Double-Blinded Randomized Control Trial Comparing Liposomal Bupivacaine and Bupivacaine Hydrochloride in Transversus Abdominis Plane Blocks Prior To DIEP Flap for Breast Reconstruction
Phase: PHASE4
Conditions: Breast Reconstruction, Anesthesia, Transverse Abdominis Plane Block
Sponsor: Vanderbilt University Medical Center

 
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Protocol Title:  
Double-Blinded Randomized Control Trial Comparing Liposomal Bupivacaine and 
Bupivacaine Hydrochloride in Transversus Abdominis Plane Blocks Prior To DIEP Flap 
for Breast Reconstruction 
 
Protocol Version Date: 
10/01/2018 
 
 
NCT #   03700970 
 
Principal Investigator: 
Galen Perdikis, MD – Professor, Department of Plastic Surgery, Vanderbilt University 
Medical Center 
D-4207 Medical Center North, Nashville, TN 37232-2345 
 
Sub-Investigators: 
Uma Devi Shastri, MD – Assistant Professor, Department of Anesthesiology, Vanderbilt 
University Medical Center 
Matthew David McEvoy, MD – Professor, Department of Anesthesiology, Vanderbilt 
University Medical Center 
Kye Higdon, MD – Associate Professor, Department of Plastic Surgery, Vanderbilt 
University Medical Center 
Lyly Nguyen, MD – Department of Plastic Surgery, Vanderbilt University Medical Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Background 
Perioperative and postoperative analgesia is a high priority for patients undergoing plastic 
and reconstructive surgery. It is of particular interest in patients undergoing abdominally-
based free flaps for breast reconstruction (e.g., deep inferior epigastric artery perforator 
flaps) that includes excision of abdominal skin and subcutaneous tissue since the majority 
of pain after these operations is derived from the abdominal donor site  (Jablonka et al, 
PRS 2017). Although intravenous and oral opioids have been the mainstay of postoperative 
pain control for this patient population, they are associated with a number of detrimental 
effects that can delay recovery and increase length of hospital stay. For example, they can 
lead to nausea, vomiting, constipation, lethargy, cough suppression, confusion, and 
orthostatic hypotension (Pizzi et al; Pharmacotherapy 2012). By reducing these side 
effects, resumption of a normal diet and ambulation can be achieved faster, which can 
accelerate recovery. This is turn can lead to decreased length of hospital stay and its 
associated cost, as well as improvement in the perceived quality of life for this patient 
population.  
 
Local analgesia, in the form of transversus abdominis plane (TAP) block that is 
administered in the operating room prior to the incision under ultrasound guidance, has 
been advocated to provide improved analgesia in the perioperative and postoperative 
periods. This is a promising approach that can decrease or even eliminate the need for 
narcotics in the postoperative period.  This is a standard procedure at VUMC, and part of 
the Enhanced Recovery Pathway, for patients undergoing abdominally-based free flap 
breast reconstruction.  However, there is debate regarding the best local anesthetic for these 
purposes. Liposomal bupivacaine has been used widely and is believed to provide adequate 
analgesia for more than 48 hours after surgery. On the other hand, plain bupivacaine is 
significantly cheaper and has also been shown to have promising and lasting analgesic 
results.  To date, there are not randomized trials comparing the two local analgesics in a 
well-defined group of plastic surgery patients in general and also specifically in patients 
undergoing abdominally-based free flap breast reconstruction. 
 
 
Rationale and Specific Aims 
This study is designed to compare the efficiency of TAP blocks using liposomal 
bupivacaine versus plain bupivacaine that is administered in the operating room under 
ultrasound guidance prior to the incision in patients undergoing abdominally-based free 
flap breast reconstruction.  
 
The primary aim of the study will be to compare the amount of supplemental postoperative 
narcotic analgesia (both intravenous and oral) required by the study groups in oral 
morphine equivalents from postoperative days 0 to 7. The amount of postoperative 
analgesia will be documented daily until postoperative day 7. It will be obtained from the 
medical records during hospitalization, and with daily phone calls after the patients get 
discharged with instructions to document this data daily. 
 

