Download mechanisms of la toxicity

19 July 2013
No. 24
LOCAL ANAESTHETIC TOXICITY
Veena Ramson
Commentator: D Pillay
Moderator: L Padayachee
DISCIPLINE OF ANAESTHETICS
CONTENTS
INTRODUCTION ................................................................................................... 3
INCIDENCE OF LA TOXICITY ............................................................................. 3
MECHANISMS OF LA TOXICITY ......................................................................... 4
CLINICAL PRESENTATION OF LAST ................................................................ 7
TREATMENT OF LAST ........................................................................................ 8
LIPID EMULSION THERAPY ............................................................................... 9
TYPES OF LIPID EMULSIONS ............................................................................ 9
TIMING OF THERAPY AND SAFETY ................................................................ 10
USE OF LIPID EMULSION IN CHILDREN ......................................................... 10
USE OF LIPID EMULSION IN PREGNANCY ..................................................... 11
THE PROTOCOL ................................................................................................ 11
CONCLUSION .................................................................................................... 16
APPENDIX 3 ....................................................................................................... 17
REFERENCES ................................................................................................... 18
Page 2 of 19
LOCAL ANAESTHETIC TOXICITY
INTRODUCTION
The resurgence of regional and neuroaxial anaesthesia in our current practice has
prompted the avid use of local anesthetic drugs (LA). Inasmuch as these drugs
produce beneficial analgesic and anaesthetic effects; in high enough doses; these
drugs are much feared for its toxicity.In recent years, there has been much
interest in interrogating and explaining the underlying mechanisms of LA toxicity in
attempt to adequately treat and prevent the disastrous effects of overdose.
The much-dreaded cardiovascular collapse that is seen in human beings has led
to most experiments and evidence being demonstrated in animal models. The
purpose of this review is to elucidate on the mechanisms of LA toxicity, discuss
the clinical presentation and formulate a concise management plan, based on
current evidence.
INCIDENCE OF LA TOXICITY
The latest literature quotes Local Anaesthetic Systemic Toxicity (LAST) as
occurring between 7.5 to 20X per 10000 peripheral nerve blocks and 4X per
10000 epidurals.[1]However, there are certain individual nerve blocks that have
been associated with higher rates of toxicity: interscalene and supraclavicular
blocks may cause a n incidence of toxicity be as high as 79 per 10000. [2]
Agarwal et al, listed patients associated with a higher risk of developing LA toxicity
even within normal therapeutic dosage ranges. [3]
These are:
 Extremes of age
 Cardiac Conduction Deficits
 Ischaemic Heart Disease
 Liver disease
 Metabolic or respiratory acidosis
 Cardiac disease resulting in decreased ejection fraction
 Higher risk type of block and location of block
 Older LA compound
 Higher total dose administered
Page 3 of 19
MECHANISMS OF LA TOXICITY
LA toxicity can be divided into 2 broad categories:
A. LA in situ toxicity – affecting local muscle and nerves
B. LA systemic toxicity (LAST) – manifesting as CNS and CVS collapse
A. LA “In Situ” Toxicity
The infiltration of LA’s during peripheral nerve blocks has been shown to be
cytotoxic to both neighboring myocytes as well as neurons. LA myotoxicity
was very robustly demonstrated in ophthalmic surgery, where the use of
bupivacaine in retro- and peribulbar blocks resulted in persistent diplopia from
direct damage to the affected extraocular muscles.[4, 5]
They cause damage in 2 main ways:
1. Destruction of the tissue ultrastructure with concomitant
inflammatory reaction
2. Interference with cellular energy metabolism at a mitochondrial level
1.1. Destruction of the tissue ultrastructure: Myocytes
High dose of LA injected directly into muscle (16mg/kg bupivacaine)
or a bolus dose (3-5mg/kg of bupivacaine) followed by an infusion yielded the
following microscopic changes: [6]
 interstitial oedema
 disjointed muscle fibres and subsequent disruption of the myofilaments
 lysis of the sarcoplasmic reticulum
 mitochondrial lysis
 pycnosis of nuclei
1.2 Destruction of the tissue ultrastructure: Neurons[7]
Axonal tissue that was incubated in LA for prolonged periods showed the
following changes:
 Axonal swelling and necrosis
 Loss of normal myelin architecture an axonal demyelination
 Formation of myelin globules and vacuoles
 Neuronal apoptosis with subsequent macrophage phagocytosis of
epineural and endoneural collagen
A recent study has shown that bupivacaine (and all other LA’s) cause time and
dose dependent death of schwann cells; with brief exposure of high doses of the
drug being just as dangerous as prolonged exposure of intermediate and low
concentrations of bupivaciane [8]
2.1. Interference with cellular energy metabolism : calcium homeostasis [9]
LA’s have been shown to result in increased intracellular calcium
concentration:
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 Increased entry of calcium through the plasma membrane; and increased
calcium release from the sarcoplasmic reticulum (SR) via activation of
calcium ryanodine receptors (RyR)
 Decreased calcium reuptake into the SR via inhibition of calcium ATPase.
