Clinical trial NCT02499159
Conditions: Pain
Keywords: Exparel Thoracoscopy Bupivicaine Liposomal
Sponsor: Inova Health Care Services
Start date: 2014-12-01; Completion date: 2017-07-01
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is looking to evaluate the efficacy of liposomal bupivicaine (Exparel) on decreasing the amount of consumed pain medications.

Patients will be randomly selected to received either Exparel or standard bupivicaine injection during surgery. Patients will be followed up to assess pain levels using a visual pain scale, and to assess how much pain medication was consumed.

Detailed description:
Exparel is a formulation of liposomal bupivacaine that is reported to allow local anesthesia for up to 72 hours post injection.

It is the investigators' aim to follow their prior study with a randomized trial to compare local infiltration of liposomal bupivacaine at the conclusion of each procedure with injections of standard .25% bupivacaine.

Patients in group A will receive, at the end of the surgical procedure, injections of liposomal bupivacaine (Exparel) (266 mg, 20 mL, diluted at surgeon's discretion) into the thoracoscopic port incision sites and around the intercostal nerves serving that space.

Patients in group B will receive, at the end of the surgical procedure, injections of standard .25% bupivacaine into the thoracoscopic port incision sites and around the intercostal nerves serving that space.

Arms: arm 1: Liposomal Bupivicaine (Exparel) - 266 mg, 20 mL total, diluted at surgeon's discretion, Two doses of 10 mL each, into two separate incisions, delivered via 22 gauge needle. arm 2: Bupivicaine - 0.25%, 20 mL total. Two doses of 10 mL each, into two separate incisions, delivered via 22 gauge needle.
Interventions: intervention 1: Liposomal Bupivicaine intervention 2: 0.25% standard bupivicaine
Intervention descriptions: intervention 1: 266 mg, 20 mL total, diluted at surgeon's discretion, delivered by 22 gauge needle. intervention 2: standard 0.25% bupivacaine, 20 mL total, delivered by 22 gauge needle.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
A randomized controlled trial of the effectiveness of liposomal 
bupivacaine (Exparel) when compared to local injection of bupivacaine 
after thoracoscopy 
 
 
 
 
Principal Investigators  
Sandeep J. Khandhar, MD 
Joby Chandy, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac Vascular & Thoracic Surgery Associates 
Fairfax Anesthesiology Associates of American Anesthesiology 
 
 
Department of Surgery 
Department of Anesthesiology 
Inova Fairfax Hospital 
3300 Gallows Road 
Falls Church, VA 22042 
 
 
Date of Protocol:  12/23/2014 
Date of Revision: 10/26/2015 


 
INTRODUCTION 
 
Video-Assisted Thoracic Surgery (VATS) has been shown to hasten patient recovery by attenuating the 
physiologic stress of surgery and decreasing post-operative pain.1 Despite this approach, incisions in the 
chest are proportionally more painful than in other parts of the body, and most patients require some form 
of narcotic pain medication. 
 
Multiple strategies for post-operative pain control have been attempted in thoracic surgery with no obvious 
superiority of one versus another. Pain catheters have been increasingly used over the past decade in 
different surgical procedures in order to minimize incisional pain for the first 3 to 7 days after an operation.   
 
For the past 5 years we have routinely used an axial subpleural tunneling technique that delivers local 
anesthetic to the intercostal space, without leakage elsewhere, creating a functional multi-level rib block. 
The published literature is equivocal as to the efficacy of such approaches following thoracic surgery with 
most recent series reporting no benefit in the use of these catheters. 2-6 Despite our own positive subjective 
results, objective data is lacking and therefore we conducted our own randomized trial to assess the efficacy 
of these catheters to standard intraoperative injection of bupivicain.   This study confirms that there is no 
difference in patient pain, satisfaction, or narcotic use.   
 
Exparel is a formulation of liposomal bupivacaine that is reported to allow local anesthesia for up to 72 
hours post injection.  It is our aim to follow our prior study with a randomized trial to compare local 
infiltration of liposomal bupivacaine at the conclusion of each procedure with injections of standard .25% 
bupivacain.   
 
