Exparel and Ankle Surgery

Managing postoperative pain remains a paramount topic in anesthesiology, since a significant
amount of patients continue to report discomfort after their inpatient and outpatient
surgeries. Orthopedic lower limb surgeries are known to induce prolonged pain after the
procedure requiring the increased use of multi-modal analgesia. Popliteal fossa nerve block
targeting the sciatic nerve has been utilized to effectively control postoperative pain and
to lower opioid requirements for patients undergoing foot and ankle surgeries.The sciatic
nerve divides into its tibial and common fibula branches approximately 4 to 13 centimeters
above the popliteal crease. The tibial nerve innervates the heel and the plantar aspect of
the foot, while the common fibula nerve, also known as the common peroneal nerve, supplies
the lateral aspect of the leg and the dorsum of the foot.

Bupivacaine, a local anesthetic and analgesic, is currently used as an agent to address
postsurgical analgesia. However, administering a large dose of bupivacaine for nerve blockade
has been reported to lead to complications such as infection, hematoma, vascular puncture,
toxicity and, even severe systemic side effects. EXPAREL® (multi-vesicular liposomal
bupivacaine) is a multi-vesicular liposomal form (DepoFoam drug delivery systems) of
encapsulated bupivacaine that allows for the slow diffusion of the drug over an extended
period of time of 72 hours, versus the 8 hour duration of Bupivacaine Hydrogen Chloride
(HCl). EXPAREL® has been shown to provide successful prolonged analgesia after wound
infiltration during several surgical procedures.In addition to the long lasting pain relief,
studies also highlight the improved clinical outcomes of patients and lower economic costs
associated with liposomal bupivacaine when compared to bupivacaine Hydrogen chloride.
However, studies evaluating the use of EXPAREL® for nerve blocks are limited. Richard et. al.
demonstrated the safety of EXPAREL® to Bupivacaine and saline on the brachial plexus of dogs
and rabbits revealing no irritation or tissue damage even at high doses. Furthermore, after
administering liposomal bupivacaine via single epidural injections into humans, Viscussi et.
al. reported longer sensory blockade and shorter motor blockade compared to bupivacaine HCl,
enabling quicker recovery and mobility for the patient.

The primary objectives of this study is to (1) evaluate the efficacy of the study drug
EXPAREL® with respect to the safety and duration of the postoperative analgesic effect on
five subjects following single dose injection via a popliteal nerve block. Based on the data
analysis from this case series, a decision will be made as to whether a large randomized,
double-blinded, prospective study is warranted.

Methods and Materials The purpose of the popliteal nerve block with the use of EXPAREL® will
be explained to the potential subject. Demographic information will be obtained including
age, gender, past medical history, past surgical history, hospitalizations, current
medications, allergies, and history of drug and alcohol abuse. Preoperative baseline pain
score, motor strength and sensation will be documented by a study team member, prior to
carrying out study procedures. The Visual Acuity Scale (VAS) will be explained to the
patient. A Semmes Weinstein monofilament exam with a size 5.07 monofilament will be performed
to rule out any occult nerve injury.

On the day of surgery all eligible subjects will receive a single dose of study drug EXPAREL®
1.3% 20 ml (266mg) will be administered within 1 hour prior to the surgical procedure as a
popliteal nerve block. This block will be done by a trained anesthesiologist, using an
ultrasound-guided technique (Mindray model # M-7). Prior to induction of anesthesia, standard
monitoring devices such as non-invasive blood pressure, EKG and pulse oximetry for oxygen
saturation will be started. Bispectral Index (BIS) will be maintained in a range of 30-60.
Continuous vital sign monitoring will be done intraoperatively. All patients will be
administered midazolam 0.5 mg to 4 mg/kg to achieve anxiolysis. Induction of anesthesia will
also include Lidocaine 1.5mg/kg, Propofol 1.5-3 mg/kg, Fentanyl 1-2mcg/kg. If indicated the
muscle relaxant of the anesthesiologists choice: either Succinylcholine 1.5 mg/kg, Rocuronium
0.6mg/kg or Nimbex 0.2mg/kg to titrate Train of Four (TOF) at 1-2 twitches until 30 minutes
prior to the end of the surgical procedure. Anesthestic maintenance with 0.8 to 1.5 Minimum
Alveolar Concentration (MAC) of sevoflurane as indicated by end tidal concentration in oxygen
and air mixture of 50% each and fraction of inspired oxygen ( FiO2) may be increased if
oxygen saturation is less than 96%. The use of fentanyl will be permitted during surgery.
However, intraoperative administration of any other narcotics or analgesics (including
intrathecal opioids), local anesthetics, or anti-inflammatory agents is prohibited, unless
needed to treat an adverse even (AE). The amount of fentanyl used will be recorded.
Ondansetron0.1mg/kg will be used as an antiemetic prior to reversal of muscle relaxant with
neostigmine and glycopyrrolate.

