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South African Journal Of Regional Anaesthesia LOCAL ANAESTHETIC AGENT TOXICITY
Dr H van Rooyen
Pharmacodynamics of local anaesthetic
either via the lipid phase or through the open pore.
Dissociation via the lipid phase appears to occur 20- 50 times as rapidly as via the channel, but requiresthat the molecule be in the unionised base form.
Local anaesthetic agents reversibly block the action Extracellular protons may bind to the amine portion of potentials responsible for nerve conduction. This the local anaesthetic in the channel and tend to trap it action is demonstrable in any part of the nervous sys- there. The clinical implication of this is that a decrease in pH increases the binding of local anaesthetic mole-cules to Na+ channels, increasing toxic potential.
The Na+ selective transmembrane pore of the chan-nel is presumed to reside in the centre of a nearly Phasic inhibition (Frequency dependent blockade) symmetrical structure formed by the four homologous refers to the phenomenon of increased impulse block- domains of a 300KDa protein complex. A change in ade due to repetitive stimulation of a nerve fibre. This the transmembrane potential towards the threshold is thought to occur because the local anaesthetic mol- value induces conformational changes in the mole- ecule in its charged form gains access to the binding cule, which cause the Na+ channel to open. This gives site only when the Na+ channel is in its open state.
rise to a rapid influx of Na+ with further depolarisation After binding, the channel is then stabilised in the of the cell membrane. After it opens, the Na+ channel inactive state. Because binding therefore takes place inactivates within a few milliseconds due to closure of only during depolarisation and dissociation occurs between action potentials, rapid stimulation of a nervefibre leads to accumulation of inactivated (bound) Local anaesthetic agents produce conduction block- channels at rapid stimulation rates. As mentioned ade by decreasing or preventing the large transient before, in order for the local anaesthetic molecule to increase in the permeability of excitable membranes dissociate from the channel (via the open channel to Na+ that normally is producedby a slight depolarization of themembrane. This seems to occur Local anaesthetic diffusion to site
of action:
anaesthetic molecule with a bind-ing site inside the (open) voltage-gated Na+ channels. Binding ofthe local anaesthetic agent sta-bilises the inactive state of thechannel. This binding site is onlyaccessible from the intracellularside of the cell membrane. In orderto reach this site the delivered(water soluble) cationic acid firstneeds to dissociate into its lipidsoluble nonionised base form. Dissociation of the local anaes-thetic molecule from its bindingsite within the channel may occur South African Journal Of Regional Anaesthesia pore) it should preferably be in its water soluble state ent in breast milk, the concentrations found (40% of - more hydrophobic drugs tend to dissociate slowly serum levels) would not be expected to produce from the pore (dissociation constant for bupivacaine typically up to 2 seconds). Smaller and morehydrophilic drugs dissociate more rapidly, so a higher 2.3 Serum elimination half-lives:
frequency of stimulation is needed with these drugs to Lignocaine: 1.5-2 hours. Active metabolites MEGX = yield frequency-dependent block. A clinical correlate of this is the reduced therapeutic index of the more hydrophobic drugs (e.g. bupivacaine).
Ropivacaine: 1.6-5.5 hours.
Levobupivacaine: 2.06-2.6 hours.
Pharmacokinetics of local anaesthetic
2.4 Attempts at enhancement of local
Absorption from the GI tract is rapid, with peak plas- anaesthetic elimination:
ma levels occurring within 30-60 minutes. There is Diuresis: less than 5-10% of a dose is excreted in significant first-pass hepatic metabolism of amide- the urine as unchanged drug. Although acidifica- type agents. Bioavailability of orally ingested ligno- tion of the urine will enhance the excretion, the contribution to overall elimination is small and therisk outweighs the benefit.
Ester type agents are rapidly metabolized in the plas-ma by pseudocholinesterases, with minimal liver Both haemodialysis and haemofiltration are inef- esterase metabolism. Amide type agents are metabo- lized by hepatic microsomal enzymes. Their elimina- tion is prolonged by liver disease, immaturity, anddecreased hepatic blood flow. Only small amounts of Local anaesthetic toxicity may be classified into sys- either type of drug are excreted unchanged in the Systemic toxicity:
2.1 Blood levels according to administra-
The following additional mechanisms of action may tion site:
The following lists some sites of administration in approximate order of their associated blood levels: Inhibition of voltage gated Ca2+ currents across Intercostal nerve blocks (highest level), the neuronal cell membrane leads to diminished neurotransmitter release, contributing to analge-sia in neuraxial administration. As far as car- diotoxicity is concerned, it has been shown that the sensitivity of myocardial Ca2+ channels to Spinal anaesthesia, on the other hand, requires bupivacaine is comparable to that of the voltage very little drug and is associated with very low Inhibition of K+ channels:Local anaesthetic agents block neuronal K+ 2.2 Reproductive system redistribution:
channels in high concentrations - probably not of Local anaesthetic agents readily cross the placenta.