AIMS 
 
1. 
To establish a safe and effective role for liposomal bupivacaine (Exparel) in thoracoscopy. 
2. 
To provide patients with a superior and longer lasting form of pain relief. 
3. 
To improve patient satisfaction and decrease perioperative narcotic use. 
 
HYPOTHESIS 
 
We hypothesize that injection of liposomal bupivacaine (Exparel) into thoracoscopic port incision sites and 
alongside the involved intercostal nerves will provide more durable pain relief when compared to local 
injection of standard bupivacaine as measured by patient pain scores and pain medication used. 
 
STUDY DESIGN 
Study Type 
This is a prospective randomized controlled trial. 
 
Setting/Location 
Patients will be recruited from the Cardiac Vascular and Thoracic Surgery Associates (CVTSA) practice.  
Operations, injections of Exparel, and pain pump administration will occur at Inova Fairfax Medical Center 
(IFMC).  The final patient outcome at 30 days will occur in the CVTSA offices during follow-up.  Data 
analysis will then be performed at IFMC. 
 
 
Duration of Study 
Consented and randomized subjects will participate for a maximum of 30 days post-operatively (+/- 10 
days).  Data for the first 7 post-operative days will be recorded, beginning during the hospital stay and 
continuing at the patients’ homes.  The next and final day of subject participation is on post-operative day 
30.  Biological specimens will not need to be collected from the subject for the purposes of this study. 
 


 
Number of Subjects  
A total of 100 patients (50 per study arm) are expected to participate in this study. 
 
Study Population Demographics 
Male and female patients will be considered for this study. Any patient over the age of 18 and having an 
isolated thoracoscopic procedure for a therapeutic or diagnostic purpose will be screened.  No study 
exclusions will be based on the racial or ethnic considerations. This study will not include minors or other 
vulnerable populations. 
 
Recruitment  
Patients who fit the inclusion and exclusion criteria will be asked to participate in the study when seen prior 
to their operation either in the CVTSA offices or in the pre-anesthesia unit.   
 
Inclusion Criteria 
All patients 18 years of age or older 
 
Isolated thoracoscopic procedure for therapeutic or diagnostic purposes 
 
Exclusion Criteria 
 
Previous ipsilateral thoracic surgery 
 
Need for operative pleurectomy or pleurodesis 
 
Chronic use of pain medication (narcotics or NSAIDS), sedatives, or hypnotics 
 
Allergies to bupivacaine or other local anesthetics, narcotics, NSAIDs or acetaminophen 
 
Liver dysfunction (INR > 1.5, albumin < 2.8g/dl, bilirubin > 2mg/dl) 
 
Renal dysfunction (eGFR < 60ml/min/1.73m2) 
 
History of peptic ulcerative disease 
 
Severe COPD requiring continuous oxygen supplementation 
 
Inability to consent 
 
Pregnancy 
 
Study Methods and Intervention 
All patients will receive a standard balanced anesthetic consisting of a mild preoperative sedative 
(midazolam 0.01-0.03mg/kg), induced with propofol (1-2mg/kg) or etomidate, fentanyl (1-2 mcg/kg) and 
rocuronium (0.6mg/kg) and maintained on a potent inhalation agent (sevoflorane 1.5%-2.5%) during 
procedures.  Prior to emergence from anesthesia, all patients will receive ketorolac 30mg IV once, 
neuromuscular reversal agents, and an antiemetic (ondansetron 4mg).  Patients will also be given additional 
narcotics (fentanyl) upon emergence, as needed, to facilitate patient comfort and extubation. 
 
All subjects shall receive a standardized inpatient and outpatient pain regimen in accordance with ASA 
guidelines for acute pain management in the perioperative period. This includes a multimodal approach 
utilizing 3 drugs with different mechanisms of action. All patients shall receive 1,000 mg of acetaminophen 
orally every 6 hours, scheduled for 5 days. Other drugs will be given on an as needed basis (PRN) to 
maintain an analog pain score of ≤ 3, as outlined in the table below. 
 