Upon extubation, the patient will be transferred to the post-anesthesia care unit (PACU). At
this time quality of the regional block will be assessed. Motor strength will be rated as
follows: 2=no voluntary movement, 1=some muscle weakness and 0=no muscle weakness. The
sensory block (cold test) will be evaluated by the following criteria: 2=no sensation,
1=decreased sensation and 0=normal sensation. All blocks rated as 0 for both sensory and
motor testing, will be considered failed blocks and will be excluded from the data collection
for the remainder of the study.

All subjects will receive rescue medication upon request for pain control whether they remain
in the data collection or not. Patients will be treated with intravenous Hydromorphone 0.5mg
for a pain score ≥ 4 out of 10 on the VAS scale for a maximum of 2 divided doses. Vital signs
(heart rate, blood pressure, respiratory rate and pulse oxymetry) will be continuously
monitored in the Post Anesthesia Care Unit (PACU) and recorded as to the standard protocol
that is every 5 minutes for the first 15 minutes, 15 minute intervals for the next hour and
then every 30 minutes until discharge. Pain score and sedation scores will be obtained using
the VAS and Ramsay sedation scale, respectively. All pain scores will be assessed with
patient in the resting position. No patient will be discharged from the PACU with a VAS >than
4 out of 10. If this cannot be achieved with the rescue medication indicated above the
patient will be started on Patient Controlled Analgesia (PCA). PCA orders are as follows
Hydromorphone 0.02mg every 6 minutes, no basal rate, and no four-hour maximum. Neurological
and sensory assessment will be assessed on arrival, at 60 minutes and at 120 minutes. Those
parameters assessed will include numbness of tongue, lips and mouth, metallic taste, problems
with hearing or vision, muscle twitching and does the subject feel cold in the innervated
dermatomes.

Time to discharge readiness from PACU will be documented. After PACU discharge oxycodone
5mg/325mg acetaminophen 1 or 2 tablets every 6 hours will be offered for breakthrough pain.
The doses and timing of all pain medications will be recorded while hospitalized and the
subject's will be provided a diary to record pain and medication taken at home. The research
coordinator will follow-up with the patients on post-operative days for those who have been
discharged to home, in order to ensure that questionnaires and diaries are completed.

On POD 1, POD 2 and POD 3, a pain questionnaire will be completed addressing the quality of
postoperative pain relief, pain scale, and incidence and severity of any side effects,
including palpitations, nausea, vomiting as well as burning, numbness, tingling, and rebound
pain. Peripheral neuropathy sequelae will be assessed subjectively via the questionnaire. The
subject will also be evaluated for amount of pain medication required and any opioid side
effects will be documented. On POD 3 the subject will be asked to provide an overall opinion
of the pain control using a 5-point Likert scale.

Inclusion Criteria:

- ankle fracture open reduction or internal fixation

- American Society of Anesthesiologists rating of I-III

- have a working telephone

Exclusion Criteria:

- non English speaking

- BMI >40

- allergy or contraindication to local anesthetics

- history of drug abuse

- impaired kidney function, rheumatoid arthritis or loss of sensation in extremities

- abnormal liver function

- long term (greater than 10 days) use of NSAIDS

- uncontrolled anxiety, psychiatric or neurological disorder that might interfere with
study assessments