any clinical significance in therapeutic doses, but Foetal or neonatal poisoning may occur as a result of may be of importance in the development of car- maternal poisoning. Bupivacaine foetal toxicity after maternal administration may be lower than that of lig- Inhibition of mitochondrial oxidative metabolism: nocaine, most probably related to higher maternalprotein binding. Although local anaesthetics are pres- Implicated in cardiac toxicity as well as myotoxicity: South African Journal Of Regional Anaesthesia 'Mitochondrial uncoupling' at low concentra- ing potency. The rank order of toxicity is as follows (low to high toxicity): Prilocaine < Lignocaine < Respiratory inhibition at higher concentrations.
Mepivacaine < Ropivacaine < Levobupivacaine <racemic Bupivacaine < R-Bupivacaine < Etidocaine < Tetracaine. The dissociation time constant for bupiva- caine from sodium channels is approximately 2 sec- G-protein modulation of Ca2+ and K+ chan- onds - this is at least tenfold longer than that of ligno- caine. The pharmacodynamics of lignocaine at the Substance P binding to its neuronal receptor.
sodium receptor are commonly referred to as being Binding of muscarinic agonists to their receptor.
"fast-in-fast-out," in contrast with bupivacaine being"fast-in-slow-out". This timing results in greater car- diac depression by bupivacaine, which is out of pro- portion to its potency at sodium channels. Overdose istherefore more likely to result in cardiovascular col- It is important to note that toxicity of anaesthetics may lapse with bupivacaine than with other agents. For be potentiated in patients with renal or hepatic com- example, the dose needed for cardiovascular collapse promise, respiratory acidosis, pre-existing heart block, divided by the dose needed for convulsions is 3.7 for or heart conditions. Toxicity may be potentiated during bupivacaine compared with 7.1 for lignocaine. When pregnancy, at the extremes of age, or in those with bupivacaine toxicity occurs, it is also more likely to hypoxia. However, the most common cause of local result in ventricular arrhythmias than with other anaesthetic toxicity is inadvertent intravascular injec- agents. Pregnant women appear to be more sensitive tion. In this respect the degree of protein binding a drug exhibits may play a role: It is thought that thehigh degree of protein binding by bupivacaine causes The two most important components of local anaes- free drug levels to suddenly rise disproportionately thetic cardiac toxicity are arrhythmias and contractile when available binding sites become saturated - depression. Peripheral vasodilatation also occurs, underlining the importance of fractionated injection worsening the hypotension. Furthermore, local anaes- thetic overdose is likely to cause seizures, hypoxia, oracidosis, all of which may exacerbate cardiotoxicity.
Systemic toxic reactions to local anaesthetics are The resulting cycle of systemic and myocardial manifested by a progressive spectrum of neurological hypoperfusion, tissue acidosis, and worsening cardiac symptoms as blood levels rise. Initial symptoms sug- performance can lead to failed resuscitation.
gest some form of central nervous system excitationand are often described as a ringing in the ears, a 3.1.1 Manifestation:
metallic taste in the mouth, or a circumoral tingling.
With increasing blood levels of local anaesthetics, The circulatory effects of local anaesthetic agents there is progression to motor twitching in the periph- ery followed by grand mal seizures. These higherblood levels are associated with coma and eventually 3.1.1.1 Vasomotor:
respiratory arrest. At extremely high levels, cardiac Direct effects of local anaesthetic agents on blood arrhythmia or hypotension and cardiovascular col- vessels are highly variable, with some studies show- ing vasoconstriction and others vasodilatation. Thisdiscrepancy may reflect dose-dependent effects as 3.1 Cardiovascular
well as the confounding effects of the sympathetic The most dreaded form of toxicity to local anaesthet- nervous system in the intact animal. In the initial ics is cardiovascular toxicity. There is a positive corre- phase or in mild intoxication, catecholamine release lation between the cardiotoxic potency of a local and vasoconstriction may cause hypertension and anaesthetic agent, its lipid solubility and nerve block- tachycardia. Late hypotension and cardiovascular col-lapse may be due to sympathetic blockade (neuraxial South African Journal Of Regional Anaesthesia block), depression of the medullary vasomotor centre, with progressive widening of the QRS complex, ven- hypoxia, acidosis or vasodilatation.
