Pharmacokinetics of high dose Ropivacaine with and without epinephrine for combined femoral and sciatic nerve block in lower extremity surgery. A pilot study.

Ropivacaine is a widely used long-acting amide local anesthetic. It was
introduced into the market as a safer alternative to bupivacaine after reports
of cardiac arrest with prolonged resuscitation after accidental intravascular
injection of bupivacaine (1,2). Ropivacaine is structurally closely related to
bupivacaine; however, unlike bupivacaine which is a racemate, ropivacaine is a
pure S(-)-enantiomer of n-propivacaine (3). The S-enantiomer was chosen
because it has a lower toxicity than the R-enantiomer (4).
Animal and volunteer studies indicate that ropivacaine is safer than
bupivacaine in terms of its neurologic and cardiac toxicity profile (5). It has
a higher convulsive threshold in different animal models, fewer CNS symptoms
after intravenous administration in human volunteers, and fewer excitatory
changes in the EEG than bupivacaine (2). In addition, ropivacaine has a lower
cardiac toxicity as compared to both racemic and levobupivacaine (6-19).

Like other local anesthetics, ropivacaine elicits nerve block via reversible
inhibition of sodium ion influx in nerve fibers. This action is potentiated by
dose-dependent inhibition of potassium channels. Ropivacaine is less lipophilic
than bupivacaine (3). Lipid solubility appears to be the primary determinant of
intrinsic anesthetic potency (2).
Ropivacaine is extensively (94%) bound to plasma proteins, mainly α1-acid
glycoprotein (AAG). Systemic toxicity is considered to be related to the
unbound drug concentration (3). A threshold for CNS toxicity in healthy adult
subjects is apparent at unbound ropivacaine plasma concentrations of 0.56
(0.34-0.85) mg/L (20). During prolonged postoperative epidural infusion of
ropivacaine, unbound plasma drug concentrations plateaued or gradually declined
despite a progressive increase in total concentrations (21-24). The total
plasma concentration increase during continuous epidural infusion of
ropivacaine is caused by an increase in the degree of protein binding and
subsequent decrease in clearance of ropivacaine (3). Surgery stimulates the
synthesis of AAG in the liver and, therefore, the local anesthetic binding
capacity is enhanced and the risk of toxicity reduced post-operatively (25).
Total ropivacaine plasma levels have a putative safe level for systemic
toxicity of 2-4.5 mg/L (5).

Peripheral nerve block (PNB) as an anesthetic technique is rapidly gaining
popularity among anesthesiologists and patients. Compared to general anesthesia
or central neuraxis blockade, interference of PNB with vital functions is
minimal and postoperative analgesia is excellent.
In the Sint Maartenskliniek in Nijmegen, The Netherlands, the combined femoral
and sciatic nerve block is commonly used for lower extremity orthopedic
surgery. Obtaining adequate anesthesia and long lasting analgesia requires the
use of large volumes of ropivacaine in high concentration. As a consequence,
doses up to 60 mL of ropivacaine 0,75% (450 mg) are no exception. A potential
problem with high doses of local anesthetics is that they exceed the
recommendations for maximum doses that are, in large part, not (yet) evidence
based and published by the manufacturer as a necessary step in the registration
process (25). As a consequence, these recommended maximum doses (200-300 mg)
are conservative and, especially in case of PNB, widely disregarded in
clinical practice.
In the Sint Maartenskliniek, the vast majority of surgery is performed under
regional anesthesia. In the past years, the safety of high doses ropivacaine in
combined sciatic femoral nerve block has been established in more than 10,000
patients, with symptoms of systemic toxicity being both rare and mild.
Differences in absorption of local anesthetic from different injection sites
support block-specific and site-specific dose recommendations (26). I.e., in
the absence of evidence-based recommended maximum doses, there is a need to
support the clinically experienced safety of high doses of local anesthetics
with pharmacokinetic data.

It is not clear whether the addition of epinephrine 5 µg/mL (1:200.000) offers
pharmacokinetic advantages over ropivacaine alone. The primary action of
epinephrine is probably local vasoconstriction that reduces systemic absorption
from the site of injection and by a direct agonist effect on spinal α2
receptors. This reduces the risk of local anesthetic toxicity when large doses
are given. Because ropivacaine has intrinsic vasoconstrictor properties in
concentrations <1%, the addition of epinephrine has been considered unnecessary
by some (27).
The literature is mixed about the advantages of adding epinephrine. Some
studies found an advantage compared to ropivacaine alone (2,27,28), whereas
others did not (29-31).

To confirm safety of using high doses of ropivacaine, large scale investigation
of mean peak plasma concentration (Cmax) and mean time to peak plasma
concentration (Tmax) is necessary. Thereafter we can determine block specific
maximum doses of ropivacaine with or without epinephrine. To investigate Cmax
and Tmax, we first need a complete pharmacokinetic profile of ropivacaine.

(For references, we refer to the study protocol)

The purpose of the present study is to obtain a pharmacokinetic profile of
ropivacaine in serum with epinephrine, and of ropivacaine in serum without
epinephrine, used for high dosed combined femoral and sciatic nerve block in
lower extremity orthopedic surgery. Results of this pilot study will be used in
a follow-up study to determine block specific maximum doses using the
determined width of Cmax¬ found in this study.

The design of this pilot study is parallel, prospective, double blind and
explorative. Twelve patients scheduled for combined femoral and sciatic nerve
block in lower extremity orthopedic surgery will be studied. The study will be
conducted at the Sint Maartenskliniek Nijmegen, The Netherlands according to
the Declaration of Helsinki and later revisions thereof and in accordance with
the ICH guidelines for Good Clinical Practice. No patients will be recruited
before written approval has been obtained from the local Medical Ethics Review
Committee as well as from the board of Directors of the Sint Maartenskliniek
Nijmegen.

We are aware of the burden of taking bloodsamples during the night. By
determining the range and duration of Cmax in a pilot study, we can limit the
inconvenience for future patients in a larger follow up study designed to
establish block specific recommendations considering maximum dosage of
ropivacaine.