REVIEW

URRENT
C
OPINION

Local anesthetic in-situ toxicity during peripheral

nerve blocks: update on mechanisms
and prevention
Karine Nouette-Gaulain a,b, Xavier Capdevila c,d, and Rodrigue Rossignol a

Purpose of review
Peripheral nerve blocks induce undesired side-effects linked to the toxicity of local anesthetics on neuron
and myocytes via different cell targets. The effects of local anesthetics on these targets are now well known
and summarized in this review.
Recent findings
Local anesthetic-induced local cell toxicity involved different pathways leading to cell death, necrosis and
different factors closely associated with the clinical practice modulated this toxicity. High concentration and
prolonged duration of local anesthetic administration are closely associated with severe lesions.
Summary
Phenotypic analyses revealed that local anesthetics could induce histological damage with lesions ranging
from local to extreme in skeletal muscle. Metabolic alterations were also described involving sarcoplasmic
reticulum and calcium dysregulation, alteration of mitochondrial physiology and of oxidative
phosphorylation with associated overproduction of harmful reactive oxygen species, typically leading to
apoptosis or necrosis.
Biochemical and cell biology investigations now indicate that local anesthetics interact with different
molecular targets in mammalian cells as respiratory chain complex I or the prosurvival kinase Akt.
Functional dysfunction in both muscle and neuron remains to be investigated with caution in patients, as
local anesthetic toxicity remains under-evaluated. Likewise, the use of adapted local anesthetics in patients
with particular diseases and neuromuscular disorder could further reduce the risk of undesired effect.
We need to improve our practice, and the optimization of our clinical protocol could prevent from these
side-effects. Lastly, experimental studies highlight the preventive effects of antioxidant drugs or of
recombinant human erythropoietin but the pharmacokinetic feature of such strategies remain to be
evaluated.
Keywords
apoptosis, local anesthetic, local toxicity, muscle, neuron

INTRODUCTION
During peripheral nerve blocks, local anesthetic
spreads into contact with the nerve, inhibits voltage-gated sodium channels, and prevents the propagation of action potentials within the nervous
system. Peripheral nerve blocks performed with local anesthetics improve postoperative analgesia and
rehabilitation in patients. However, local anesthetics can induce in-situ toxicity mediated by their
pleiotropic effects on cell metabolism and tissue
ultrastructure in the neighborhood of neurons
and muscle. In this review article we summarized
first the reported iatrogenic events published in
different clinical case reports and we discuss the
underlying mechanisms of this toxicity from the

analysis of different cell biology and biochemical

studies. We conclude with a discussion on suggested
preventive approaches of local anesthetic toxicity.
a

University Bordeaux, Maladies Rares, Genetique et Metabolique

(MRGM), bCHU de Bordeaux, Service dAnesthesie Reanimation 3,
Pole dAnesthesie Reanimation, Bordeaux, cCHU de Montpellier, Service
dAnesthesie Reanimation A and dInserm U1046, Bat Crastes de Paulet,
Montpellier, France
Correspondence to Karine Nouette-Gaulain, Hopital des Enfants,
Service dAnesthesie Reanimation 3, Centre Hospitalier Universitaire
de Bordeaux, Place Amelie Raba Leon, 33076 Bordeaux, France. Tel:
+33 5 56 79 56 10; fax: +33 5 56 79 56 61 96; e-mail: karine.nouettegaulain@chu-bordeaux.fr
Curr Opin Anesthesiol 2012, 25:589595
DOI:10.1097/ACO.0b013e328357b9e2

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Regional anesthesia

KEY POINTS

Local anesthetics induce a large spectrum of muscle
and neuron ultrastructure abnormalities.

Local anesthetics induce an intracellular Ca2
mobilization and can change Ca2 homeostasis
through the Ca2-influx pathway in both myocytes
and neurons.

Local anesthetics induce a reduction of the
muscle mitochondrial content and the kinetic
inhibition of oxidative phosphorylation
associated with an overproduction of reactive
oxygen species.

Local anesthetic-induced toxicity is time and
concentration-dependent. Low concentration of local
anesthetics induces neuronal apoptosis and high
concentration of local anesthetics leads to necrotic
cell death.

Toxicity prevention is based in clinical practice
on the determination of the minimum low
anesthetic concentration for different peripheral
blocks, the duration of the protocol, and the
target site in which the injection of local anesthetic
should occur.

LOCAL ANESTHETIC-INDUCED
CYTOTOXICITY IN CLINICAL PRACTICE
Direct cytotoxicity of the local anesthetics was
described in both muscle and neuron. Local anesthetic-induced myotoxicity is well known after
cataract surgery and other intraocular procedures.
Bupivacaine induced persistent diplopia through
direct damage to the extraocular muscles, from
retrobulbar or peribulbar anesthesia [1,2]. Likewise,
repeated bupivacaine injections (1.14 g of bupivacaine during 34-h period) through an interscalene
catheter after surgery for capsular release of left
shoulder induced persistent pain over the 3 postoperative months [3]. The muscle biopsy performed
on the 54th day revealed the coexistence of degenerating and regenerating muscle fibers with structural evidences of myophagy [3].
Apart from the muscle, local anesthetic-induced
peripheral nerve injury is also rare (from 4 : 1000 to
3 : 100 of transient neurological deficit in interscalene block [46]) and can even be observed in
patients after 6 months [7].

