Postoperative Analgesia After Cardiac Surgery - A Double-Blind, Prospective and Randomized Comparison of Wound Infiltration With Liposomal Bupivacaine and Bupivacaine Hydrochloride
Phase: PHASE3
Conditions: Coronary Artery Disease, Coronary Artery Stenoses, Valve Regurgitation, Mitral, Valve Regurgitation, Tricuspid
Sponsor: Kathirvel Subramaniam

POSTOPERATIVE ANALGESIA AFTER CARDIAC SURGERY-AN OPEN-LABEL 
DOUBLE BLIND,A DOUBLE-BLIND PROSPECTIVE AND RANDOMIZED 
COMPARISON OF WOUND INFILTRATION WITH LIPOSOMAL BUPIVACAINE 
AND BUPIVACAINE HYDROCHLORIDE  
Date: 12/06/2018 
Principal Investigator:  
Kathirvel Subramaniam, M.D., M.P.H 
Associate Professor, Department of Anesthesiology 
University of Pittsburgh Medical Center (UPMC) 
UPMC Presbyterian Hospital, C-Wing 
200 Lothrop Street Pittsburgh, PA 15213 
Sub-Investigator; Christopher Sciortino MD 
Co-investigators 
Michael L. Boisen MD 
Stephen A. Esper MD MBA 
Kilic, Arman MD 
Marquez, Jose MD 
Sullivan, Erin MD 
Place of Study; UPMC Health System, Pittsburgh PA 
Study coordinator; Amy Monroe 
 
 

 
Executive Summary 
Moderate to severe pain is common in up to 75% of patients undergoing sternotomy for cardiac 
surgery and 4% of them develop chronic post-sternotomy pain1. Pain after cardiac surgery is 
multifactorial and caused by skin incision, sternotomy, sternal retraction, internal mammary artery 
dissection, mediastinal and pleural drains, saphenous vein harvest, position of the patient and 
stretching of brachial plexus.  Pain after cardiac surgery is often undertreated because of fear of 
inducing cardiorespiratory depression in otherwise compromised patients. Untreated and 
undertreated pain has severe adverse consequences in cardiac surgical patients. Inadequate pain 
control can lead to increased sympathetic discharge, increased myocardial demand, myocardial 
ischemia, cardiac arrhythmias, decreased ventilator effort and clearance of secretions, prolonged 
mechanical ventilation, increased postoperative pulmonary complications, delayed patient 
mobilization, poor patient satisfaction, increased length of intensive care unit and hospital stay and 
increased cost of health care1. Commonly used treatment modalities include acetaminophen, oral 
opioids, non-steroidal anti-inflammatory drugs and intravenous opioids. Opioids are used 
sparingly because of fear of side effects namely excessive sedation, respiratory depression 
(hypoxemia and carbon-dioxide retention), prolonged ileus, constipation, urinary retention and 
postoperative nausea and vomiting. Neuraxial anesthesia and analgesia (spinal, epidural and 
paravertebral blocks) are avoided in cardiac surgery due to the risk of inducing neuraxial 
hematoma with anticoagulation and neurological deficits. Neuraxial catheters also need 
management by specialized acute pain service teams. Current practice of local anesthesia 
infiltration into the wound is limited by the short duration of action of available local anesthetic 
drugs (lidocaine and bupivacaine) and was associated with increased incidence of wound 