 
 
 
Pain score > 3 ≤ 5 
Pain score > 5 
Immediate post-operative period 
(OR/PACU) 
Ketorolac 30mg IV once 
Dilaudid 0.5 mg IV Q10 min 
Inpatient floor 
Ketorolac 15mg IV Q6h or 
Ibuprofen 400mg PO Q6h 
Dilaudid 0.5-1mg IV Q2h or 
Dilaudid 2-4 mg PO Q4h 
Outpatient 
Ibuprofen 400 mg PO Q6h 
Dilaudid 2-4 mg PO Q4h 
 
Patients in group A will receive, at the end of the surgical procedure, injections of liposomal bupivacaine 
(Exparel) (266 mg, 20 mL, diluted at surgeon’s discretion) into the thoracoscopic port incision sites and 
around the intercostal nerves serving that space. 


 
 
Control Group  
Patients in group B will receive, at the end of the surgical procedure, injections of standard .25% 
bupivacaine into the thoracoscopic port incision sites and around the intercostal nerves serving that space.  
 
Randomization  
Study ID numbers will be randomly assigned to treatment groups using statistical software.  Sequentially 
numbered opaque envelopes will be filled with the randomly selected treatment group.  All the envelopes 
will then be sealed, placed in numerical order, and given to the PI for storage in the CVTSA office.  Upon a 
patient’s consent, the envelope with the corresponding study ID number will be opened in the OR prior to 
surgery to reveal to the patient’s assigned study group.  This will allow time for all required materials to be 
obtained and set up for administration. The randomization results will be recorded in the patient’s study file 
to make sure the proper study treatment is received on the day of surgery. 
 
The Department of Surgery research epidemiologist/biostatistician will prepare all envelopes.  Due to her 
knowledge of the envelope contents, the research team will not take part in the randomization process that 
occurs after a patient consents to participate.  Study personnel and the surgical team working in the CVTSA 
office will perform the post-consent randomization. 
 
Patients may be excluded from the trial, at the discretion of the study investigators, if any of the follow 
occur: 
 
Need for conversion from a VATS procedure to a thoracotomy 
 
Patient is discharged from the hospital with a chest tube in place 
 
Patient fails to comply with post-operative instructions 
 
 
Primary outcomes. 
The primary outcome will be overall amounts of pain medications through postoperative day 7. 
 
Secondary outcomes 
Secondary outcomes include summed visual analog pain scores, patient satisfaction, analog pain scores at 
post-operative day 30, incidence of paresthesias, hospital length of stay (days), return to baseline activity, 
return to work, and overall hospital cost calculated as a factor value.  
 
Consent 
Patients shall be consented by one of the study investigators or approved clinical staff either in the 
outpatient office setting or in the pre-anesthesia unit.  Patients will be enrolled for up to 1 year from the 
date that IRB approval is received. 
 
Monitoring Subjects and Criteria for Withdrawal of Subjects from the Study.    
The surgical team and/or study personnel shall perform in-hospital data collection. The assessment will 
include visual analog pain scores upon admission and discharge from the post-anesthesia care unit (PACU). 
Complaints such as paresthesias (numbness) shall also be recorded. Intra-operative narcotic utilization shall 
be clearly recorded in the anesthesia records and collected retrospectively.  Any amount of pain medicine 
administered will be collected from the charted medications tab in the electronic medical records after 
subjects’ discharge.   Date of birth (DOB), past surgical history (PSH), past medical history (PMH), 
psychiatric history, and any use of steroid medication will also be collected from the patient’s medical 
records to test for confounding effects. 
 
Outpatient data collection will depend on patients or family members by way of a standardized data 
collection sheet. The timing of visual analog pain score recording should be whenever a pain medication is 
taken but at least three times a day (morning, afternoon, night). Each administered medication should also 
be recorded on a real time basis.  Detailed instructions will be given to the patient and/or caregiver to 
ensure proper data collection. 
 