Alteration of myocyte ultrastructure and of

mitochondrial architecture
Various local anesthetics were used in experimental
studies to investigate the mechanisms of necrosis
and subsequent muscle regeneration [8,9]. High
concentration of bupivacaine (16 mg/kg) injected
directly in rat muscle induced myonecrosis, with
disjointed fibers, interstitial edema, and infiltrating
cells [9]. Likewise, an initial bolus (35 mg/kg bupivacaine or ropivacaine) followed by a continuous
infusion (0.61 ml/kg during 6 h) of local anesthetic
causes a widespread interstitial and myoseptal
edema, followed by disruption and condensation
of the myofilament, lytic degeneration of the sarcoplasmic reticulum and of mitochondria, and
pycnotic changes of the nuclei in pig [10]. Likewise,
rats treated with 2.5 mg/kg bupivacaine presented
a wide spectrum of muscle and mitochondrial
abnormalities [11,12].

Alteration of neuron ultrastructure

Incubation of the axonal compartment with 40 mM
lidocaine for 24 h induced axonal degeneration with
retraction of distal neuritis and fragmentation
of neuritis [13]. Moreover, lidocaine, ropivacaine,
and bupivacaine reduced the number of neurons
[14]. In SH-SY5Y cells, 20 min treatment with 10 mM
lidocaine induced retraction of the cell extension
[15]. Continuous infusions of 0.50.75% bupivacaine for 72 h in the vicinity of the sciatic nerves
of rats induced severe wallerian degeneration, with
varying degrees of disruption of the normal myelin
architecture, formation of myelin globules and
vacuolization, and focal loss of myelin staining
[16 ]. Lastly, infusion of 600 mM lidocaine just
outside of the perineurium was associated with
swollen axons, macrophage phagocytosis of degenerated tissue, and epineurial and endoneurial collagen [17].
&&

IMPACT OF LOCAL ANESTHETICS ON

ENERGY METABOLISM
Local anesthetic-induced in-situ toxicity is mediated by sarcoplasmic reticulum and mitochondria,
closely linked, both structurally and functionally
[18]. Numerous effects coexist and lead the neuron
and the myocyte to apoptosis (Fig. 1).

CELL ULTRASTRUCTURAL DAMAGES

INDUCED BY LOCAL ANESTHETICS

Mobilization of intracellular calcium by local

anesthetics

Microscopic analysis of myocyte and nerve showed

that local anesthetics damaged cell ultrastructure
and induced local inflammatory reaction.

Local anesthetics interact with calcium homeostasis

through their effects on Ca2 entry and on intracellular Ca2 mobilization. In skinned muscle fiber

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Local anesthetic in-situ toxicity Nouette-Gaulain et al.

Akt, ERK

Caspase 9

Fragmentation
DNA
Transcription

Ca2+

p38 MAPK

Reactive oygen
species

ER/RS
stress

CHOP

Cytochrome c

Apoptosis

Caspase 3/7

Cell survival

OXPHOS uncoupling
Mt network fragmentation
Mitophagy
ATP synthesis
ETC activity

Nucleus
Bcl2

Necrosis

FIGURE 1. Local anesthetics interact with many targets leading mammalian cell to death by necrosis or apoptosis via different
pathways. White arrows represent the inhibitor or the activator effects of LA on the target. Ca2, calcium; CHOP, C/EBP
homologous protein; ETC, electron transport chain; LA, local anesthetic; Mt, mitochondrial.

preparations, bupivacaine (515 mM) induced Ca2

release from the sarcoplasmic reticulum by acting
on the Ca2 release channel-ryanodine receptors
(RyR), and inhibits Ca2 reuptake into the sarcoplasmic reticulum, which is mainly regulated by
sarcoplasmic reticulum Ca2 ATPase activity
[19,20]. Bupivacaine might inhibit these receptors
by direct binding, but this has never been demonstrated. Moreover, the production of reactive
oxygen species (ROS) induced by 1.5 mM bupivacaine could modify oxidizable residues (cysteine,
tyrosine) of sarcoplasmic reticulum-associated
calcium channels, such as RyR (S-nitrosylation)
and SR/ER Ca2 ATPases (by tyrosine nitration),
causing their dysfunction and sarcoplasmic reticulum calcium depletion [21,22]. After seven injections of levobupivacaine via a femoral nerve
catheter, this regional analgesia regimen induced
a significant increase in the frequency of Ca2 sparks
(caused by release of increment of Ca2 via sarcoplasmic reticulum) associated with a decrease in
sarcoplasmic reticulum Ca2 content [23].
On rat-isolated dorsal root ganglion, lidocaine
induced intracellular Ca2 mobilization with an
increase in intracellular [Ca2] concentration and
increased [Ca2] influx through both plasma membrane and intracellular store membrane [24].

Moreover, lidocaine (>0.5%) and bupivacaine

(>0.125%) caused an initial, short-lived, moderate
increase in [Ca2]cytosolic [25]. After 60 min exposure
period, high concentrations of lidocaine (2.5%) or
bupivacaine (5%) caused a significant sustained
increase in [Ca2]cytosolic associated with cell death
in neurons. The accumulation of Ca2 inside the cell
could explain the lidocaine-induced inhibition of
axonal transport and the decrease in the number
of particles in both anterograde and retrograde
directions [26].