infections2. Recent studies explored the use of liposomal bupivacaine (Exparel; Pacira 
Pharmaceuticals, Inc., Parsippany, NJ) and duration of analgesia with this slow release 
bupivacaine preparation may last up to 72 hours. Liposomal bupivacaine produced significant 
analgesic benefit in hemorrhoidectomy, bunion surgery, total joint arthroplasties, arthroscopic 
surgery, breast implantations and abdominal surgical procedures3. There are no studies to date that 
investigated the use of liposomal bupivacaine in cardiac surgical population. Our aim is to study 
the analgesic efficacy and safety of wound infiltration with liposomal bupivacaine in patients 
undergoing cardiac surgery with sternotomy and cardiopulmonary bypass (CPB) and compare it 
with bupivacaine hydrochloride infiltration.  
Background 
Liposomal bupivacaine (LB) has recently been the target for many clinical trials with the 
expectation that long lasting analgesic efficacy would improve patient satisfaction and patient 
outcomes. Several randomized studies have shown positive effect on postoperative pain relief with 
the use of LB (Table 1).  The following evidence-based research indicates the utility of LB in 
specific surgical populations.  
Abdominal surgery 
Kalogera et al4 in a retrospective cohort study examined the utility of wound infiltration with LB 
after gynecologic surgery through laparoscopy and laparotomy. Median oral morphine 
equivalents, IV patient controlled analgesia (IVPCA) opioids requirements, IV rescue analgesia 
with opioids and opioid related side effects were significantly reduced with LB in their enhanced 
recovery after surgery (ERAS) population. Efficacy was better in laparoscopy population than in 
laparotomy patients.  

Hutchins et al5 in a randomized observer blinded study compared ultrasound guided transversus 
abdominal plane (TAP) blocks with LB versus non-liposomal bupivacaine for analgesia after 
laparoscopic hand assisted donor nephrectomy. There was a significant decrease in maximal pain 
scores and IVPCA fentanyl injection up to 72 hours after injection in LB group. The same research 
group in another prospective randomized observer blinded study evaluated the use of subcostal 
TAP injection using bupivacaine and LB for patients undergoing robotic assisted hystrectomy6. 
There was decrease in maximal pain scores, opioid consumption as well as decreased incidence of 
PONV with liposomal TAP blocks for first 72 hours after surgery. A trend was noted in the LB 
group towards a shorter hospital stay duration. Beck et al7 compared patients receiving multimodal 
analgesia that included LB infiltration and patients using conventional pain management using IV 
opioids in their ERAS program for major colorectal surgery. Patients receiving multimodal 
analgesia had lower pain scores, lower IV opioid consumption, decreased opioid related side 
effects and decreased length of hospital stay. 
In spite of many impressive studies showing positive effects of LB in acute pain management of 
abdominal surgery, a few others failed to show significant benefit. Knudson et al8 compared LB 
and bupivacaine hydrochloride for wound infiltration in colorectal surgery in a non-sponsored, 
prospective randomized and double blinded clinical trial (n=57). IVPCA hydromorphine 
requirements were comparable for both groups and they suggested larger clinical trials to define 
the effectiveness of LB. In another cohort study using propensity- matched analysis, TAP block 
with LB was compared with IVPCA and epidural analgesia in patients undergoing major 
abdominal surgery (106 patients in each group). TAP block was non-inferior to epidural block and 
was comparable to IVPCA in terms of pain scores9. They recommended a larger clinical trial 
comparing these techniques. Knight et al10 in a prospective, randomized, patient blinded clinical 

trail evaluated wound infiltration with LB and bupivacaine hydrochloride for postoperative 
analgesia after urologic surgery. No difference was found between the groups in pain scores, 
opioid consumption, adverse events or length of hospital stay.  
Failure to demonstrate analgesic benefit in the above mentioned studies could be related to sample 
size, study methods (prospective versus retrospective cohort), variation in wound infiltration 
method and LB volumes, type of surgery (laparotomy versus laparoscopy), other analgesics used 
and duration of follow up. 
Orthopedic surgery 
Shoulder surgery 
Routman et al11 studied the effect of adding LB infiltration to multimodal analgesia (consisted of 
narcotics, gabapentin, non-steroidal anti-inflammatory drugs, acetaminophen and single injection 
interscalene block) on postoperative analgesia and duration of hospital stay. The LB cohort had 
fewer narcotic requirements, better visual analog scores and shorter hospitalization after shoulder 
arthroplasty. However, when local infiltration with LB was compared with interscalene block in a 
prospective randomized clinical trial, no significant benefits could be demonstrated with the use 
of LB infiltration12. 
Knee arthroplasty 
A systematic review conducted by Kuang et al13, of studies comparing standard periarticular 
injections and LB injections have shown that LB had comparable length of stay, ambulation 
distance, PONV, pain scores and narcotic consumption after total knee arthroplasty (TKR). 
Considering the cost, they questioned the use of LB in pain management after TKR. Ma et al14 

