Liposomal Bupivacaine in Simultaneous Bilateral Total Knee Arthroplasty

Total knee arthroplasty (TKA) is a commonly performed and successful surgical procedure that
has been shown to dramatically decrease pain and improve patient's function and quality of
life. Certain patients may present with significant pain and limitations due to pain in both
knees and based on age, health and degree of deformity may be candidates for bilateral
simultaneous total knee arthroplasty. The safety and efficacy of simultaneous bilateral
total knee arthroplasty has been well documented in the literature.

Inadequate postoperative pain control following TKA has been one of the greatest sources of
patient dissatisfaction following total knee arthroplasty. Traditionally, it has been
managed with parenteral and oral narcotics. Recently, a number of studies have demonstrated
the efficacy of multimodal analgesia following a variety of surgical procedures. These
multimodal regimens vary and consist of any number of medications including non-steroidal
anti-inflammatories, anti-epileptics, and peripheral nerve blocks among others. These
multimodal regimens have been associated with a reduction in the use of opioid analgesics,
leading to fewer opioid-associated adverse events.

One of the newest modalities introduced on the market is liposomal bupivacaine (Exparel).
Liposomal bupivacaine is a lipid encapsulated bupivacaine that allows for depo
administration of the medication into the soft tissue during a surgical procedure. The
lipids are engineered to slowly release over an approximately 72 hour time period, resulting
in the slow release of free bupivacaine in to the soft tissue of the surgical site. This has
the proposed advantage of a longer duration of analgesia compared to standard bupivacaine
injections.

Liposomal bupivacaine is applied in a periarticular injection at the conclusion of TKAs to
aid in post-operative pain control. Due to the lipid encapsulation of the bupivacaine, only
3% free bupivacaine is released into the tissue at initial infiltration, with the remainder
released slowly over approximately a 72 hour time frame. To cover, this gap period, the
liposomal bupivacaine is mixed with standard bupivacaine to allow for an immediate analgesic
effect.

A potential risk, although low, is the concern for bupivacaine toxicity. Toxicity from
bupivacaine is associated with central nervous system issues (seizures) and cardiac
toxicity. Toxicity is dose dependent and recommended levels should not exceed 400mg/24 hr
period. With the use of bupivacaine into each surgical site, there is a theoretical risk, if
administered intra-vascularly, of bupivacaine toxicity. To date, no study has evaluated the
safety of liposomal bupivacaine when used in simultaneous bilateral total knee arthroplasty.
The use of liposomal bupivacaine is FDA approved for infiltration of one vial into one
surgical site. Other specialties have evaluated the use of one vial of liposomal bupivacaine
into two surgical sites (breast augmentation) at one surgery without any adverse events.

To date, approximately 8-10 patients at the investigator's institution have undergone
simultaneous bilateral total knee arthroplasty with the use of liposomal bupivacaine without
a known adverse event. A recent study published by Bramlett (2012) used 2 vials (532mg) in
one knee to evaluate efficacy. There were no changes in patient's vitals signs or cardiac
events in those patients receiving liposomal bupivacaine at the highest dose. In addition, a
study by Bergese looked at doses of up to 600mg of liposomal bupivacaine in a Phase 2 safety
study and found no adverse cardiac events. The purpose of this study is to evaluate the
serum levels (pharmacokinetics) of bupivacaine in a series of patients undergoing
simultaneous bilateral total knee arthroplasty with the use of a standardize periarticular
injection containing free bupivacaine and liposomal bupivacaine.

Inclusion Criteria:

- Patients deemed appropriate candidates for simultaneous bilateral total knee
arthroplasty.

- Patients receiving general anesthesia

- Understands the local language and is willing and able to follow the requirements of
the protocol

- Understands the informed consent and signs the institutional review board/
independent ethics committee (IRB/IEC) approved informed consent form

Exclusion Criteria:

- Patients less than 18 years of age

- Allergy to bupivacaine

- Allergy to epinephrine

- Patients who are not medically cleared to undergo bilateral total knee replacement
surgery, or

- Patient-reported liver impairment (per investigator discretion)

- Patient-reported renal impairment (per investigator discretion)

- Patients receiving spinal anesthesia

- Females who are pregnant or lactating