Inhibition of mitochondrial energy

metabolism by local anesthetics
Muscular and nervous tissues are particularly rich in
mitochondria and strongly rely on aerobic ATP
production. Inhibition of mitochondrial energy
production involves different mechanisms combining the direct interaction between local anesthetics
and the respiratory chain localized in the inner
mitochondria membrane, and the effects induced
by a prolonged exposure over at least 24 h.
Local anesthetic-induced myotoxicity is now
well established [2729]. Repeated injections of
0.25% bupivacaine (1 ml/kg via femoral nerve
catheter) exhibited changes in mitochondrial

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structure with a significant inhibition of ATP production (around 3050%) in the psoas muscle
surrounding the catheter. This was explained by
a reduction of the muscle mitochondrial content [30], and the kinetic inhibition of oxidative phosphorylation [11,23]. Bupivacaine-induced
inhibition on mitochondrial energy metabolism
includes various mechanisms: the specific inhibition of mitochondrial respiratory chain complex
I, oxidative phosphorylation uncoupling, the
specific inhibition of the mitochondrial F1-F0 ATP
synthase, the decrease of mitochondrial membrane
electric potential, the fragmentation of the mitochondrial network, the possible onset of mitoptosis,
and the reduction of the respiratory chain protein
content, which can be observed for long-lasting
exposure to bupivacaine. Likewise, in the ND7 cell
line derived from rat dorsal root ganglion, the complete loss of mitochondrial membrane potential
occurred within 5 min after exposure to 19 mM
lidocaine and a release of mitochondrial cytochrome c to cytoplasm was observed within 2 h [31].
In a global approach, chronic effects of bupivacaine iterative injections via sciatic nerve catheter in
rats were quantified using P31 NMR [32 ]. In the
presence of bupivacaine, the lack of difference in
elasticities of muscle energetics during contraction
obtained in treated rats in comparison with healthy
control rats clearly showed the absence of global
dysfunction in the control of muscle contraction by
energy production. Yet, this work was performed on
healthy animals and should be repeated on diseased
animals. In particular, the functional consequences
of local anesthetic toxicity could be evaluated in
muscle fibers and neurons of individuals or animal
models suffering from metabolism dysfunction
as diabetes, pure mitochondrial disease, or even
cancer.
An important feature of local anestheticinduced cytotoxicity is oxidative stress (elevated
levels of ROS) [33]. After an 8-h bupivacaine
exposure, ROS production in bupivacaine-treated
myotubes was described in a dose-dependent manner [34]. Likewise, in the human neuroblastoma cell
line SH-SY5Y, the intracellular ROS level peaked at
3 h after 1 mM bupivacaine treatment [35 ]. ROS
production can be amplified by the activation of
AMP-activated protein kinase pathway (AMPK) [36]
upon energy crisis as well as by P66shc [37].
&

&

Local anesthetic-decreased cell viability in

neuron and in myocyte
All local anesthetics but not tetrodotoxin can
induce a decrease in cell viability in myotubes
and in neuron from many minutes to a few hours
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of local anesthetic exposure [12,15]. This effect

was explained by two mechanisms: apoptosis and
necrosis. At low concentrations, all local anesthetics
induce apoptosis [31,38]. On the contrary, at high
concentration, necrotic cell death predominated
[31,38,39].
Local anesthetic-induced apoptosis includes the
activation of caspases, p38 MAPK phosphorylation,
Akt inhibition, and sarcoplasmic reticulum/endoplasmic reticulum stress. Apoptosis is controlled by
caspases and 1 mM bupivacaine treatment-caused
caspase 3/7 activation in SH-SY5Y. Local anesthetic
toxicity was also associated with cytochrome c
release in ND7 cell line [31,39], caspase 9 activation
in human Jurkat cells and myotubes [34,39], poly
(ADP-ribose)polymerase (PARP) down-regulation
(involved in DNA repair and genome surveillance)
in Schwann cell line and myotubes [34,40], and
DNA fragmentation [41]. As expected, the lack of
caspase 9, as well as overexpression of Bcl-2 protein
(antiapoptotic protein), prevents caspase 3 activation [39]. These findings highlight the role of
mitochondrial pathway in local anesthetic-induced
apoptosis.
Recent studies indicate that the p38 MAPK pathway might play a central role in local anestheticinduced cytotoxicity. The p38 MAPK is involved in
regulation of apoptosis, gene expression, mitosis,
and cell death. The direct neurotoxic effects of
lidocaine, ropivacaine, and bupivacaine leading to
cell apoptosis are associated with a phosphorylation
of p38 MAPK and in c-Jun N-terminal kinase (JNK)
in adult rat dorsal root ganglion neurons [14]. The
inhibition of p38 MAPK phosphorylation had no
effect on bupivacaine-induced ROS production and
mitochondria depolarization, suggesting that mitochondria injury could be upstream of p38 MAPK
phosphorylation [42 ]. An inhibitor of caspase 1 and
3 did not prevent selective axonal injury, whereas
caspase inhibition is neuroprotective in dissociated
neuronal culture submitted to lidocaine treatment
[13]. In conclusion, this suggests that the mechanisms involved in cell toxicity depend upon whether
the entire neuron or only the axon is submitted to
local anesthetic exposure.
Another molecular target of Las involved in
apoptosis inhibition is the kinase Akt which plays
a pivotal role in cell survival. Lidocaine and bupivacaine can induce Akt inhibition, and in mouse
C2C12 myoblast, a negative correlation between the
levels of Akt activation and the degree of local
anesthetic-induced apoptosis was observed [43].
Of interest for the prevention of local anesthetic
toxicity, the activation of Akt phosphorylation
could protect from local anesthetic-induced neuron
damage [44].
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Lastly, the sarcoplasmic/endoplasmic reticulum

stress could be considered as a target of local
anesthetics. Caspase 7 is involved in endoplasmic
reticulum stress-mediated apoptosis, as well as
expression of the endoplasmic reticulum stress
markers X-box-binding protein 1 (XBP-1), activating
transcription factor 6 (ATF-6), and C/EBP homologous protein (CHOP). In myotubes, 8-h bupivacaine treatment induces CHOP expression (a key
downstream transcription factor in sarcoplasmic
reticulum stress-induced apoptosis) as well as
expression of XBP-1 and ATF-6 (two transcription
factors that control expression of CHOP) [34]. Blocking ROS production during bupivacaine treatment
in myotubes decreases CHOP expression and inhibits expression of activated caspases.

