Pharmacokinetic Profile of Ropivacaïne after Periarticular Local Infiltration Analgesia for Primary Total Knee Arthroplasty

Knee osteoarthritis is a leading cause of disability in our ageing society.
Total knee arthroplasty (TKA) has been shown to be an effective treatment in
reducing pain and improving function and quality of life in individuals
suffering from severe knee osteoarthritis. For an optimal and fast recovery
after TKA, a fast track rehabilitation protocol has been developed. Fast track
surgery results in quicker functional recovery, reduced morbidity, decreased
length of convalescence, increased satisfaction and * as a secondary gain *
reduced hospital costs.
Finding the most appropriate analgesic technique for fast track TKA is
challenging: the patient needs to be pain free to mobilize for physical
therapy, while side effects of the pain treatment like drowsiness (opioids) and
impaired motor function (femoral nerve block) impede the fast track protocol.
Therefore, a technique for the control of pain following knee and hip surgery,
to allow virtually immediate mobilization and earlier discharge from the
hospital called *local infiltration analgesia* (LIA) has been developed.
For the LIA a relatively high dose long acting local anesthestic, ropivacaine,
is injected in the soft tissue surrounding the knee and the subcutis around the
incision. Ropivacaine is slowly absorbed into the circulation from the
injection site. Epinephrine is added to the ropivacaïne injected in the soft
tissue to decrease absorption speed and lower peak plasma concentrations by
inducing vasoconstriction.
A potential hazard of the LIA technique is the relatively high dose of local
anesthetic used, increasing the risk of LAST (local anesthestic systemic
toxicity). Usually a dose of 400 mg ropivacaïne is used for LIA, which is in
most cases above the recommended maximum dose of 3-4 mg/kg. Nevertheless, in
the past few years thousands of patients have been undergoing LIA for knee
surgery with high doses of ropivacaïne, and only one case of LAST after LIA has
been described.
In the plasma, approximately 95% of the ropivacaïne is bound to *1-glycoprotein
[ref]. approximately 5% of the total plasma concentration of ropivacaïne is the
free, unionized form. The unbound ropivacaïne interacts with receptors inducing
its pharmacological properties. When the free, unbound ropivacaïne
concentration exceeds the toxic threshold in the central nervous system (CNS)
or heart, symptoms of toxicity (LAST) occur. Typical CNS toxicity symptoms are
perioral numbness, tinnitus and visual disturbances. More severe LAST symptoms
of CNS toxicity are convulsions, coma and respiratory arrest. In ropivacaine
induced LAST, cardiac toxicity symptoms may be mild or even absent, but when
present they range from rhythm disturbances to circulatory arrest due to
cardiac arrest.
Although LIA with ropivacaine is frequently applied, little is known about the
pharmacokinetic profile of ropivacaïne applied for LIA of the knee. Knowledge
of the pharmacokinetic parameters will give more insight in the onset (Tmax),
duration (halve live) and extent (Cmax) of ropivacaine concentrations.
Knowledge of the Tmax (time when highest plasma concentration is reached) can
provide more insight to the time frame in which the patient is at risk of LAST
and should be monitored. Cmax of ropivacaïne for LIA gives insight in the range
to toxic concentrations. Knudsen et al. administered ropivacaïne intravenously
in healthy volunteers and found that symptoms of toxicity occurred at arterial
plasma concentrations of 4.3 mg/L for total and 0.56 mg/L for unbound
ropivacaïne concentrations. It is unclear whether this *toxic concentration* of
ropivacaïne can also be applied to a situation where ropivacaïne is injected in
soft tissue (LIA) instead of injected intravenously. Serum concentrations of
ropivacaïne rise much slower in LIA, than when injected intravenously as did
Knudsen et al., because of the slow drug uptake from the tissue site into the
blood stream. Even so, the study of Knudsen et al. is the only study
investigating toxic concentrations of ropivacaïne in humans and therefore, it
is generally accepted that serum concentrations of ropivacaïne should remain
below 4.3 mg/L for total and 0.56 mg/L for unbound ropivacaïne.

The primary objective of this study is to describe a pharmacokinetic profile of
bound and unbound plasma concentrations of ropivacaïne, when used in the LIA
technique for the knee. Especially describing the Cmax and Tmax gives arguments
for dosage of ropivacaïne when used for LIA and for monitoring time of patients
after surgery in everyday medical practice.

Cohort study

In this study, patients will receive standard anesthesia according to the
hospital protocol. Blood samples will be drawn from an indwelling peripheral
intravenous catheter (PIVC), placed on the contralateral side of the PIVC that
is used for routine monitoring. If the catheter fails, another will be placed,
or the remaining sample(s) can be drawn by venipuncture if the PIVC is not
necessary for the patient*s medical care (if the patient receives no
intravenous antiemetics or intravenous pain medicine, the PIVC will be
discontinued by hospital protocol the day after surgery).
Per patient 45 mL of blood will be drawn in total, i.e. 9 times 3-5 mL. The
patient will not experience any consequences from this minimal blood loss. For
comparison: total blood volume of an average adult person is 5L and for
voluntary blood donation 0.5L is drawn. The much smaller amount of blood drawn
for this study won*t induce health concerns.
Because of the sampling schedule, which does not include sampling between t=6
hours and t=24 hours, no blood will be drawn during night hours, guaranteeing
no nightly disturbances for the patient for study purposes.
By participation in this study the patient is subjected to a small risk of
hematoma at the puncture site and a very small risk of infection at the
puncture site.