 
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The secondary aims will be: 
1) Pain control, as measured by a visual analog NPS number ranging from 0 (no pain 
at all) to 10 (worst pain ever) between the 2 groups. This will be evaluated 
immediately after surgery in the postanesthesia care unit (PACU), on the day of 
surgery and all subsequent postoperative days until discharge and on postoperative 
day 7. In the PACU patients will be asked about their current pain. For the inpatient 
postoperative days and postoperative day 7, patients will be asked to record their 
average, current, and maximum Numeric Pain Scale (NPS) score for the previous 
24 hours 
2) Time to first opiate use: time from end of surgery (i.e. patient went to recovery or 
ICU) until time of first opioid intake)  
3) Time to return of bowel function: time from end of surgery (i.e. patient went to 
recovery or ICU)  
4) Incidence of narcotic complications (i.e. nausea, vomiting, constipation, urinary 
retention, dizziness, etc.); defined as the number of occurrences of the complication 
per day for the first 7 days after surgery 
5) Quality of life (QoL) as measured with: 
Baseline (during consenting before surgery): WHODAS, QoR-15, PROMIS-29 
0-7 days: QoR-15 
Day 7 and 14: PROMIS-29 
Day 30:  PROMIS-29, WHODAS 
 
 
Inclusion/Exclusion Criteria 
Inclusion criteria will include:  
1) age between 18-85 years 
2) males or females 
3) plastic surgery for abdominally-based free flap breast reconstruction.  
 
Exclusion criteria will include:  
1) those not candidates for TAP blocks due to allergies to the medications (e.g., 
bupivacaine)  
2) those with anatomic contra-indications to performing a TAP block  
3) those unwilling to participate in follow-up assessments 
4) vulnerable populations 
5) chronic pain or associated diagnosis 
 
 
Enrollment/Randomization 
Patients undergoing abdominally-based free flap breast reconstruction under general 
anesthesia will be randomized to receive a TAP block with either liposomal bupivacaine 
or plain bupivacaine to determine if narcotic requirements and/or pain control is better 
achieved with one of the above methods. Patients in this study will be recruited in the 
plastic surgery outpatient clinics. No advertising will be done and there will be no 
recruitment tactics.  
 

 
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Patients eligible for the study will be seen by the participating attendings at Vanderbilt 
University Medical Center, or one of their associates. The patient will be told about the 
study and given an opportunity to read the consent. If they wish to participate, they will be 
asked to sign the consent.  
 
Participants will be randomized to receive liposomal bupivacaine or plain bupivacaine in 
a permuted block fashion, in block of sizes 2 or 4. For each block, block size will be 
selected uniformly at ransom. This method of randomization ensures balance between 
groups following every second or fourth allocation. The patients will be randomized after 
providing written informed consent in the outpatient clinic. Following randomization, the 
plastic surgeons performing the surgery and assessments will be blinded to study treatment 
arm. Patients will also be blinded to the study treatment arm. The anesthesia team and some 
of the ancillary research staff will not be blinded to study treatment arm. 
 
 
Study Procedures 
Patients randomly assigned to the liposomal bupivacaine group or plain bupivacaine group 
will receive this intervention intra-operatively prior to the initiation of surgery. 
 
Local analgesia (TAP blocks) will be administered under ultrasound guidance in the 
operating room after the patient is intubated and under general anesthesia. Transfascial 
injections will be performed by the anesthesiologist using an epidural needle. Under sterile 
conditions and ultrasound guidance, the fascial plane between the internal oblique and 
transversus abdominis muscles (muscles of the abdominal wall) will be identified at the 
anterior axillary line, midway between the costal margin and iliac crest. The epidural 
needle will be inserted through the skin to the appropriate fascial plane, and the local 
anesthetic will be injected in that plane. Then the needle will be removed and discarded, 
and the patient will be prepped and draped to start the surgery. 
 
Liposomal bupivacaine group:  20mL of Exparel® 1.3% mixed with 20mL of 0.25% 
bupivacaine, for a total of 40mL of local anesthestic mixture, 20mL to be injected on each 
side. 
 
Regular bupivacaine group:  20mL of 0.25% bupivacaine injected on each side. 
 
The Anesthesia team will follow standard care procedures regarding perioperative pain 
management (including preoperative, intraoperative, and postoperative analgesic 
regimens). Patients in all groups will also receive instructions in the preoperative period 
dictating the recommended approach to postoperative pain control. 
 
 
Risks 
Injection with the local anesthetic may cause participants to experience some discomfort, 
redness or a small bruise at the site of the injections. These will be temporary and will 
disappear in a couple of days. 
 

 
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With any nerve block there is a very small possibility of damage to the nerve, which could 
result in numbness of the surrounding area. According to the medical literature the 
likelihood of this injury is 1 in 10000 to 1 in 100000.   
 