Limitations
All laboratory experiments were performed in the
presence of 110 mM local anesthetic, for both
bupivacaine and lidocaine. This was chosen to
mimic the effects of direct local anesthetic exposure
of in-situ cell at clinically relevant concentration.
Whereas such high concentrations are systematically discussed in the literature, we know that
lipophilic local anesthetics accumulate in tissue
and that the real cell concentration remains
unknown. Thus, concentrations commonly used
should not be so far from clinical practice [34].
Moreover, the cell model used for toxicity
analyses could play a major role, and the results
must be interpreted according to the cell type. For
instance, we demonstrated that cell type (cancer cell
or not) as well as metabolic profile of cancer cell
could mitigate local anesthetic-induced toxicity
[45 ]. Thus, the conclusions drawn from in-vitro
experiments based on a cancer cell should be interpreted with caution.
&

PREVENTION
Today, protective strategies based on optimization
of local anesthetic protocol for regional analgesia
are proposed to prevent in-situ toxicity. Antioxidant
drugs or new galenic local anesthetic remains in the
investigation field and many studies are still needed
before clinical use.

Optimization of clinical protocol

All local anesthetics we daily use, induce Schwann
cell and myocyte toxicity in a time and concentration-dependent manner. The severity of local
anesthetic-induced in-situ toxicity increases along
with increase of the concentration and incubation

time of local anesthetics [12,39]. This concerns

histological damage as well as metabolism alterations [12,25,31,46,47]. For clinicians, this requires
us to determine the minimum low anesthetic
concentration for different peripheral blocks, the
duration of the protocol, and to better define the
target site in which the injection of local anesthetic
should occur [48]. Using ultrasound guidance for
peripheral nerve block contributes to the decrease
in the volumes of local anesthetic administered.
Further studies will confirm or not if this advantage
will be associated with a decrease in neural or muscle
cell injuries.
Moreover, proper biochemical properties of
local anesthetics should be considered while assessing their toxicity. Lidocaine has been described
especially toxic for neurons when given intrathecally [4953], whereas bupivacaine have been
shown to be the most toxic in myoblast [43,54]. It
seems likely that the mechanism of injury is dependent not only on local anesthetics and type of cell but
also on the pathway investigated. Thus, this biochemical classification of toxicity does not appear
clear in all studies [13,15,55].
Finally, the importance of the cellular context,
in particular the energy state of the cell, could
determine in large part the extent of local anesthetic
toxicity. The mitochondrial inhibitory effects make
the use of some local anesthetic particularly careful
in patients with compromised energy production,
such as observed in the case of mitochondrial rare
disorders, chronic hypoxia, diabetes, and statin
treatment [27,56,57].

Perspectives
Antioxidant drugs prevent many dysfunctions
induced by local anesthetics. N-acetyl-l-cysteine
prevents cell death, inhibition of both complexes
I and III activities [33], sarcoplasmic/endoplasmic
reticulum stress, activation of caspases 9, 3/7, and
PARP degradation [34,40]. Resveratrol mimics
N-acetyl-l-cysteine protection from bupivacaineinduced in-situ toxicity [34]. Alpha-lipoic acid prevents bupivacaine-decreased cell viability, Akt
phosphorylation, and apoptosis [58]. Recombinant
human erythropoietin (5000 UI/kg/24 h) prevents
the inhibitory effects of bupivacaine on mitochondrial bioenergetics in rat and bupivacaine-induced
reduction of mitochondrial membrane potential
and fragmentation of mitochondria in human myoblasts [12].
Other potential therapeutic strategy could be
available: dexamethasone prevents bupivacaine
and lidocaine-decreased Akt phosphorylation
[44], nandrolone decanoate administration could

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enhance mouse muscle regeneration during the

recovery from bupivacaine-induced injury [59].
Lastly, suspension of liposomes and microparticles with prolonged local anesthetic release
are tested in animals but inflammatory reactions
were observed. Local anesthetic in liposomes is
mainly used for analgesia and not for anesthesia
because these new galenic forms could reduce the
initial burst of local concentration. Moreover, the
release of bupivacaine could occur over several
days [60 ,61]. Indeed, very low concentrations
of bupivacaine seem to be myotoxic if the duration
of exposure is sufficiently prolonged. Further
investigations are still requested before human
use.
&

CONCLUSION
Regional anesthesia improves analgesia after surgery, facilitates postoperative rehabilitation, and
enhances patient satisfaction. Thus, the peripheral
nerve catheter is a gold standard for postoperative
analgesia and it should be systematically proposed
to the patient when indicated despite the risk
of toxicity. In-situ toxicity induces histological
damage, metabolic alteration with cell death and
apoptosis, and functional dysfunction in both
muscle and neuron. Improving our practice with
the optimization of our clinical protocol could
prevent from these side-effects; antioxidant use
and suspension of liposomes releasing local anesthetics over several hours remain in perspective
area.
Acknowledgements
None.
Conflicts of interest
There are no conflicts of interest.

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38. Werdehausen R, Fazeli S, Braun S, et al. Apoptosis induction by different
local anaesthetics in a neuroblastoma cell line. Br J Anaesth 2009; 103:711
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39. Werdehausen R, Braun S, Essmann F, et al. Lidocaine induces apoptosis
via the mitochondrial pathway independently of death receptor signaling.
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40. Park CJ, Park SA, Yoon TG, et al. Bupivacaine induces apoptosis via ROS in
the Schwann cell line. J Dental Res 2005; 84:852857.
41. Unami A, Shinohara Y, Ichikawa T, Baba Y. Biochemical and microarray
analyses of bupivacaine-induced apoptosis. J Toxicol Sci 2003; 28:7794.
42. Lu J, Xu SY, Zhang QG, et al. Bupivacaine induces apoptosis via mitochondria
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and p38 MAPK dependent pathways. Eur J Pharmacol 2011; 657:5158.
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43. Maurice JM, Gan Y, Ma FX, et al. Bupivacaine causes cytotoxicity in mouse
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mechanism. Neuroscience 2010; 167:329342.
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pivacaine and aminoimidazole carboxamide ribonucleotide on human cancer
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muscle. Can J Anaesth 2010; 57:836842.