tricular arrhythmias, electromechanical dissociationand refractory asystole. These differences are thought Myocardial contractility:
to reflect the different binding characteristics of these Local anaesthetic agents produce a dose dependent drugs at the cardiac Na+ channel. Adrenaline used decrease in myocardial contractile force, probably via during resuscitation is more likely to cause tach- interference with myocardial energetics. At higher yarrhythmias in the face of bupivacaine toxicity than doses, they may also act via reduction of intracellular Blockade of Ca2+ channels leads to diminished 3.1.2 Management of cardiac toxicity:
Initial management of cardiac toxicity is according toACLS guidelines. Because hypercapnia, hypoxia and acidosis exacerbate local anaesthetic toxicity, airway management and suppression of seizure activity are Local anaesthetic agents seem to inhibit the func- key therapeutic interventions. Ventilation should not tion of the sarcoplasmic Ca2+ release channel be aimed at hypocapnia, but rather at the normalisa-tion of arterial pH and oxygen delivery. Because of the Arrhythmias:
strong binding of bupivacaine to cardiac receptors, Local anaesthetic agents depress cardiac automatici- resuscitation should be continued for "far longer than ty. Phase 4 depolarisation of pacemaker cells during is usual". It may be worthwhile to plan for cardiopul- diastole is slowed due to Ca2+-channel blockade.
monary bypass early in the course of resuscitation.
Cardiac impulse conduction is slowed due to dimin-ished inward Na+ current. This leads to a prolonged 3.1.2.1 Specific therapy:
PR interval, widened QRS complex and AV block.
Slowed conduction predisposes to unidirectional probably by raising coronary perfusion pressure block and re-entry, which may cause ventriculartachycardia and fibrillation. A CNSmechanism may also contribute to Ionic currents forming pacemaker action potentials (left) and ventricular action potentials (right) in the heart. Note that the initial upstroke of pacemaker potentials is due to calcium flux and the initial upstroke of ventricular action potentials is due to sodium flux. bupivacaine is followed by ventriculararrhythmias, probably via sympatheticnervous system activation.
Therapeutic lignocaine concentrationshave no effect on the QRS duration,although the QT time and AV refracto-ry period may decrease. Lignocaine inprogressively increasing doses leadsto prolongation of the PR time, AVblock (especially in patients withunderlying bundle-branch disease),widening of the QRS complex (appar-ently uncommon) and eventual circu-latory failure and hypotension. Sinusbradycardia is a common manifesta-tion of toxicity. On the other hand,bupivacaine toxicity tends to present South African Journal Of Regional Anaesthesia and thereby facilitating washout, but also bycounteracting the low output state that is central The potential effects of induced hyperglycaemia on to this condition. High doses of adrenaline - in the neurological outcome merit consideration when this order of 2-3 times usual doses - should be used.
technique is used in more severe cases of local Some authors point out that adrenaline may exac- anaesthetic toxicity. Also, it is worth noting that hyper- erbate arrhythmias without increasing cardiac kalaemia potentiates local anaesthetic cardiotoxicity.
output - this may be especially problematic incases of bupivacaine toxicity. Vasopressin may Drugs not to use:
have a theoretical advantage in these circum- Calcium channel blockers: Additive toxicity and increased mortality has been shown in mice.
Arrhythmias are probably best managed with amio- Phenytoin: Increases toxicity due to Na+ channel darone. Although there may be theoretical reasons to use lignocaine in cases of bupivacaine toxicity,this is not consistently supported by studies.
Lipid emulsion: Pre-treatment with lipid emulsionhas been shown to increase the toxic dose of 3.2 Central Nervous System:
bupivacaine, and the use of lipid emulsion during Although local anaesthetics are anticonvulsant at low resuscitation has similarly been shown to improve concentrations (probably mediated by potentiation of outcome. There are two possible mechanisms: inhibitory GABA-ergic neurotransmission - lignocaine Bupivacaine severely impairs transport of fatty 1.5-2 mg/kg has been recommended for the manage- acid molecules in cardiac mitochondria, where ment of refractory status epilepticus), they are convul- they are the dominant fuel for aerobic metabo- sant at toxic concentrations. The proconvulsant lism. Increased concentrations of fatty acids may effects of local anaesthetic agents are additive. A overcome this bupivacaine-induced blockade.
rapid rise in blood concentration leads to CNS mani-festations at lower blood levels than would be evident An artificially induced lipid phase in blood may with slower administration. Hyponatraemia, possibly decrease the effective plasma concentration secondary to SIADH, has been reported after ligno- of lipophilic local anaesthetic molecules.
