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CHAPTER 26 Local Anesthetics 469

Lipid Resuscitation

Based on a case of apparent cardiotoxicity from a very low The mechanism by which lipid is effective is incompletely
dose of bupivacaine in a patient with carnitine deficiency, G. L. understood, but almost certainly some of its effect is related to
Weinberg postulated that this metabolic derangement led to its ability to extract a lipophilic drug from aqueous plasma, thus
enhanced toxicity due to the accumulation of fatty acids within reducing its effective concentration at tissue targets, a mecha-
the cardiac myocyte. He hypothesized that administration of nism termed “lipid sink.” However, the extent of this extraction
lipid would similarly potentiate bupivacaine cardiotoxicity, but does not appear adequate to account for the magnitude of clini-
experiments performed to test this hypothesis demonstrated cal effect, suggesting that other mechanisms at least contribute
exactly the opposite effect. Accordingly, he began systematic to the efficacy of lipid rescue. For example, bupivacaine has been
laboratory investigations, which clearly demonstrated the poten- shown to inhibit fatty acid transport at the inner mitochondrial
tial efficacy of an intravenous lipid emulsion (ILE) for resuscita- membrane, and lipid might act by overcoming this inhibition
tion from bupivacaine cardiotoxicity. Clinical confirmation came serving to restore energy to the myocardium or derive benefit
8 years later with the report of the successful resuscitation of a via elevation of intramyocyte calcium concentration. Although
patient who sustained an anesthetic-induced (bupivacaine plus numerous questions remain, the evolving evidence is sufficient
mepivacaine) cardiac arrest refractory to standard advanced to warrant administration of lipid in cases of systemic anesthetic
cardiac life support procedures (ACLS). Numerous similar reports toxicity. Its use has been promulgated by a task force of the
of successful resuscitations soon followed, extending this clinical American Society of Regional Anesthesia (http://www.asra.com/
experience to other anesthetics including levobupivacaine and checklist-for-local-anesthetic-toxicity-treatment-1-18-12.pdf),
ropivacaine, anesthetic-induced CNS toxicity, as well as toxicity and administration of lipid has been incorporated into the most
induced by other classes of compounds, eg, bupropion-induced recent revision of ACLS guidelines for Cardiac Arrest in Special
cardiovascular collapse and multiform ventricular tachycardia Situations. Importantly, propofol cannot be administered for
provoked by haloperidol. Laboratory investigations have like- this purpose, as the relatively enormous volume of this solu-
wise provided evidence of efficacy for treatment of diverse toxic tion required for lipid therapy would deliver lethal quantities of
challenges (eg, verapamil, clomipramine, and propranolol). propofol.

The mechanism of local anesthetic neurotoxicity has been remain to be established, but differences between factors affecting
extensively investigated in cell culture, isolated axons, and in TNS and experimental animal toxicity argue strongly against a
vivo models. These studies have demonstrated myriad deleterious common mechanism mediating these symptoms and persistent or
effects including conduction failure, membrane damage, enzyme permanent neurologic deficits. Nonetheless, the high incidence of
leakage, cytoskeletal disruption, accumulation of intracellular cal- TNS has greatly contributed to dissatisfaction with lidocaine as a
cium, disruption of axonal transport, growth cone collapse, and spinal anesthetic, leading to its near abandonment for this tech-
apoptosis. It is not clear what role these factors or others play in nique (although it remains a popular and appropriate anesthetic
clinical injury. It is clear, however, that injury does not result from for all other applications, including epidural anesthesia). Chloro-
blockade of the voltage-gated sodium channel per se, and thus procaine, once considered a more toxic anesthetic, is now being
clinical effect and toxicity are not tightly linked. explored for short-duration spinal anesthesia as an alternative to
lidocaine, a compound that has been used for well over 50 million
2. Transient neurologic symptoms (TNS)—In addition to spinal anesthetic procedures.
the very rare but devastating neural complications that can occur
with neuraxial (spinal and epidural) administration of local
anesthetics, a syndrome of transient pain or dysesthesia, or both, ■ COMMONLY USED LOCAL
has been recently linked to use of lidocaine for spinal anesthesia. ANESTHETICS & THEIR
Although these symptoms are not associated with sensory loss,
motor weakness, or bowel and bladder dysfunction, the pain APPLICATIONS
can be quite severe, often exceeding that induced by the surgical
procedure. TNS occurs even at modest doses of anesthetic and ARTICAINE
has been documented in as many as one third of patients receiv-
ing lidocaine, with increased risk associated with certain patient Approved for use in the USA as a dental anesthetic in April 2000,
positions during surgery (eg, lithotomy) and with ambulatory articaine is unique among the amino-amide anesthetics in having a
anesthesia. Risk with other anesthetics varies considerably. For thiophene, rather than a benzene ring, as well as an additional ester
example, the incidence is only slightly reduced with procaine or group that is subject to metabolism by plasma esterases (Table 26–1).
mepivacaine but appears to be negligible with bupivacaine, prilo- The modification of the ring serves to enhance lipophilicity, and
caine, and chloroprocaine. The etiology and significance of TNS thus improve tissue penetration, while inclusion of the ester leads