Toxicity of local anaesthetics and

Lipidrescue.
Has the silver bullet been identified?
Bernhard M. Graf
Meanwhile multiple studies and case reports have shown that the incidence of cardiac intoxication by long acting local anaesthetics is a rare but
then catastrophic event. As classic neuronal sodium channel inhibitors, these drugs block peripheral fast voltage-gated sodium channels on neuronal
axons, but also on the CNS and the cardiovascular system. Although seizures
as sign of cerebral overdose of local anaesthetics are an impressive clinical
syndrome, they can normally be managed without permanent damage for
the patient. More important are the cardiac toxic effect of these long acting
drugs, which can be divided into indirectly cerebral and directly myocardial
mediated components. Like CNS-toxicity in general, indirect cardiotoxicity
demonstrates an initially stimulating cerebral effect, followed by a depressive component at higher concentrations. Direct myocardial actions are comprised of negative chronotropic, dromotropic and inotropic side effects.
Since all clinically used local anaesthetics are excellent neural blockers
the driving force for new product development was and is the diminution
of these side effects till this day. Despite approximate identical local anaesthetic potencies of both optically isomers of bupivacaine stereoselectivity was found for dromotropy. Using S-(-)-isomers of the long-acting
local anaesthetics cardiac conduction time was shorter delayed compared to
racemic mixtures or the R-(+)-enantiomers. For inotropy no stereospecific
depression was noted between the isomers of ropivacaine or bupivacaine,
but bupivacaine produced a significantly greater depression of LV pressure
 Dept. of Anaesthesiology and Intensive Medicine, University of Regensburg, FranzJosef-Strauss-Allee 11, D-93053 Regensburg, Germany, e-mail: bernhard.graf@klinik.
uni-regensburg.de
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versus ropivacaine, mepivacaine or lidocaine (1). In addition, pharmacokinetic differences in lipophilicity of these drugs correlate well with depression
of mitochondrial ATP-synthesis in fast metabolizing cells (2). Intracellular
ATP-levels may be involved in contractility and survivability of cardiomyocytes as be proven by different in-vitro and in-vivo data (3). Therefore the
use of pure optically S-(-)-isomers of local anaesthetics may help to reduce
rare but then catastrophic adverse reactions of local anaesthetics.
Another rare and uncommon but long time well-known side effect of
local anaesthetic drugs is next to neurotoxicity skeletal muscle toxicity. Intramuscular injections of these agents result in myonecrosis. The extent of
muscle damage is dose-dependent and worsens with serial or continuous
administrations. All local anaesthetic agents that have been examined yet
are myotoxic, whereby procaine produces the slightest and bupivacaine the
most pronounced muscle injury. Histological pattern and time course of skeletal muscle injury appear rather uniform: hypercontracted myofibrils become evident directly after injection, followed by lytic degeneration of striated
muscle sarcoplasmic reticulum, and by myocyte oedema and necrosis over
the next 12 days. Sub cellular path mechanisms of local anaesthetic myotoxicity are not yet understood in detail. Increased intracellular Ca2+ levels
appear to be the most important element in myocyte injury together with a
reduced ATP-synthesis. Depending on their lipophilicities local anaesthetics
provoke the release of Ca2+ from SR and block coevally the reuptake of
free intracellular Ca2+, which tend to result in intracellular Ca2+ overloading.
Next to lipophilicity dysregulation of intracellular calcium homeostasis is
additionally depending on stereoselectivity, whereby R(+)-isomer appear
to be less toxic than the clinically used less cardiotoxic S(-)-isomers (4). In
particular, the occurrence of clinically relevant myopathy and myonecrosis
have been described after continuous peripheral blockades, infiltration of
wound margins, trigger point injections (5), and peri- and retrobulbar blocks
(6), respectively.
To avoid life-threatening adverse effects especially of long-acting local
anaesthetics, forward-looking application of these potent drugs is the most
important step. Prevention of systemic intoxication is significantly more
effective than treating complications of the intoxication. Rules for application of local anaesthetics are:
using nerve stimulation/ultrasound to reduce necessary doses
be careful!
use of local anesthetics with low toxic profiles
combination of (pharmacological) different local anesthetics
control of recommended maximal doses
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If a systemic adverse reaction happens, it is important to recognize this

