Exparel vs. Bupivacaine Hydrochloride vs. Placebo for Hernia Repair

This will be a double-blind, 3-arm, randomized controlled trial with a treatment 1: treatment
2: control allocation ratio of 1:1:1. Primary outcomes of interest are opioid requirements
and pain scores over initial 72 hours of the postoperative period. Opioid requirements will
be assessed by measuring the cumulative dose of opioids administered intravenously (infused
through a patient-controlled analgesia device as well as the quantity of opioids administered
intravenously as rescue, if needed) and the quantity of opioids administered through oral
preparations. This will be assessed at time points: while patients are at the post-anesthesia
care unit (PACU), at postoperative days 1(24h±4 hours), 2(48h±4 hours), 3(72h±4 hours) and at
the date of hospital discharge. The total dose of opioids used at each time point will be
recorded and converted into morphine equivalents for standardization and analysis. The
cumulative dose of opioids from 0 hours to 72 hours after the operation and for the total
hospital length of stay will be recorded. In addition, the dose of opioids administered
intra-operatively by the anesthesiologist, time for first oral opioid dose over the first 72
hours (discontinuation of PCA), and the percentage of patients not requiring opioids over the
first 72 hours will also be recorded.

Pain scores will be determined using a 100mm visual analog scale (VAS). The VAS is a 100mm
horizontal line with two endpoints: 0 (no pain) and 100 (worst imaginable pain). Pain scores
will be assessed at baseline during preoperative evaluation, at the PACU, at postoperative
days 1(24h±4 hours), 2(48h±4 hours), 3(72h±4 hours), and at the time of hospital discharge.

Additional pain scores will be obtained using the Patient-Reported Outcome Measurement
Information System (PROMIS) Pain Intensity 3a survey at baseline and 30-day follow-up. This
survey will be completed by patients in person during enrollment and 30-day follow-up.
Secondary outcomes of interest include the length of hospital stay and Patient-Reported
Quality of Life (PRQOL). Both information is already routinely collected through the Americas
Hernia Society Quality Collaborative (AHSQC). Length of hospital stay will be recorded in
days. PRQOL will be assessed using the Hernia-Related Quality-of-Life survey (HerQLes). The
HerQLes is a 12-item, validated, hernia-specific survey that assesses quality of life through
abdominal wall function after ventral hernia repair. HeQLes scores will be assessed at
baseline and 30 days after the operation.

All patients will undergo the same operation, under a standard of care protocol. Skin
preparation, hair removal, perioperative antibiotics and venous thromboembolism prophylaxis
will be performed per Surgical Care Improvement Project protocol guidelines. The procedure
will be performed through a midline incision. Upon entering the abdominal cavity, all
adhesions between intra-abdominal contents and the anterior abdominal wall are routinely
lysed using sharp dissection. When present, hernia contents are reduced back to the cavity.
At the end of adhesiolysis, the surgeon will ask the OR nurse to contact the investigational
pharmacy via telephone, who will randomize the subject. The investigational pharmacy will be
responsible for preparing and dispensing the assigned intervention. The OR nurse will receive
the drug from the investigational pharmacy in a standardized bag and will dispense it to the
surgeon at the time of the TAP block. Neither the surgeon nor other members of the surgical
team will be informed about which of the interventions were assigned to the specific patient.
Electronic medical records will contain the information: "Patient was randomized and assigned
to receive intervention according to randomization performed by investigational pharmacy."
Retromuscular hernia repair is performed initially incising the posterior rectus sheath just
lateral to the linea alba. The release will be performed at least 5 cm above and below the
fascial defect, and retrorectus dissection is carried out laterally in the direction of the
linea semilunaris. If deemed necessary, a posterior component separation will be performed by
incising the posterior lamella of the internal oblique, dividing the fibers of the
transversus abdominis muscle and dissecting the preperitoneal and retroperitoneal spaces of
the lateral abdominal wall laterally.

At the end of the myofascial release, randomization will occur and the assigned intervention
drug will be dispensed in syringes to the surgeon who will perform the perform a TAP block
under direct visualization. Patients will be randomized using a computer-generated random
allocation sequence, by the investigational pharmacy personnel.