 
All patients shall have a post-operative visit at 1 week (+ 4 business days) for retrieval of these data sheets.  
At 30-days post-operatively (+/- 1 week), patients will receive a telephone call from a member of the study 
research personnel for one final assessment of the visual analog pain score and complaints of paresthesias. 
 
All data from the study will be collected and maintained by database managers at Mednax Medical Group.  
Upon completion of data collection, this data will be released to the IFMC DOS 
epidemiologist/biostatistician for data analysis. 
 
Patients who, for whichever reason, need other surgical procedures within 30 days of enrollment shall be 
removed from the trial.  Patients are allowed to voluntarily withdraw from the trial at any time. 
 
STATISTCAL EVALUATION  
Our pre-study sample size estimate assumes equivocal measurement (50% difference) of use of 
postoperative pain medications between the group receiving the liposomal bupivacaine, Exparel, and the 
group receiving standard bupivacaine injections. We found that a two-arm study of 50 patients per group is 
needed, assuming α-level=0.05 and power=80%. We plan to perform an interim analysis midway through 
randomization for assessment of statistical validation of our predictions. 
 
Statistical analyses will be performed using SAS v.9.3.  Demographics, comorbidities, and past medical 
history will be described for both study groups, and compared using Χ2 tests and Fisher’s exact tests (for 
categorical variables) and Student’s t-tests or Wilcoxon rank-sum tests (for continuous variables).  Due to 
the randomization process, study groups are expected to be similar with respect to these factors. 
 
The primary outcome, overall amounts of pain medication administered through postoperative day 7, will 
be compared between the study groups using analysis of covariance (ANCOVA) controlling for potential 
covariates of interest.  Secondary outcomes, such as hospital length of stay, incidence of parasthesias, will 
also be compared among study groups using Student’s t-tests and Wilcoxon rank-sum tests.   
 
Statistical significance will be assessed at α =0.05.  Power calculations were performed, assuming a 50% 
difference in the amount of overall pain medication for group A.  A power of 80% will be achieved by 
including 50 patients in each study arm, for a total of 100 subjects.   
 
LIMITATIONS 
There are inherent limitations with using patient reported subjective pain scores to evaluate the 
effectiveness of a treatment, which is why we will be measuring overall use of pain medication as well.  
We suspect that use of pain medications will be small in both arms.  
Then incidence of paresthesia is extremely small and this study will not be powered enough to study it. 
 
TIMELINE 
IRB approval 
1-2 months 
Enrollment  
8-9 months 
Data analaysis 
1-2 months 
Submission for publication  
1-2 months 


 
 
BUDGET 
Cost of Exparel, .25% bupivacain  
$30,000 (approx. $300 per pt x 100). 
Should be covered by patient’s insurance 
Research Assistant (for data collection/analysis and 
patient follow up) 
$15000 (0.25 FTE) 
 
 
 
REFERENCES 
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assisted thoracoscopic surgery versus thoracotomy approaches to lobectomy. Annals of Thoracic Surgery 
2008;86:2008-2018. 
 
2 Allen MS, et al. A Randomized Controlled Trial of Bupivacaine through Intracostal Catheters for Pain 
Management after Thoracotomy. Ann Thorac Surg 2009;88:903-10. 
 
3Vincent WS, et al. Analgesic and Pulmonasry Effects of Continuous Intercostal Nerve Block Following 
Thoracotomy. Can J Anaesthes 1991;38:733-9. 
 
4 Debreceni G, et al. Continuous Epidural or Intercostal Analgesia Following Thoracotomy: A Prospective, 
Randomized Double-Blind Clinical Trial. Acta Anaesthesiol Scand 2003;47:1091-5. 
 
5 Kaiser AM, et al. Prospective, Randomized Comparison of Extrapleural versus Epidural Analgesia for 
Postthoracotomy Pain. Ann Thorac Surg 1998;66:367-72. 
 
6 Practice Guidelines for Acute Pain Management in the Perioperative Setting. An updated report from the 
American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology 
2004;100:1573-81.