and to announce it to a clear emergency. In this case you have to start at
once with a non-specific or symptomatic therapy. In severe cases this will
be advance-life-support. You should have in your mind that long-acting
local anesthetics bind for longer time to the voltage-gated sodium channels
(more than an hour). There are case reports about successful resuscitations
by using a cardiopulmonary bypass. During this time it is very important to
avoid acidosis or to compensate acidosis. During acidosis local anesthetics
are ionized and the electropositive molecules are trapped in the cells (called
ion trapping). So, the aim is actually a gentle alkalosis of the blood.
Recently case reports have been published about the successful treatment
of systemic local anaesthetic intoxications by using lipids (7). The fundament basic study was done by Weinberg et al. more than 10 years ago (8).
This group could show on isolated hearts of rats, that adding lipids cardiac toxic concentration of bupivacaine has been increased significantly.
These finding has been certified using different in-vivo animal studies, and
meanwhile many case reports have shown the beneficial effects of lipids by
intoxications with local anaesthetics, antidepressants, psychoactive drugs
and verapamile (7). In contrast some animal studies could not confirm these
results, so that more studies are necessary to investigate the mechanism
of lipids (9,10). In our studies on isolated rat hearts the lipids showed only
a lipid sinks effect for very lipophilic local anaesthetics like bupivacaine,
but we couldn`t demonstrate a positive effect for less lipophilic local anaesthetics like mepivacaine, prilocaine and lidocaine (11). Our findings are in
accord with studies in chemistry by Laine J, et al. (12) showing that already
at a concentration of 1 mg/ml Intralipid the level of free bupivacaine had
decreased by 88%. They could also show that the interaction of Intralipid
with bupivacaine was considerably stronger than with the less lipophilic
prilocaine and lidocaine, suggesting a lipid sinks effect. For this reason
lipidrescue is an important step for a safer regional anaesthesia especially
for using high lipophilic anaesthetics like bupivacaine or levobupivacaine.
By intoxication with lipophilic local anaesthetics we recommend unspecific
advance life support the injection of intralipid 20% (1 ml/kg BW as a bolus
and then 0,5 ml/kg BW/min for 30 minutes)(13). But lipidrescue is still not
the silver bullet, since prevention is better than cure. Lipidrescue therefore
is not first choice, it is mostly ultimo ratio.

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References:

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1. Graf BM, Abraham I, Eberbach N, Kunst G, Stowe DF, Martin E. Differences in cardiotoxicity of bupivacaine and ropivacaine are the result of physicochemical and stereoselective properties. Anesthesiology 2002; 96(6):1427-34.
2. Sztark F, Ouhabi R, Dabadie P, Mazat J. Effects of the local anesthetic bupivacaine on mitochondrial
energy metabolism: Change from uncoupling to decoupling depending on the respiration state. Biochem Mol Biol Int 1997; 43:9971003.
3. Groban L, Deal D, Vernon J, James R, Buterworth J. Ventricular arrhythmias with or without programmed electrical stimulation after incremental overdosage with lidocaine, bupivacaine, levobupivacaine, and ropivacaine. Anesth Analg 2000; 91:110311.
4. Zink W, Seif C, Bohl JRE, et al. The acute myotoxic effects of bupivacaine and ropivacaine after continuous peripheral nerve blockades. Anesth Analg 2003;97:11739.
5. Hogan Q, Dotson R, Erickson S, et al. Local anesthetic myotoxicity: a case and review. Anesthesiology
1994;80:9427.
6. Gomez-Arnau JI, Yanguela J, Gonzalez A, et al. Anaesthesiarelated diplopia after cataract surgery. Br J
Anaesth 2003;90: 18993.
7. www.lipidrescue.com
8. Weinberg GL, VadeBoncouer T, Ramaraju GA, Garcia-Amaro MF, Cwik MJ: Pretreatment or resuscitation
with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Anesthesiology
1998; 88:1071-5.
9. Mayr VD, et al. A comparison of the combination of epinephrine and vasopressin with lipid emulsion
in a porcine model of asphyxial cardiac arrest after intravenous injection of bupivacaine. Anesth Analg
2008; 106:1566-71.
10. Hicks SD, et al. Lipid emulsion combined with epinephrine and vasopressin does not improve survival in
a swine model of bupivacaine-induced cardiac arrest. Anesthesiology 2009; 111:138.
11. Zausig Y, et al. Lipid Emulsion Improves Recovery from Bupivacaine-Induced Cardiac Arrest, but Not
from Ropivacaine- or Mepivacaine-Induced Cardiac Arrest. Anesth Analg 2009;109:1323.
12. Jaana Laine, et al. Interaction of a commercial lipid dispersion and local anesthetics in human plasma:
implications for drug trapping by lipid-sinks. Anal Bioanal Chem 2010; 396:2599.
13. Guideline of the German Society of Anaesthesiology and Intensive Care (DGAI) - Intoxication with
long-acting local Anaesthetics 2009.

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