 Production of reactive oxygen species
The result of the above is depletion of calcium in the SR, while the sustained
increase in intracellular calcium concentrations result in cell death.
2.2. LA-induced inhibition of cellular ATP production [10]
Due to the following mechanisms:
 Direct destruction and depletion of mitochondria and mitochondrial network
 Direct inhibition of mitochondrial respiratory chain complex I
 Uncoupling of oxidative phosphorylation
 Inhibition of mitochondrial ATP synthase
 Decreased mitochondrial resting membrane potential
 Production of ROS
B. LA Systemic Toxicity (LAST)
Systemic toxicity is a result of delayed absorption of LA from site of injection into
the systemic circulation; or direct infusion of the drug into the vasculature- either
deliberately (Bier’s Block) or inadvertently. This leads to interference of a number
of ionic and non-ionic pathways at a
cellular level.
Page 5 of 19
The voltage-gated sodium (Nav) channel is primarily involved when local
anaesthetics bind; which leads to decreased electrophysiological conduction.
There are 9 isoforms of these channels, and it has been postulated that different
LA’s have different affinities for these isoforms and thus manifest as varying
degrees of toxicity clinically [11]
In addition to the Nav channels, LA’s affect cardiomyocytes at other channels and
receptors.
Bupivacaine inhibition of calcium channels are implicated in myocardial
depression as a result of decreased muscular contractility. Many authors have
also shown that LA affect the transient outward potassium (K) channels as well;
thereby slowing repolarization and impairing conduction. [12, 13]
There has been numerous studies that have also demonstrated other biochemical
mechanisms causing cardiovascular collapse, including:
 Inhibition of NA/K ATPase pump
 Decrease in the Mg-ATP concentration (which is important for actin-myosin
cross-bridging, and hence, muscle contraction) [14]
 Uncoupling of oxidative phosphorylation:
Bupivacaine inhibits carnitine acylcarnitine transferase (CACT) in cardiac
mitochondria of rats. CACT is the only enzyme that transports acylcarnitines
across mitochondrial membranes in the fatty acid transport chain during
phase I mitochondrial respiration. [15]
This is important for aerobic
metabolism. and may be implicit in inducing the severity of LA-induced
toxicity that is unresponsive to ACLS techniques.
(Other biochemical mechanisms of LA toxicity- Appendix 1)
Based on the above mechanisms, the questions that logically follow are:
1. Does LAST occur due to its electrophysiological effects on cardiac conductivity;
that is: do affected patients die from arrhythmias?
2. Is LAST a consequence of depressed cardiac contractility?
3. Is it drug/compound specific?
A summary of the evidence has shown that CVS collapse is due to a combination
of both pathologies, and it is drug specific. Multiple studies have shown that
bupivacaine has a greater predilection toward producing arrhythmias by delaying
conduction; and may or may not cause concomitant depression in myocyte
contractility (de Jong, et al; groban et al). [16-18]
Bupivacaine’s effect on conduction ranges from premature depolarization, causing
fibrillation to AV block (and potential to cause reentrant arrhythmias), complete
heart block and even pacemaker-resistant bradycardia and asystole.
Page 6 of 19
Block and Cavino have also shown bupivacaine was 8-15 times more potent than
lignocaine in inhibiting or delaying AV node conduction, QRS duration and QT
interval. [19]
Furthermore, there is consistent evidence that the R(+) enantiomer of bupivacaine
produces much more profound AV conduction delay than the S(-) enantiomer or
the racemic mixture. [20, 21]
Lignocaine, on the other hand, tends to produce myocardial depression without
causing malignant arrhythmias (hence its use as an antiarrhythmic agent); and if
arrhythmias do occur, they are less persistent or resistant to treatment than those
caused by ropivacaine or bupivacaine.