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48. Nakamura T, Popitz-Bergez F, Birknes J, Strichartz GR. The critical role of
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and ropivacaine administered intrathecally in rabbits. Anesth Analg 2003;
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rabbits: pharmacodynamic and neurotoxicologic study. Anesthesiology 2002;
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intrathecal lidocaine and bupivacaine in rats. Anesth Analg 2005; 101:541
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0952-7907 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

www.co-anesthesiology.com

595

Emulsions lipidiques intraveineuses : o en est-on ?

Karine Nouette-Gaulain1, Xavier Capdevila2, Florian Robin1, Hlne Beloeil3

1. Laboratoire Maladies Rares: Gntique et Mtabolisme (MRGM), Universit

Segalen Bordeaux 2, F-33076 Bordeaux, France; CHU Bordeaux, Ple
dAnesthsie Ranimation, Centre Franois Xavier Michelet, F-33076 Bordeaux
2. CHU Montpellier, Service dAnesthsie Ranimation A
3. CHU Rennes, Ple dAnesthsie Ranimation

Les points essentiels

Lanesthsie rgionale est en plein essor et le risque de toxicit systmique augmente

avec le nombre des indications.

Lintrt des mulsions lipidiques intraveineuses a t soulign dans de nombreux cas

cliniques et tudes exprimentales. Une rduction du temps ncessaire pour un retour
un tat hmodynamique stable et une amlioration du taux de survie sont
classiquement dcrits sur les modles animaux. Le manque dtudes chez lhomme est
responsable du faible niveau de preuve.

Le mcanisme daction de linteraction entre une mulsion lipidique intraveineuse (ELI)

et un anesthsique local (AL) est mal connu, et est lorigine dune controverse. Les
interactions ELI-AL pourraient tre secondaires un phnomne de pige lipidique
intravasculaire

mais

galement

pourraient

sexpliquer

par

des

modifications

mtaboliques intracellulaires et par une modulation de laction de lanesthsique local

sur le canal sodique.

Linteraction entre une mulsion lipidique intraveineuse et un anesthsique local

pourrait tre modifie par de fortes doses dadrnaline, par une hypoxie et une acidose.

Les mulsions lipidiques intraveineuses sont recommandes par lASRA et par la SFAR
lors dune ranimation dun arrt cardio-respiratoire induit par un surdosage systmique
en anesthsique local.

Les mulsions lipidiques intraveineuses pourraient probablement tre utilises lors dun
surdosage en btabloquants, inhibiteurs calciques, amiodarone, psychotropes. Le
risque li lutilisation dune mulsion lipidique intraveineuse est peu dcrit.

Les interactions entre les agents lipophiles et les mulsions lipidiques intraveineuses
(ELI) sont connues depuis 1962 : la dure dune anesthsie par thiopental serait rduite
lors de ladministration dune mulsion lipidique chez le rat [1]. En 1998, lquipe de
Guy Weinberg dcrit les premires interactions entre la bupivacane et les ELI [2].
Deux types de rsultats sont obtenus :i) Aprs un prtraitement par Intralipid chez des
rats, la dose toxique de bupivacane entrainant un arrt cardio-respiratoire est
significativement plus leve que chez des rats contrles recevant uniquement du
srum sal, ii) Lors dun arrt cardio-respiratoire induit par une dose toxique de
bupivacane, le taux de mortalit des rats est significativement plus faible sils reoivent
une solution dIntralipid lors de la ranimation. Suite ces rsultats, de nombreux
travaux exprimentaux complmentaires ont explor les mcanismes daction qui
pourraient expliquer ces phnomnes et la littrature a t enrichie partir de 2006 par
la publication de nombreux cas cliniques soulignant les effets bnfiques des ELI [3].
Les ELI ont ainsi trouv progressivement une indication dans le traitement dun
surdosage en anesthsique local (AL) puis dans les recommandations internationales
[4, 5]. Mais, labsence dtude humaine randomise et lhtrognit des rsultats des
tudes exprimentales ont donn naissance une controverse concernant les effets
bnfiques

des

interactions

ELI-AL.

Ces

diffrents

points

seront

abords

successivement dans cette revue.

1. Les mcanismes pouvant tre impliqus dans linteraction ELI-AL

Suite aux effets dune injection dELI sur la toxicit induite par la bupivacane chez le
rat, ces rsultats ont ensuite t retrouvs sur cur isol [6] et sur des chiens au cours
dune anesthsie gnrale [7]. Les mcanismes impliqus dans cette prvention, voir
protection, ne sont pas clairement connus. Plusieurs hypothses sont dcrites, parfois
complmentaires les unes des autres.

Pharmacocintique des anesthsiques locaux

Avant daborder ces hypothses, faisons un bref rappel sur la pharmacocintique des
AL. Les AL sont des molcules liposolubles, mais dont la liposolubilit varie en fonction
de la molcule. Dans le sang, les AL sont globalement soient lis une protne
(lalbumine, lalpha-1 glyco-protine),

soit libres et responsables de la toxicit

systmique. Le mtabolisme est essentiellement hpatique. Lors dune administration

intravasculaire accidentelle dAL, lAL va dans un premier temps diffuser dans les
organes richement perfuss (le cur, le cerveau), puis dans les organes peu perfuss
tels la graisse[8].