Injections of the designated drug (group 1, 2 or 3) will be performed under direct
visualization by the attending surgeon, in 5 vertical levels, to the thoracoabdominal nerves
(from T7 to T11).

The interventions are:

- Treatment 1- Administration of a solution of Exparel® combined with Bupivacaine
Hydrochloride 0.25% and normal saline, through a bilateral TAP block performed
intraoperatively by the attending surgeon, during open ventral hernia repair;

- Treatment 2: Administration of a solution of Bupivacaine Hydrochloride 0.25% and normal
saline, through a bilateral TAP block, performed intraoperatively by the attending
surgeon, during open ventral hernia repair ;

- Control (Placebo): administration of normal saline through a bilateral TAP block
performed intraoperatively by the attending surgeon, during open ventral hernia repair.

The posterior sheath will be reapproximated, and a standard piece of polypropylene mesh will
be placed in the retromuscular space.

Mesh type will be defined by the surgeon intraoperatively according to the patient and
hernia-specific variables. Mesh fixation will be performed circumferentially using mechanical
sutures. Closed suction drains will be placed above the mesh and in the subcutaneous space,
and the timing of removal will be based on the surgeon's standard practice. Fascial closure
and management of wound dressings will also follow the surgeon's standard practice.

For postoperative analgesia, all patients will also receive a patient-controlled analgesia
(PCA) device according to the standard of care; preferably:

• Hydromorphone HCL 0.5mg/ml (Dilaudid®, Purdue Pharmaceuticals, Stamford, CT) in 100ml of
normal saline, with no basal rate infusion, a patient bolus dose of 0.2-0.4mg, bolus interval
of 6 minutes (maximum 10 doses per hour).

To ensure the comfort and adequate pain postoperative pain control, additional intravenous or
oral opioids are allowed in the protocol, to be administered for breakthrough pain (as
needed). Subjects should only receive rescue medication upon request, and for pain control.

Estimated patient accrual time is 2 years with data collection to occur over 30 days from
randomization of each patient. Data analysis and manuscript production will occur within 6
months of the completion of data collection.

As with any surgical procedure, patients may experience pain, bleeding, and discomfort.
Common occurrences following hernia repair include seroma, hematoma, inflammation, wound
dehiscence, and infection. Risks of Bupivacaine Hydrochloride include allergic reactions,
arrhythmias, chest pain or pressure, dizziness, confusion, restlessness, tinnitus, blurred
vision, dyspnea, seizures, nausea, emesis, and lethargy. Risks of Exparel® include nausea,
vomiting, constipation, as well as (rarely) seizures and cardiac arrest. Patients receiving
placebo intraoperatively will not necessarily experience higher levels of pain, as all
individuals, regardless of intervention arm, will be provided a multimodal pain management
regimen with patient-controlled analgesia postoperatively. There are no direct benefits to
subjects for participation in this study. Subject participation will, however, help
physicians and hospital administrators better understand the outcomes of Exparel® use
concerning postoperative pain management and its influence on opioid consumption, hospital
length of stay and quality of life. Patients are under no obligation to participate in this
study. A member of the research team will discuss all available surgical options with
patients. It will be emphasized that refusal to participate in this study will not impact any
patient's ability to receive surgical care. There will be no payment for the subjects for the
participation in this study.

Inclusion Criteria:

- Patients with Primary Ventral or Incisional Hernias

- Scheduled to undergo hernia repair through an open approach

- Hernia repair performed in an elective setting

- Hernia repair performed through a midline incision

- Hernia repair performed in a clean wound

- Hernia repair performed with mesh placed in the retromuscular position

Exclusion Criteria:

- patients with less than 18 years old of age

- patients scheduled to undergo a minimally invasive hernia repair

- patients where hernia repair is planned to be performed with mesh placement in a
different position than retromuscular

- patient undergoing hernia repair with a clean-contaminated, contaminated or infected
wound

- patients undergoing hernia repair in an non-elective fashion

- patients with allergy, hypersensitivity or contraindication to bupivacaine

- patients with history of chronic liver disease with moderate or severe impairment in
liver function defined as a Child-Pugh class B or C

- patients with chronic kidney disease on dialysis

- chronic opioid users, defined as daily or near daily use of opioids for at least 90
days in the past year

- patients unable to provide informed written consent