published another systematic review of 6 clinical trials comparing femoral nerve block and LB 
injection and found that pain scores were comparable with both techniques but narcotic 
consumption was lower with LB. Adverse events were similar with both groups.  
Hip Arthroplasty 
Yu et al15 compared standard pain management (n=686) to LB infiltration (n=586) in total hip 
arthroplasty (THR) patients. Pain scores were similar. Patients who received LB had lower narcotic 
consumption, better achievement of physical therapy milestones, decreased length of hospital stay 
and improvement in disposition to home. Barrington et al reported several large series of 
arthroplasty patients treated with LB and demonstrated superior pain relief with better outcomes 
using this drug16,17,18. 
Spine surgery 
Puffer et al19 studied the analgesic efficacy of LB infiltration and compared with standard IV 
narcotic analgesia in patients undergoing single level discectomy procedures. Patients in LB group 
received shorter duration of IV analgesics (average difference 10.3 hours) but no differences in 
pain scores, total narcotic consumption or length of stay were detected when compared to standard 
pain management group. Kim et al studied LB infiltration versus standard bupivacaine infiltration 
in patients undergoing unilateral interbody lumbar fusion. They demonstrated significantly 
reduced opioid consumption, reduced pain scores and length of hospital stay in their patients who 
received LB infiltration20. In patients undergoing posterior spinal decompression, Grieff et al21 
compared standard bupivacaine and LB infiltration and found no statistically significant difference 
in pain scores, narcotic consumption and length of hospital stay. However, there was a trend 
towards less narcotic consumption in LB group.  

Plastic surgery 
Several studies evaluated the use of LB and demonstrated its benefits in plastic surgical procedures 
such as breast reconstruction, augmentation mammoplasty, abdominal wall reconstruction, 
mastectomy, bunionectomy and abdominoplasty22-26. Vyas et al27 performed a systematic review 
of 160 studies and found eight studies comparing LB and standard pain relief techniques (nerve 
blocks, epidural analgesia, patient controlled analgesia and IV narcotics). They reported safety, 
tolerability and equivalent or better efficacy with LB in plastic surgery.  
Cardiothoracic surgery 
Very few clinical trials examined the role of LB in postoperative analgesia after cardiac surgery. 
Thoracotomy is associated with significant pain and inadequate pain relief may lead to poor 
outcomes. Epidural analgesia is commonly used to treat post thoracotomy pain but is associated 
with hypotension, respiratory depression, pruritus and need for acute pain service consult (for 
infusion pumps management and follow-up). Intercostal block with LB was tested and compared 
with epidural analgesia in a retrospective study by Khalil et al28. There was a significant 
improvement in pain scores on days 1 and 3 but no significant difference on day 2. No significant 
difference could be shown in narcotic consumption but there was significant decrease in 
pulmonary complications in LB group. Total length of hospital stay was less in LB group.  
Robotic cardiac surgery with multiple thoracic ports and incisions can be associated with 
significant postoperative pain. Balkhy et al29 compared bupivacaine (n=30) and LB (n=30) 
infiltration through incision and port sites in patients undergoing robotic cardiac surgery. Patients 
in LB group had less pain intensity, reduced narcotic consumption and reduced incidence of PONV 