Other indirect mechanisms that contribute to cardiovascular collapse that of
hypotension secondary to vasodilatation, and inhibition of autonomic reflexes. [22]
Of note, is that bupivacaine causes vasoconstriction at low doses (ropivacaine
and levobupivacaine to a lesser extent). [23] The implication of this is that in
addition to the negative inotropy, there is also an increase in ventricular afterload
leading to decreased cardiac output. This effect is mediated by α1
adrenoreceptors.
CLINICAL PRESENTATION OF LAST
The clinical presentation of LAST is typically a biphasic one, involving the CNS
and CVS; by initially causing excitation and then depression. The reason for this
is that these two organ systems are especially sensitive to electrophysiological
changes; and are also most vulnerable to hypoxia due to high mitochondrial
metabolic activity.
Usually (but not always) neurological signs appear first, which is then followed by
cardiovascular excitation and then depression. As previously mentioned, this
collapse leads to cardiac arrest that can be resistant to standard resuscitation
efforts. If extremely high plasma concentrations of LA is achieved, or if
bupivacaine is injected intravascularly, cardiovascular compromise may ensue
without any preceding CNS involvement.
The added quandary of general anaesthesia and its depressant effects
exacerbate hypotension and ventricular contractility.
Hypotension that is resistant to fluid administration or the use of vasopressors
may be the only discernable sign of LAST under GA. Unfortunately, at this point
these findings may herald imminent cardiac arrest.
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The typical progression of signs are as follows:
TREATMENT OF LAST
While it is intuitively accepted that successful resuscitation in any medical
emergency involves rapid ACLS measures of securing and supporting the
circulation, airway, oxygenation and ventilation; there are a few key features that
need to be considered in treating LAST.
 Immediate suppression of seizures using benzodiazepines (midazolam) or
boluses of propofol is vital in preventing intracellular acidosis.
 In terms of CVS support: maintaining coronary perfusion, attenuating tissue
acidosis and reversing the negative inotropy are key principles in
management.
Prior to the advent of lipid emulsions, cardiopulmonary bypass had been the only
successful intervention in rescuing patients from LA cardiovascular toxicity. That,
in itself, is wrought with logistic and practical issues, which precludes most
patients from its use.
Since its introduction in 2001, lipid emulsion therapy has now been consistently
shown to improve cardiac contractility and re-establish coronary perfusion, by
binding and removing the LA from the myocardial tissue.
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LIPID EMULSION THERAPY
The exact mechanism of action of lipid emulsion is unknown, and in fact its
discovery in use as a therapeutic agent was a paradoxical finding.
Researchers based their hypothesis that lipid emulsion will worsen LA-induced
arrhythmias (more specifically bupivacaine); based on the fact that FFA’s cause
accumulation of intracellular toxic metabolites, and also cause uncoupling of
oxidative phosphorylation which exacerbates tissue damage during periods of
myocardial ischaemia and low flow states.
When this theory was tested out on rats, the protective effects of lipid infusions
were discovered, and reproduced in several further studies. [24]
(appendix 2)
The “Lipid sink” theory is the most widely quoted of mechanism of action of lipid
emulsions. [14] The lipid emulsion literally acts like a sink that “drains” the LA from
plasma after selectively binding to these highly lipophilic drugs. Other theories
also postulated include
 lipid possibly increasing LA metabolism and distribution [25]
 lipid releases FFA’s which are important in restoring the oxidative
phosphorylation pathways that bupivacaine interferes with [15]
TYPES OF LIPID EMULSIONS
Most lipid emulsions are composed of soya bean, egg and differing lengths of
triglyceride chains.
Intralipid:
composed solely of long chain triglycerides
Medialipid: has equal amounts of long-chain and medium chain triglycerides
(50/50)
Structolipid: 64% long chain triglycerides and 34% medium chain triglycerides
Most recent evidence by Candela et al has shown that there is no significant
difference in outcome between the use of intralipid versus an agent with a mixture
of long and medium chain triglycerides [26]. Thus, anaesthetists need to be aware
that their hospital may choose to stock agents other than Intralipid. Further
studies are needed to validate the efficacy and supremacy of one agent over the
other in human cohorts; as the evidence is ultimately conflicting. Van de Velde et
al showed that acute administration of Medialipid in dogs was associated with
decreased myocardial contractility and increase in the systemic vascular
resistance; both of which could prove to be disastrous in the face of LA
cardiotoxicity. [27]
Propofol, by virtue of also being a lipid emulsion, has been purported to be an
effective therapeutic agent. However, the dose and volume needed for effective
treatment of LAST can actually be lethal. Propofol is, thus, reserved for treatment
of convulsions associated with LAST.