Propofol: It seems as if propofol reduces ligno-caine- or bupivacaine-induced hypotension inde-pendent of the effects of the lipid carrier. In addi-tion to this, propofol may be useful by:• Aiding in the recovery from tissue hypoxia viaantioxidant effects Insulin/Glucose/K: Insulin treatment (with or with-out Potassium) has been shown to improve out-come of resuscitation in laboratory animals. Thismay be due to two mechanisms:• Insulin increases the amount of K+ enteringcells, which may counteract the bupivacaine-induced inhibition K+ channels, allowing forimproved myocardial repolarisation.
Insulin/Glucose may improve intracellularavailability of alternative substrates in thepresence of Bupivacaine induced inhibition oflipid substrate utilisation. South African Journal Of Regional Anaesthesia 3.2.1.1 Interactions:
Treatment of lignocaine overdose:
Prophylactic administration of benzodiazepines reduce the likelihood of CNS manifestations oftoxicity without affecting that of cardiovascular toxicity, thereby potentially abolishing early warn- Systemic hypercarbia decreases lignocaine b. Oral ingestion: Administer charcoal and seizure threshold, probably via effects on pH as c. Seizures: Administer diazepam, up to 5- Muscle paralysis prevents systemic acidosis and hypoxia, but does not prevent cerebral lactic aci- dosis. This results in further cerebral ion trapping a. Sodium bicarbonate: 0.5-1 mEq/kg IV.
of local anaesthetic agent. Increased blood-brain barrier permeability secondary to ongoing convul- sions may increase CNS uptake even further, chronotropic suppression of the myocardium.
Co-administration of local anaesthetic agents with adrenaline may lead to hypertension with conse- quent lowering of the seizure threshold.
(avoid using other type Ib antiarrhythmic 3.2.1.2 Management of seizures:
Initial control should be attempted with a benzodi- a. Administer normal saline, 2-3 ml/kg every Persistent convulsions should be treated with Phenytoin should be avoided as it may worsen b. If patient is still hypotensive, consider pul- 3.3 Haematological:
i. If low SVR, administer dopamine or nora- Methaemoglobinemia has been reported primarily with prilocaine toxicity (even after use of EMLA ii. If low cardiac output, administer isopro- cream). Lignocaine and benzocaine have also been implicated, although co-administered drugs may have c. If patient has intractable cardiogenic shock, consider intra-aortic balloon pumpassistance or cardiopulmonary bypass 3.4 Allergic reactions:
Amino esters are derivatives of para-aminobenzoic
acid (PABA), which has been associated with acute allergic reactions. Previous studies indicate a 30% the patient is cyanotic or symptomatic, or rate of allergic reactions to procaine, tetracaine, and chloroprocaine. Amino amides are not associated with PABA and do not produce allergic reactions with the a. Consider hemoperfusion in patients with same frequency. However, it has been noted that massive poisonings with circulatory and / preparations of amide anaesthetics may sometimes contain methylparaben, which structurally is similar to PABA and thus may give rise to allergic reactions. South African Journal Of Regional Anaesthesia Local toxicity:
75mg lignocaine was administered. Peculiarly, theincidence can be related to the type of surgery per-formed (knee arthroscopy), outpatient status and 4.1 Neurovascular
patient positioning (lithotomy). Reports of caudaequina syndrome after continuous lignocaine spinal Other than numbness and paraesthesia, which is anaesthesia and the potential concentration-depend- expected in the normal range of anaesthetic applica- ent neurotoxicity of lignocaine have led several tion, very high doses of anaesthetics (e.g. 5% ligno- authors to label TRI as a manifestation of subclinical caine) administered directly onto a desheathed nerve neurotoxicity. On the other hand, concentrations of lig- can produce irreversible conduction block within 5 min- nocaine <40 mM (equivalent to 1%) have been shown utes. This toxicity has been shown to be concentration- not to be neurotoxic to desheathed peripheral nerves dependent between 40 and 80mM (1-2%). The mech- -this argues against a concentration-dependent neu- anism of this neurotoxicity remains uncertain, but is probably related to increased intracellular calcium lev-els. Of the currently available drugs, lignocaine Only 1% of patients treated with hyperbaric bupiva- appears to have the greatest potential for neurotoxicity.