compared to bupivacaine group. The results did not achieve statistical significance because of 
small sample size but there was a trend towards better analgesic efficacy with LB.  
There are no studies to date on the use of LB infiltration and its analgesic efficacy in cardiac 
surgery done through sternotomy. Although other surgical approaches are useful in selected group 
of patients and surgeries, majority of cardiac surgery is still done through sternotomy approach. 
We hypothesize that a randomized clinical trial to evaluate the benefits of LB infiltration in cardiac 
surgery will be beneficial for this surgical population.  
Specific Aims 
1. To study the analgesic efficacy and safety of sternal wound infiltration with 
liposomal bupivacaine on postoperative analgesia in patients undergoing elective 
cardiac surgery with cardiopulmonary bypass 
2. To study the effect of wound infiltration with liposomal bupivacaine on functional 
patient recovery, patient satisfaction, chronic sternal pain and composite 
complications after elective cardiac surgery 
3. To study the cost effectiveness of liposomal bupivacaine in elective cardiac 
surgery 
Research Design 
Trial Design 
Study design will be a prospective, randomized and double-blinded open-label double-blind 
clinical trial. The study will include patients over 18 years of age undergoing cardiac surgery with 
sternotomy approach at University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.  
 
 

 
 
Recruitment 
Potential participants will be screened by the cardiac surgeons and study coordinators at the 
preoperative/surgical clinics or the day before surgery for inpatients. They will be asked for their 
interest in participating in a research study related to pain control after before their cardiac surgery 
Randomization Process 
Participating patients will be randomized by computer generated random numbers to either the 
bupivacaine or liposomal bupivacaine group.  
Eligibility Criteria 
Inclusion: 
 
Patients over the age of 18 
 
Male or Female 
 
All races 
Open cardiac surgery through sternotomy approach (eg. coronary artery bypass graft, 
valvular heart procedures, and other open cardiac procedures along with coronary artery 
bypass) 
Surgery with the use of cardiopulmonary bypass 
Exclusion 
Minimally invasive heart surgery through thoracotomy approach 
Patients receiving regional analgesia such as intrathecal morphine 
Patients undergoing procedures under deep hypothermic circulatory arrest 
Patients with active infections such as infective endocarditis 

Emergency surgery 
Patients undergoing transplantations and ventricular assist device insertion 
Patients on any mechanical circulatory support preoperatively 
Patient’s refusal 
End stage liver or renal disease 
Allergy to bupivacaine 
Patients who cannot understand the study procedure or refuse to participate 
Redo-sternotomy 
Participation in another study 
Patients with severe right or left ventricular dysfunction (EF <25%) 
Patients requiring chronic opioids for chronic pain conditions 
 
Treatment Groups 
Patients will be randomized to Liposomal bupivacaine or Bupivacaine group. 
At the end of surgery, infiltration of the sternotomy wound and mediastinal /chest tube sites will 
be done by one of the two methods. Wound infiltration will be done on both sides of the wound 
from subcutaneous space till periosteum. Injection will be done approximately at 20 cc per inch of 
sternotomy wound.  
Group 1; Liposomal bupivacaine 20 cc (266 mg) + Bupivacaine Hydrochloride 0.25% 40 cc (100 
mg) + made up to calculated volume with normal saline solution based on length of the incision 
and the number of chest tubes (20cc per tube and 20cc per inch of incision).  