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TIMING OF THERAPY AND SAFETY
Intralipid was initially recommended as a last resort after failure of response to
standard resuscitation, but the trend has now moved to early use of the drug in
order to prevent progression to cardiac arrest; and case reports have even
associated the use of lipid with reversal of altered mentation and convulsions in
addition to the reversal of cardiotoxicity. [28-30]
This approach gives rise to 3 issues:
 Lipid emulsion is not an innocuous agent. The exact consequences of high
dose and volumes of lipid therapy is not known. While long term lipid
infusions have been associated with cytokine production and increased
infection risk as well as thrombolytic effects and pulmonary emboli (if the
lipid particles are very large), short term use of lipid in LAST evokes the
possibility of allergy or anaphylaxis.
The use of lipid therapy cannot be a prophylactic measure by any means; as
the risk : benefit ratio of large doses of lipid use versus LAST is not known.
 Bolus doses of intralipid seem to be inadequate in treatment of LAST, as
initial studies showed a transient improvement in cardiovascular profile,
followed by a steady decline. This problem has been ameliorated by a
concomitant infusion; and it has been suggested that this infusion be
continued for at least 12 hours.
 A recent study looked at the effects of an adrenaline injection during
concomitant lipid resuscitation in a rat model with bupivacaine overdose.
Interestingly, they found a threshold effect with adrenaline. Adrenaline doses
higher than 10mg/kg were found to impair lipid resuscitation from
bupivacaine toxicity, possibly by causing acidosis and hyperlactatemia. [31]
Seeing that LAST and effective safe dosing ranges cannot be elicited by
performing RCT’s in human cohorts, the guidelines that have been published by
the Association of Anaesthetists of Great Britain and Ireland.
USE OF LIPID EMULSION IN CHILDREN
There have been case reports of successful intralipid use in children and
neonates [32], however there is no consensus on maximum safe doses. Mirtallo et
al examined the use of parenteral lipid infusions and noted that fat overload
syndrome only occurred with very large daily doses of between 3.0 – 5.4g/kg/day
over a mean period of 28-114 days. [33]
Christensen et al did a cohort analysis of 1366 neonates. After minimal of lipid
for 14 days, they showed the incidence of adverse effects. [34]
Neonates receiving lipid for 14–28 days had a 14% incidence of parenteral
nutrition associate liver disease (PNALD); 29–56 days of therapy was associated
with a 43% incidence; while 57–100 days of therapy had a 72% incidence. Those
neonates receiving lipid for >100 days had an 86% incidence.
Page 10 of 19
Patients identified with the highest risk of developing PNALD were extremely low
birth weight babies of <500 g or 500–749 g, gastroschisis and jejunal atresia.
USE OF LIPID EMULSION IN PREGNANCY
Pregnancy is thought to be associated with enhanced sensitivity to local
anaesthetic systemic toxicity.
Several mechanisms have been postulated to account for this.
 Entrainment of local anesthetic and catheter migration more likely due to
epidural vein distention.
 Uptake of local anesthetic from the epidural space and distribution to
potential target sites are altered by the increased cardiac output state.
 Pregnancy results in decreased plasma protein, thereby increasing the free
drug concentration in the vascular compartment. Oestrogen and
progesterone also appear to alter cardiomyocyte electrophysiology to
increase arrhythmogenic risk and cardiotoxicity. [35]
 Increased neuronal susceptibility to LA’s may also occur decreasing
convulsion threshold.
Weinberg and Bern, in their review, have postulated that lipid works similarly in
pregnant women as in non-pregnant patients, but they also brought up some
important unanswered questions regarding lipid use in parturients. It is possible
that the lipid sink effect could demonstrate different characteristics due to
pregnancy-associated changes in circulating blood volume, cardiac output, protein
composition and binding, and overall metabolism. The effects- if any- of rapid
intralipid infusion on uteroplacental circulation and drug exchange are not known.
Again, high quality BLS/ACLS is advocated, with early recognition of LA toxicity or
high index of suspicion. Early airway management in paturients cannot be overemphasized, especially with a gravid uterus causing splinting of the diaphragm
and decreasing FRC.