In rare cases the local anaesthetic may be absorbed into the bloodstream. In such rare 
scenario, the systemic absorption of the local anaesthetic may cause one of the following 
side effects: 
▪ Slow-irregular heartbeats, low blood pressure, abnormal heartbeats, and cardiac 
arrest (2.3 events every 100,000 patients). 
▪ Toxicity to the brain, including seizures (13.7 events every 100,000 patients); 
▪ Respiratory arrest (4.6 events every 100,000 patients). 
 
The blocks are performed in a monitored setting in the operating room.  Patients are 
connected to monitors including blood pressure cuff, ECG and oxygen saturation.  These 
monitors allow close monitoring for any signs of local anesthetic toxicity.  The area is 
equipped with all resuscitation medication and equipment, and personnel are adequately 
trained in treatment of these complications.  
 
Blocks are performed under direct ultrasound guidance so full visualization of the needle 
and the local anesthetic is observed.  This will protect against nerve injury.  
 
 
Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others; Study Withdrawal/Discontinuation 
The progress of the study will be discussed formerly at regularly scheduled research 
meetings. These will serve as a forum for the voicing of concerns or problems with the 
study. If participant safety is a concern, the research investigators will immediately notify 
the P.I.  Adverse events will be reported to the IRB according to IRB policies and 
procedures, as there are specific guidelines at IRB Policy and Procedure III.L.1 that must 
be followed.  
 
Local anesthetic toxicity or nerve injury will be considered serious adverse events.  Also 
allergic reactions to the local anesthetic will be considered adverse events. These patients 
will be withdrawn from the study and appropriate treatment will be instituted.  The 
anesthesia care team will identify such an event and report it.  
 
 
Statistical Considerations 
Sample size calculations were based on demonstrating superiority of the TAP block with 
liposomal bupivacaine. 
 
The sample size calculation for the oral morphine equivalent requirements was based on 
one of our previous studies on Enhanced Recovery Pathway for free flap breast 
reconstruction. Calculations showed that randomizing 60 patients will obtain 80% power 
to detect a difference between the two groups. 
 

 
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Privacy/Confidentiality Issues 
Collected data will be stored in a password protected REDCapTM database with sole access 
delineated by the investigators and study personnel of the study.  
 
 
Follow up and Record Retention 
The data will be extracted from the EMR via of EPIC (eStar) and entered in a RedCapTM 
database. Paper copies of the surveys will be kept in a locked cabinet by the investigators 
of the study until study completion of all data analysis and then subsequently securely 
destroyed. 
 
Collected data will include demographics, amount of supplemental postoperative narcotic 
analgesia both intravenous and oral, visual analog pain scale, time to return of bowel 
function, time to first opiate use, incidence of narcotic complications, and Quality of Life. 
Some of these variables will be collected at several times points as described above. 
 
Records will be retained for 6 years following the study completion.  
 
 
References 
Jablonka EM, Lamelas AM, Kim JN, et al. Transversus Abdominis Plane Blocks with 
Single-Dose Liposomal Bupivacaine in Conjunction with a Nonnarcotic Pain Regimen 
Help Reduce Length of Stay following Abdominally Based Microsurgical Breast 
Reconstruction. Plast Reconstr Surg. 2017 Aug; 140(2):240-251. 
 
Hivelin M, Wyniecki A, Plaud B, et al. Ultrasound-guided bilateral transversus abdominis 
plane block for postoperative analgesia after breast reconstruction by DIEP flap. Plast 
Reconstr Surg. 2011 Jul; 128(1):44-55 
 
Practice guidelines for acute pain management in the perioperative setting. A report by the 
American Society of Anesthesiologists Task Force on Pain Management, Acute Pain 
Section. Anesthesiology. 1995; 82(4):1071-81. 
 
Yu N, Long X, Lujan-Hernandez JR, et al.Transversus abdominis-plane block versus local 
anesthetic wound infiltration in lower abdominal surgery: a systematic review and meta-
analysis of randomized controlled trials. BMC Anesthesiol. 2014 Dec 15; 14:121.  
 
Knackstedt R, Gatherwright J, Ghaznavi A, et al. Comparison of local anesthetic infusion 
pump bupivacaine versus transversus abdominis plane (TAP) block liposomal bupivacaine 
for pain management after bilateral deep inferior epigastric perforator free flap 
reconstruction. J Plast Reconstr Aesthet Surg. 2017 Dec; 70(12):1779-1781. 
 
Ayad S, Babazade R, Elsharkawy H, et al. Comparison of Transversus Abdominis Plane 
Infiltration with Liposomal Bupivacaine versus Continuous Epidural Analgesia versus 
Intravenous Opioid Analgesia. PLoS One. 2016 Apr 15; 11(4):e0153675.