Group 2; Bupivacaine 0.25% 2 mg/kg not to exceed 150 mg – made up to calculated volume with 
normal saline solution based on length of the incision and the number of chest tubes (20cc per tube 
and 20cc per inch of incision).  
Anesthetic Management 
After the patient signs informed consent, patients are enrolled into the study. Midazolam 1-2 mg 
IV premedication will be administered in the holding area or in the operating room before arterial 
line placement. Induction of anesthesia method and medications are not standardized and will be 
decided by the anesthesiologist. After intubation, oxygen and a volatile anesthetic (isoflurane or 
sevoflurane) will be used for maintenance of anesthesia and muscle paralysis achieved with non-
depolarizing muscle relaxants titrated to neuromuscular monitor. Intermittent fentanyl will be 
administered to all patients as analgesic and will be titrated by anesthesia care team 
During CPB, isoflurane will be administered through CPB circuit and neuromuscular paralysis is 
maintained. Bispectral index is monitored to keep the values between 40-60. Additional 
Midazolam is administered during rewarming or any other period if BIS is higher than 60. Higher 
BIS can also be managed with increasing the concentration of inhalational agent if tolerated. 
Additional vasopressors or vasodilators are administered and inotropes initiated as required by the 
anesthesia care team. Sevoflurane is preferred for post bypass period in view of extubating patients 
in the operating room or early in the intensive care unit. During post CPB period, ondansetron 4 
mg IV will be administered to all patients in both groups. IV hydromorphine 1 mg will be 
administered for all patients during sternal wiring.  After the drapes come down, patient’s 
neuromuscular blockers will be reversed and extubation performed in the operating room. Patients 
who could not be extubated will be transferred on propofol to intensive care unit and will be 
extubated shortly by the ICU staff.  

Outcomes 
Postoperative pain scores and total narcotic consumption in the first 72 hours postoperative period 
will be co-primary outcomes. Pain intensity will be evaluated by numeric rating scale, NRS (0- no 
pain 10- worst pain) at rest, deep inspiration or cough and at movement.  NRS scores will be 
evaluated every 4 hours for 24 hours, every 8 hours for 48 hours and every 12 hours for 72 hours.  
Rescue post-operative analgesia will be provided by intravenous or oral acetaminophen, non-
steroidal anti-inflammatory drugs, oral oxycodone (5-10mg), IV narcotics administered by the 
nurse and patient controlled analgesia (PCA) with narcotics based on the patient’s ability to take 
oral drugs and the intensity of pain. Three commonly used IV narcotics include: hydromorphone, 
morphine and fentanyl. All narcotics administered in the first 72 hours will be converted to total 
IV morphine equivalent for comparison between the two groups.Patient controlled postoperative 
analgesia with hydromorphine (0.2 mg every 6 minutes) without a basal infusion will be primarily 
used during ICU stay. Intravenous hydromorphine (0.2-0.4 mg) will be administered by nurses 
before starting on IVPCA or if IVPCA was ineffective. Oral oxycodone and IV acetaminophen 
can be given as rescue analgesics. All IV and oral narcotics administered in the first 72 hours will 
be converted to IV morphine equivalent for the purpose of analysis. IVPCA is discontinued if pain 
scores were persistently less than 4 and duration of IVPCA requirement will be noted.  
Secondary outcome measures include the time to extubation, time to mobilization and out of bed 
to chair, time to oral intake, noninvasive ventilation requirement and re-intubations, use of 
incentive spirometry, postoperative nausea and vomiting, major organ dysfunction (cardiac, renal, 
respiratory and central nervous system) from Society of Thoracic Surgeon’s database, length of 
hospital and ICU stay, readmissions and 30 day and in hospital mortality.  

Other pre-specific outcome measures include: Delirium, patient satisfaction, chronic pain 
assessment, and serum cortisol levels.   
An Intensive Care Delirium Screening Checklist (ICDSC) will be administered at baseline, 48 
hours and 72 hours post-operatively. They participant will also be assessed for patient satisfaction 
regarding pain management at the time of discharge. Chronic pain assessment using 0–10 Numeric 
Pain Rating Scale Questionnaire (for both groups): Two follow-up questionnaires will be 
administered to all study subjects at 6 and 12 months after the surgery. Subjects will be asked: On 
a scale of 0 to 10, with 0 being no pain at all and 10 being the worst pain imaginable, how would 
you rate your pain? Current, worst and best pain levels will be questioned and an average pain 
score will be taken during rest and activity. 
In addition to clinical parameters, the suppression of stress response will be evaluated by 
comparing the hormone levels between the groups. Serum cortisol hormone levels will be 
measured at baseline (right before surgery), 8, 48 and 72 hours postoperatively.  
Sample Size and statistics 
Based on our previous institutional study, the estimated average narcotic consumption in the first 
48 hours after sternotomy was (IV morphine equivalent doses) 27 mg (SD 18 mg). Based on our 
previous institutional study, the estimated average narcotic consumption in the first 48 hours after 
sternotomy was (IV morphine equivalent doses) 27 mg (SD 18 mg). We anticipate mean narcotic 
consumption to be reduced to 14 mg with the use of wound infiltration with liposomal bupivacaine. 
With Alpha at 0.05 and 80% power, we estimate 30 patients will be required in each group (total 
n=60 patients). Since cardiac surgical patients may have high drop out rate (15%), we plan to 
recruit 70 patients to demonstrate the analgesic superiority (total narcotic consumption in 48 hours) 