The current ACLS guidelines for resuscitation of pregnant women need to be
adhered to; paying particular attention to early expedition of caesarian section as
soon as CVS instability is identified. Delivery of the fetus should be achieved
within 4-5min after the mother’s heart has stopped. Several studies have shown
return of spontaneous circulation and improved maternal hemodynamics only after
evacuation of the uterus; hence prompt perimortem cesarean delivery not only
improves infant survival rate, but may also prove lifesaving to the mother. [36, 37]
THE PROTOCOL
Both ASRA and the AAGBI have published protocols to guide management of
LAST. I have includes both as a quick reference.
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CONCLUSION
Local anaesthetic in situ toxicity and LAST are anaesthetic emergencies that
require prompt early recognition and decisive management strategy. All hospitals
that use local anaesthetics should have Lipid emulsion readily available for
overdose situations, and the current evidence makes it difficult for us to justify its
absence in some of our hospitals.
Lipid rescue therapy has emerged as a lifesaving modality in adults, children and
pregnant women, but exact mechanism of action; safe dosing strategy and safety
profiles still have yet to be validated. Types of lipid emulsions and their efficacy
and potential harmful effects are also areas that are being investigated in an aim
to refine current guidelines and implement universal protocols. That being said, I
cannot overstate the importance of exemplary ACLS technique as the basis of
lifesaving strategy in these patients.
APPENDIX 1 [38]
TABLE 4. Biochemical Actions of Local Anesthetics Possibly Linked to Cardiac Toxicity
Author
Year
Local Anesthetic
Sperelakis and Lee78
Chapman and Miller79
de Boland et al80
Katz et al81
Suko et al82
1971
1974
1975
1975
1976
T
P
D, T, L, P
L, PA
T, D, P, L
Singh et al83
Voeikov et al84
Chazotte and Vanderkooi85
1977
1980
1981
Vanderkooi et al87
Dorris88
Dabadie et al89
Schönfeld et al90
Butterworth et al91
1981
1983
1987
1992
1993
Butterworth et al92
Sztark et al93
McCaslin and Butterworth74
Weinberg et al94
Unami et al95
1997
1998
2000
2000
2003
Joseph et al96
2005
Enzyme or Process
Na-K ATPase of chicken heart
Antagonism of caffeine contracture in Na-free solution
D + T Antagonize ATPase and Ca transport in rabbit skeletal muscle SR
Antagonize calcium transport in canine cardiac SR
Antagonize Ca uptake, Ca-ATPase, Ca-dependant ATP-ADP phosphate
exchange in rabbit skeletal muscle SR
T
Antagonize Ach-medicated positive cardiac inotropy in frogs
D, L, T, B
Antagonize catecholamine-stimulated adenylyl cyclase in frog erythrocytes
P, T, D
Antagonizes cytochrome c oxidase, durohydroquinone oxidase, succinate
oxidase, reduced nicotinamide adenine dinucleotide oxidase, succinate
dehydrogenase, succinate-cytochrome c oxidoreductase, NADH-cytochrome
c oxidoreductase in beef heart
Tanaka and Hidaka86
1981
L, T, D
Antagonize Cacalmodulin activation of cyclic nucleotide phosphodiesterase, myosin light chain
kinase in chicken gizzard
T
Antagonizes mitochondrial F1-ATPase in bovine heart
P, 2-CP, T
Antagonize monoamine oxidase in rat and mouse myocardium
L, B
Uncouple oxidative phosphorylation in rat liver
B, QX-572
B is a protonophore in rat heart mitochondria
M, R, B
Antagonize basal, epinephrine-stimulated, and forskolin-stimulated cyclic AMP
production in human lymphocyte adenylyl cyclase
M, R, B and others Antagonize binding to A2-receptors in human lymphocytes
B, R
Uncoupling of oxygen consumption from phosphorylation in rat heart
B
Antagonizes calcium oscillations in cardiomyocytes from rat
B
Antagonizes acylcarnitine exchange in myocardial mitochondria from rat
B
Induce apoptosis in promyelocytic leukemia cells from human
B
Antagonizes norepinephrine release from adrenergic nerve terminals in rat atria
B indicates bupivacaine; 2-CP, 2-chloroprocaine; D, dibucaine; L, lidocaine; M, mepivacaine; P, procaine; PA, procainamide; R,
ropivacaine; T, tetracaine.
