patients go to a rehabilitation center, they are being monitored by 
rehabilitation physicians. It is routine standard of care that when patients go home, they will go to 
35 Buckenmaier CC III, Shields CH, Auton AA, et al. Continuous peripheral nerve block in combat casualties receiving 
low molecular weight heparin. Br J Anaesth 2006;97:874 –7
36 Idestrup C, Sawhney M, Nix C, Kiss A. The incidence of hematoma formation in patients with continuous femoral 
catheters following total knee arthroplasty while receiving rivaroxaban as thromboprophylaxis: an observational 
study. Reg Anesth Pain Med. 2014; 39: 414–417.
37 Brull R., McCartney C.J., Chan V.W., El-Beheiry H. Neurological complications after regional anesthesia: 
Contemporary estimates of risk. Anesth. Analg. 2007;104:965–974. doi: 10.1213/01.ane.0000258740.17193.ec
38https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=022496 
39 http://www.aafp.org/afp/2002/0715/p283.html
40 https://www.medicalnewstoday.com/articles/310636.php
41 Hovik, Lise Husby, et al. “Preoperative pain catastrophizing and postoperative pain after total knee arthroplasty: 
a prospective cohort study with one year follow-up.” BMC Musculoskeletal Disorders, BioMed Central, 2016
IRB NUMBER: 2017-7893
IRB APPROVAL DATE: 10/10/2017


PI: Boleslav Kosharskyy
Version-9.15. 2017
 
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physical therapy or they will have therapists that come to their home. These therapists will be sure that 
all patients will be properly taken care of during the postoperative period.
IRB NUMBER: 2017-7893
IRB APPROVAL DATE: 10/10/2017