Lhypothse du pige lipidique

Linteraction entre lELI et les AL pourraient sexpliquer par la formation dun pige
lipidique. En utilisant des mthodes de microcalorimtrie, le type de liaison entre ELI et
AL serait probablement de nature entropique [9].
Sur cur isol de rat, ladministration dELI est associe une rcupration rapide de la
contraction cardiaque et une diminution de la concentration tissulaire de bupivacane
radio marque [6]. Des tudes in vitro base sur la colorimtrie [10] et sur ltude des
liaisons ELI-AL [9] sont en faveur de lhypothse du pige lipidique. Suite des tudes
exprimentales, la modlisation pharmacocintique dune injection intravasculaire de
bupivacane suggre quune administration dELI diminue de 11% la concentration
tissulaire de bupivacane dans le cur 3 minutes aprs linjection dELI, et de 18%
dans le cerveau, 15 min aprs la fin de linjection [8]. En revanche, la concentration de
bupivacane dans le tissu adipeux augmenterait. Dans ce modle, linjection dELI
saccompagnerait dune augmentation de la concentration plasmatique totale de
bupivacane associe une diminution de la concentration de la fraction libre. Ces
rsultats suggrent une liaison des AL avec lELI. Tandis que le dlai de 3 minutes est
compatible avec lhypothse du pige lipidique et avec les rsultats dcrits dans les cas
cliniques, le dlai daction de 15 minutes au niveau du cerveau laisse supposer
limplication dautres phnomnes in vivo.

Limplication probable du mtabolisme cellulaire

En 1961, Shipp et al. dmontre que les lipides sont les substrats nergtiques
essentiels pour le cardiomyocytes [11]. Les lipides sont mtaboliss via le cycle de la
bta-oxydation et vont fournir les substrats essentiels pour la synthse de lATP
mitochondrial.
Sur un modle de rat in vivo et sur un cur isol de rat soumis un phnomne
dischmie-reperfusion, ladministration dune ELI va diminuer la taille de linfarctus du
myocarde induite par lischmie, cet effet cytoprotecteur tant significativement plus
important que celui induit par la cyclosporine A [12]. Ce phnomne observ lors de la

reperfusion du myocarde est associ lactivation de kinases favorisant la

cytoprotection, telles la phosphorylation de lAkt et de la GSK-3bta.
Par opposition, les anesthsiques locaux des fortes concentrations interagissent
galement avec le mtabolisme mitochondrial en inhibant le transport des acides gras
chane longue, en diminuant le potentiel de membrane et la synthse dATP
mitochondriale [13, 14].
En combinant les diffrents effets, la charge rapide en acide gras apporte par
ladministration dELI pourrait compenser le blocage mtabolique induit par les AL.
Cette thorie a t suggre par les travaux de lquipe de Stehr et al [15]. Sur cur
isol de rat, un apport supplmentaire en acide gras permettait de rduire laltration de
la fonction cardiaque induite par la bupivacane. Cette thorie mtabolique
mitochondriale vient dtre complte par une tude valuant leffet dun blocage
spcifique du mtabolisme lipidique en association un surdosage en AL avec
administration dELI [16]. In vivo, un blocage spcifique du mtabolisme lipidique par
une concentration leve de CVT-4325 lors dun protocole bupivacane(10mg/kg IV)ELI chez des rats induit un effondrement majeur de la frquence cardiaque, de la
fraction djection et de la fraction de raccourcissement. Cela suggre donc quun
prtraitement par CVT-4325 abolit leffet dune ELI et que le mtabolisme des acides
gras est impliqu dans linteraction protectrice ELI-AL.
Mais

dautres

voies

de

signalisation

peuvent

galement

tre

impliques.

Ladministration dELI aprs une asystolie induite par une dose toxique dAL chez le rat
pourrait permettre de prserver le mtabolisme calcique et dinhiber louverture du PTP
[16]. De plus , les acides gras pourraient interfrer sur laction des AL sur le canal
sodique [17]. Sur culture cellulaire (HEK-293 cells), lassociation acide grasbupivacane diminue significativement le bloc tonique et le bloc phasique, par
comparaison au bloc induit par la bupivacane seule. Cet effet direct sur le canal
sodique pourrait moduler galement la toxicit induite par la bupivacane et pourrait
contribuer une protection cellulaire.

Leffet de lELI sur les paramtres hmodynamiques

Lors

dun

surdosage

toxique

systmique

dAL,

les

signes

cardiovasculaires

couramment dcrits sont les troubles de la conduction, les troubles du rythme, se

compliquant dune asystolie, une diminution de la fraction djection et de la fraction de

raccourcissement, un effondrement du dbit cardiaque et des rsistances vasculaires

systmiques.
En absence dAL, ladministration isole dELI chez le rat augmente significativement le
flux aortique et la pression artrielle par rapport une administration de srum sal
isotonique.

En conclusion, les interactions ELI-AL pourraient tre secondaires un phnomne de

pige lipidique intravasculaire mais galement pourraient sexpliquer par des
modifications mtaboliques intracellulaires et une modulation de laction de lAL sur le
canal sodique.

2. La controverse concernant les interactions entre des mulsions lipidiques et

les anesthsiques locaux

Les rsultats controverss des tudes exprimentales

Tandis que les rsultats sur les modles murins, lapins ou chiens sont assez
homognes [18], les exprimentations ralises chez le cochon ne mettent pas en
vidence un effet bnfique de linteraction ELI-AL. Dans ce dernier modle, la liaison
ELI-AL nest pas dmontre et aucune amlioration du taux de survie nest observe
chez les animaux recevant une ELI [19].