of liposomal bupivacaine infiltration. We anticipate 30% reduction in narcotic consumption with 
the use of wound infiltration with liposomal bupivacaine. With Alpha at 0.05 and 80% power, we 
estimate 51 patients will be required in each group (total n=102 patients). Since cardiac surgical 
patients may have high drop out rate (15%), we plan to recruit 1187 patients to demonstrate the 
analgesic superiority (total narcotic consumption in 48 hours) of liposomal bupivacaine 
infiltration. Interim statistical analysis will be done at the end of 50 patients before proceeding 
with a complete study.  
Data will be collected on demographic variables (age, gender, weight) and procedural variables 
(type of surgery, duration of surgery, CPB duration) and postoperative outcome parameters.  
Continuous variables such as narcotic consumption, length of ICU and hospital stay, and time 
to extubation will be analyzed using Student t test or Mann Whitney U test wherever 
appropriate. Incidence of complications and other binary variables between the groups will be 
analyzed by Chi Square test or Fisher exact test. P value less than 0.05 will be considered 
significant. Confidence intervals and relative risks will be defined wherever appropriate. 
Intention-to–treat analysis will be used for the study population.   
 
 

Study Timeline and Milestones 
This study will be conducted over one year starting from the enrollment of the first 
patient. Proposed timeline for the trial is given below: 
 
OBJECTIVE 
PROPOSED TIMELINE 
 
Secure funding and ethical approvals 
May 20187 
 
Write protocol, design forms, and create 
database 
complete 
 
Assemble and train study team 
May 20187- June 20187 
 
Recruit participants 
June 20187 – July 20198 
 
Monitor initial study compliance and safety 
November 20187 
 
Interim Analysis for DSMB 
December 20187 
 
Meet with DSMB for Monitoring 
Every month meeting 
 
Final Study result analysis 
August 20198 
 
Abstract presentation 
ASA October 20198 
 
Study ends with manuscript submission 
October 20198 
 
 
 
 
 

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Table 1 
 
Study 
Study design 
Surgery 
Groups 
Primary 
outcome 
Results 
Gorfine et al 
(2011) 
RCT Multicenter 
(n=189) 
Hemorrhoidectomy 
Liposomal 
bupivacaine (LB) 
300 mg in 30 cc 
NS versus Placebo 
NRS 
Pain scores and opioid use  
were significantly  
less with LB 
Smoot et al 
(2012) 
RCT (n=136) 
Mammoplasty 
Liposomal 
bupivacaine 300 
mg versus 
 bupivacaine HCL 
200 mg 
NRS 
No difference in pain scores
but opioid consumption was
less with LB 
Golf et al 
(2011) 
RCT (n=193) 
Bunionectomy 
Liposomal 
bupivacaine 180 
mg versus placebo 
NRS 
Significant differences  
in opioid use and pain score
with LB 
Bramlett et al 
(2012) 
RCT (n=134) 
Total knee 
arthroplasty 
Multiple doses of 
LB (dose-
response) vs 
bupivacaine 
NRS 
No difference in pain scores
opioid consumption  
between  
groups