Page 16 of 19
APPENDIX 2 [14]
y
APPENDIX 3
DRUG
LIGNOCAINE PRILOCAINE BUPIVACAINE LEVOBUPIVACAINE ROPIVACAINE
2
2
8
8
6
Onset
5-10 min
5-10 min
10-15 min
10-15 min
10-15 mins
Duration
without
adrenaline
1-2 hours
1-2 hours
3-12 hours
3-12 hours
3-12 hours
Duration
with
adrenaline
2-4 hours
2-4 hours
4-12 hours
4-12 hours
4-12 hours
Max dose
without
adrenaline
3 mg/kg
6 mg/kg
2 mg/kg
2.5 mg/kg
3 mg / kg
Max dose
with
adrenaline
7 mg/kg
9 mg/kg
2.5 mg/kg
3 mg/kg
4 mg / kg
Relative
potency
Page 17 of 19
REFERENCES 1
X) Weinberg GL, Palmer JW, VadeBoncouer TR, Zuechner MB, Edelman G,
Hoppel CL. Bupivacaine inhibits acylcarnitine exchange in cardiac
mitochondria. Anesthesiology. 2000;92(2):523–528
Y) Bourne E, Wright W, Royse C.A review of local anesthetic cardiotoxicity and
treatment with lipid emulsion.Local Reg Anesth. 2010; 3: 11–19.
z) Candela D, Louart G, Bousquet PJ, et al. Reversal of bupivacaine-induced
cardiac electrophysiologic changes by two lipid emulsions in anesthetized
and mechanically ventilated piglets. Anesth Analg 2010; 110:1473–1479.
Hiller) Hiller DB, Gregorio GD, Ripper R, et al. Epinephrine impairs lipid
resuscitation from bupivacaine overdose: a threshold effect. Anesthesiology
2009;111:498–505.
Mirtallo) Mirtallo J. State of the art review: intravenous fat emulsions: current
applications,safety profile, and clinical implications. Ann Pharmacother 2010;
44: 688–700.
Christensen) Christensen RD. Identifying patients, on the first day of life, at highrisk of developing parenteral nutrition–associated liver disease.J Perinatol
2007; 27: 284–290.
Progesterone) Moller RA, Datta S, Fox J, et al. Effects of progesterone on the
cardiac electrophysiologic action of bupivacaine and lidocaine. Anesthesiology
1992; 76:604–608.
McDon) McDonnell NJ. Cardiopulmonary arrest in pregnancy: two case reports of
successful outcomes in association with perimortem Caesarean delivery. Br J
Anaesth 2009; 103:406–409.
Katz V, Balderston K, DeFreest M. Perimortem cesarean delivery: were our
assumptions correct? Am J Obstet Gynecol 2005; 192:1916–1920; discussion
1920–1921.
Page 18 of 19
REFERENCES 2
1.
2.
Dillane D FB: Local anesthetic systemic toxicity. Can J Anaesth 2010,
57(4):368-380. doi: 310.1007/s12630-12010-19275-12637. Epub 12010 Feb
12612.
Ciechanowicz S, Patil V: Lipid Emulsion for Local Anesthetic Systemic
Toxicity. Anesthesiology Research and Practice 2012, 2012:11.
3.
Agarwal J MA, Jafa S, Wahal R, Kapoor R, Awasthi A Management of
local anaesthetictoxicity. Anaesthesia Update 2011, . 14(2):19-24.
4.
Han SK, Kim JH, Hwang JM: Persistent diplopia after retrobulbar
anesthesia. Journal of cataract and refractive surgery 2004, 30(6):12481253.
5.
Gómez‐Arnau JI, Yangüela J, González A, Andrés Y, García del Valle S, Gili
P, Fernández‐Guisasola J, Arias A: Anaesthesia‐related diplopia after
cataract surgery. British Journal of Anaesthesia 2003, 90(2):189-193.
6.
Perez-Castro R, Patel S, Garavito-Aguilar ZV, Rosenberg A, Recio-Pinto E,
Zhang J, Blanck TJ, Xu F: Cytotoxicity of local anesthetics in human
neuronal cells. Anesthesia and analgesia 2009, 108(3):997-1007.
7.
Zink W, Graf BM, Sinner B, Martin E, Fink RH, Kunst G: Differential effects
of bupivacaine on intracellular Ca2+ regulation: potential mechanisms
of its myotoxicity. Anesthesiology 2002, 97(3):710-716.
8.
Nouette-Gaulain K, Dadure C, Morau D, Pertuiset C, Galbes O, Hayot M,
Mercier J, Sztark F, Rossignol R, Capdevila X: Age-dependent
bupivacaine-induced muscle toxicity during continuous peripheral
nerve block in rats. Anesthesiology 2009, 111(5):1120-1127.
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