Chez le volontaire sain au cours dune tude prospective randomise, une injection
intraveineuse de bupivacane 0,5 mg/kg a t ralise en 20 minutes, suivie dune
administration dIntralipid 20% (bolus de 1,5ml/kg en 1min puis 29 min de perfusion
continue 0,25ml/kg/min), le groupe contrle recevait de la bupivacane et du srum
sal isotonique [20]. La valeur de la concentration plasmatique de bupivacane (total et
libre) diminuait lgrement. Le seuil des concentrations toxiques de la bupivacane
ntant pas atteint, les mcanismes de protection ne sont probablement pas saturs, et
la diffrence significative entre les traitements est donc probablement difficile mettre
en vidence.

Le rle du terrain

La toxicit des anesthsiques locaux est majore en cas dhypoxie et dacidose. De

plus ces deux paramtres pourraient influencer laction dune injection dELI. Ainsi,
linjection dELI doit sintgrer dans une stratgie de ranimation avec injection dagent
vaso-actif et des objectifs stricts.
Lors dune asystolie induite par la bupivacane sur cur isol de rat, la
rcupration de la fonction cardiaque initiale est meilleure si lorgane bnficie dune
association adrnaline (0,15 mcg/kg) et ELI, plutt que dun seul des deux traitements
[21]. En revanche, lquipe de Guy Weinberg dmontre quune injection dELI a un effet
significativement meilleur que linjection dadrnaline (30 mcg/kg) au cours dune
ranimation cardio-vasculaire chez le rat [22] . Ces rsultats discordants pourraient
sexpliquer par la diffrence de posologies dadrnaline utilise et donc par leffet usedependence dmontr dans danciens travaux : les posologies dadrnaline utilises
seraient au del dun certain seuil, et donc trop leves pour tre bnfiques. Cette
hypothse a t confirme dans une tude complmentaire o diffrentes posologies
dadrnaline (1-2,5-10 et 25 mcg/kg) ont t values[23]. Chez les rats, des doses
dadrnaline suprieures 10mcg/kg saccompagnaient dune lvation des lactates,
dune acidose svre, rendant la ranimation plus complexe et moins performante [23].
Linteraction ELI-AL semblerait modifie en cas dhypoxie. En effet, dans les
deux tudes suivantes, des doses dadrnaline entre 40 et 200 mcg/kg se rvlent plus
efficaces que lELI si une priode dhypoxie est applique lanimal. Ainsi, si linjection
de 5 mg/kg de bupivacane 0,5% est suivie dune priode dhypoxie dune deux
minutes, le taux de survie des rats est meilleur dans le groupe adrnaline-vasopressine
que dans le groupe ELI seule [24]. De mme, sur un modle de lapin avec clampage de
la trache lors dune injection toxique de bupivacane, la ranimation (ventilation,
massage cardiaque, adrnaline)

dun ACR est moins performante si une ELI est

administre chez lanimal, le groupe tmoin recevant du srum sal [25].

Le pH pourrait galement modifier linteraction ELI-AL. Aprs injection de
10mg/kg de bupivacane chez le porc, une ranimation est ralise avec ventilation,
massage cardiaque et adrnaline. Une injection dELI ou de srum sal isotonique est
ensuite ralise. Dans les deux groupes, le taux de survie nest

significativement

diffrent. En revanche, lanalyse des rsultats rvle une acidose majeure lors de la
ranimation des animaux, suggrant une interaction entre lacidose et ladministration
dELI possible [26].

Lensemble de ces rsultats suggre une titration des doses dadrnaline, des
objectifs de normoxie et normocapnie lors dune ranimation dune asystolie induite par
les AL.

Proprits biochimiques des ELI et AL : quel rle ?

Schmatiquement, les ELI sont composes dacides gras chane longue (exemple
Intralipid) ou dun mlange chane longue et chane intermdiaire (exemple
Medialipid). Les proprits liposolubles sont diffrentes pour chaque AL. Des tudes in
vitro ont valu linteraction ELI-AL en fonction des proprits de chaque solution. En
prsence dune solution tampon, la solubilit et la capacit de liaison dune solution
dacides gras chane longue sont significativement meilleures que celles dune
solution comprenant un mlange dacide gras chane longue et intermdiaire [9]. En
revanche, en prsence de srum humain, une ELI compose dun mlange dacides
gras chane longue et intermdiaire paraitrait plus performante pour squestrer les
AL[27]. Il parat donc difficile de conclure au vu des rsultats trs divergents de ces
tudes in vitro. Teste chez le rat, cette hypothse serait en faveur dune ELI compose
uniquement dacides gras chane longue : le taux de rats survivant une ranimation
classique est suprieur dans le groupe Intralipid que dans le groupe recevant une ELI
compose dun mlange acides gras chane longue et intermdiaire [28]. Chez le
cochon, les deux ELI (Intralipid et un mlange acides gras chane longue et
intermdiaire) permettaient une meilleure rcupration des paramtres cardiaques et
hmodynamiques que dans le groupe srum sal isotonique, mais le manque de
puissance de ltude ne permet pas de mettre en vidence une diffrence significative
entre les ELI [29].

3. Place des mulsions lipidiques dans les recommandations professionnelles

lors dun surdosage systmique en anesthsique local

Anesthsiques Locaux et risque de toxicit systmique

Ladministration locale dAL peut se compliquer dune injection directe vasculaire ou
dune diffusion vasculaire passive, les deux cas conduisant un surdosage toxique
systmique dAL. Ces surdosages sont caractriss par des signes neurologiques et/ou
cardiaques dont les cas les plus svres conduisent des convulsions, un coma et/ou
un arrt cardio-respiratoire.

Aujourdhui, une quarantaine de cas cliniques publis souligne leffet bnfique dune
administration dELI lors de la survenue dun surdosage en AL, tels que la bupivacane
et la ropivacane, chez la plupart des patients. Dans le premier cas clinique publi en
2006, un homme de 58 ans avait bnfici dun bloc interscalnique avec mpivacane
et bupivacane [3]. A la fin du bloc, le patient a prsent des signes neurologiques
graves puis un arrt cardio-respiratoire. Aprs 20 minutes de ranimation et la
persistance dune instabilit hmodynamique, ladministration de 100 ml dIntralipid
20% a t suivie par une amlioration trs rapide des paramtres hmodynamiques et
lectriques, le patient ne prsentant par la suite aucune complication neurologique. Ces
rsultats ont t dcrits chez les adultes, mais galement chez des enfants, ds la
priode nonatale [30]. Trs schmatiquement, lors dune ranimation standard
survenant aprs un surdosage en AL, tandis que le patient est mass avec injection
dadrnaline, oxygn et ventil, ladministration complmentaire dELI saccompagne
le plus souvent dune amlioration des signes cliniques dans un dlai rapide denviron 5
10 minutes.
Nous devons cependant rester vigilants sur les relations de causes effets car : i) une
sous-estimation du nombre dchecs de la thrapie par ILE ne peut pas tre exclues, ii)
les tudes prospectives et randomises sur ce sujet ne sont pas possibles

Les Recommandations internationales

Ainsi depuis plusieurs annes, l American Society of Regional Anesthesia and Pain
Medicine a publi une check list suivre en cas darrt cardio-respiratoire induit par
une injection toxique dAL. Cinq points sont clairement identifis en 2012 [4] :
-

Appel laide

Dmarche initiale
o Gestion des voies ariennes et ventilation avec 100% doxygne
o Prise en charge des troubles neurologiques graves : les benzodiazpines
en premier lieu, et ne pas injecter de propofol
o Organiser la possibilit dune CEC

Prise en charge de lasystolie

o Massage cardiaque prolong
o Eviter la vasopressine, les inhibiteurs calciques, les bta-bloquants, ou
dautres anesthsiques locaux
o Titration des doses dadrnaline (<1mcg/kg)

Traitement par ELI (20%)

o Bolus initial de 1,5 ml/kg IV en 1 minute
o Perfusion continue de 0,25 ml/kg/min
o Rpter le bolus une ou deux fois en cas de collapsus cardiovasculaire
persistant
o Perfusion continue au moins 10 min aprs le retour un quilibre
hmodynamique satisfaisant
o Eviter de dpasser la dose maximale de 10ml/kg au cours des 30
premires minutes

Dclaration

de

lvnement

indsirable

grave

sur

le

site

http://www.lipidrescue.org/

Finalement, les auteurs proposent une surveillance prolonge suprieure 12 heures,

justifie par un risque de rcidive larrt de lELI.

Les

recommandations

disponibles

sur

le

site

de

la

SFAR

(http://www.sfar.org/accueil/article/340/toxicite-systemique-aigue-des-anesthesiqueslocaux) diffrent en quelques points, dont le recours non indispensable la perfusion

continue et la dure de surveillance rduite 6 heures.

4. Risques et perspectives

Perspectives
Aujourdhui, la littrature a t enrichie de cas cliniques au cours desquels lELI a t
utilise pour antagoniser des surdosages dautres agents liposolubles [31]. Ainsi, les
ELI ont t utilises en cas de surdosages en btabloquants, en amiodarone, en
inhibiteurs calciques, en psychotropes. Mais la description des interactions ELI-agents
liposolubles a les mmes limites que celles dcrites avec les AL : peu dtudes sur
modle animal, essentiellement des cas cliniques. De plus, se pose le problme du
patient qui arrive aux urgences pour une prise mdicamenteuse dont la nature nest pas
connue : existe til un risque administrer une ELI ?

Risques lis une perfusion dELI

10

En cas de surdosage systmique en AL, il est recommand dviter de dpasser la

dose maximale de 10ml/kg au cours des 30 premires minutes. Cette recommandation
peut sexpliquer sur les arguments suivants. Sur modle animal, la perfusion dELI lors
dun arrt cardio-respiratoire induit par un surdosage en AL va majorer la
vasoconstriction et lhyperlactatmie induite par ladrnaline [23]. Lors dune
antagonisation dun surdosage en amiodarone avec une ELI, une coloration cutane
rouge est parfois dcrite. Lors dinjection de grand volume dELI chez le rat, une
lvation des triglycrides est observe au cours des 48 premires heures, associe
une lvation de lamylase et des ASAT [32]. Ces rsultats biologiques sont dcrits
dans certains cas cliniques [5]. En histologie chez le rat, une administration de 60
80ml/kg en 30 minutes dELI saccompagne de lsions histologiques au niveau des
poumons (infiltration de neutrophiles et microhmorragies intra-alvolaires) et du foie
(statose micro vasculaire) [32]. Si nous gardons en tte que le facteur de conversion
thorique des doses dELI entre le rat et lhomme recommande par la FDA est de 6, il
est justifi de ne pas dpasser la dose maximale de 10ml/kg au cours des 30 premires
minutes [12].

5. Conclusion
Au vu des donnes issues des tudes exprimentales et des cas cliniques, les ELI font
aujourdhui partie des recommandations suivre lors dun arrt cardio-respiratoire
induit par un surdosage systmique en anesthsique local. Les ELI ne doivent pas tre
substitues aux autres moyens de ranimation, mais sont un lment supplmentaire.
Des tudes exprimentales complmentaires et un registre de cas cliniques permettront
probablement de mieux caractriser linteraction ELI-AL et de mieux connatre les
lments qui aujourdhui amnent parfois des controverses. De mme, des travaux
complmentaires permettront de mieux dfinir la place des ELI au cours de surdosages
avec dautres agents liposolubles.

11

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