caine 0.5% develop TRI after spinal anaesthesia. TRIhas been reported after both epidural and spinal ropi- With placement of anesthetic inside the perineurium, axonal degeneration and barrier changes areunequivocal and often severe. This is probably due 4.2 Myotoxicity
largely to the violation of the protective perineurial Local anaesthetic myotoxicity was first described in barrier, but pressure and compression may play a role 1959 and has since been associated with high inci- - intra-fascicular injections may result in compressive dences of muscular dysfunction after peri- and retrob- nerve sheath pressures exceeding 600 mmHg. Local ulbar block for ophthalmologic procedures. Recent anaesthetic agents themselves may decrease neural increases in the use of catheter nerve block tech- blood flow: 2% lignocaine can decrease neural blood niques have added further relevance to this problem.
flow by 39%. More substantial decrease is noted All clinically used anaesthetic agents may cause when adrenaline is added. Bupivacaine 0.25% plain skeletal muscle injury and even myonecrosis. This decreases flow 30%, but much less with higher con- toxicity is dose-dependent, and worsens with continu- centrations. Although this is an unlikely primary mech- ous and serial administration. Tetracaine and procaine anism of injury, compromised nerves (e.g., diabetes, are the least, and bupivacaine the most myotoxic chemotherapy) may be more susceptible.
(Bupivacaine is established as an agent used toinduce muscle degeneration in certain animal mod- Transient radicular irritation (TRI) was first reported in els). The clinical presentation is one of localised mus- 1993 as short-lived neurologic symptoms after spinal cle dysfunction, tenderness and swelling. The histo- anaesthesia with 5% lignocaine. The symptoms are logical presentation is that of hypercontracted myofib- described as a continuous bilateral burning radicular rils with degeneration of the sarcoplasmic reticulum pain in the buttocks, thighs, and knees (without sen- and myocyte oedema and necrosis. The structural sory or motor deficit), typically have an abrupt onset elements (basal laminae, blood vessels, neurones, (within 12 to 24 hours), last from 45 minutes to 48 connective tissue) and myoblasts remain intact, allow- hours (rarely up to 5 days), and then completely ing for regeneration of muscle within 4-6 weeks. Co- resolve without intervention or sequelae. Prospective administration of steroids or adrenaline potentiates studies reveal an incidence of 4-33% after lignocaine the myotoxicity and may lead to destruction of other spinal anaesthesia. The incidence of TRI is unrelated tissue elements, thereby predisposing towards per- to either the baricity of the solution administered or the dilution (down to 0.5%), although the addition ofadrenaline may potentiate toxicity. The majority of The mechanism, although incompletely understood, is reported cases have occurred in where more than thought to be via increased levels of intracellular South African Journal Of Regional Anaesthesia Ca2+. Bupivacaine and ropivacaine induce release of References:
Ca2+ from as well as inhibiting reuptake into the sar- Brachial Plexus Blockade: A Comprehensive Review. Fromhttp://www.asra.com/mbp_cd/Brachial_plexus.html coplasmic reticulum, whereas tetracaine only inhibits Chazalon P et al. Ropivacaine-induced Cardiac Arrest after Ca2+ release. Further support of this theory is found Peripheral Nerve Block: Successful Resuscitation. Anesthesiology in the fact that myoblasts (which remain unaffected by Drasner K. Local Anesthetic Neurotoxicity: Clinical Injury and local anaesthetic infiltration) are unable to store large Strategies That May Minimize Risk. Reg Anesth Pain Med 2002; amounts of Ca2+ intracellularly. The effects of local anaesthetic agents on the mitochondria - uncoupling Graf BM et al. Differences in Cardiotoxicity of Bupivacaine andRopivacaine Are the Result of Physicochemical and Stereoselective of oxidative phosphorylation and depletion of ATP - Properties. Anesthesiology June 2002, 96; 6 may ultimately exacerbate the rise in intracellular Groban L. Central Nervous System and Cardiac Effects From Long- Ca2+ levels. Interestingly, local anaesthetic agents Acting Amide Local Anesthetic Toxicity in the Intact Animal Model.
Reg Anesth Pain Med 2003 28;1:3-11 have been proven safe to use in patients who are sus- Haddad LM (Ed.). Clinical Management of Poisoning and Drug Halpern SH, Leighton BL. Misconceptions About NeuraxialAnesthesia. Anesth Clin North Am March 2003, 21;1 The clinical significance of local anaesthetic myotoxi- Hardman JG et al (Ed). Goodman & Gilman's The Pharmacological city is controversial. In spite of unequivocal and repro- Basis of Therapeutics. 9th ed. McGraw-Hill Heavner JE. Cardiac Toxicity of Local Anesthetics in the Intact ducible laboratory evidence of myotoxicity, the clinical Isolated Heart Model: A Review. Anesth Pain Med 2002 27;6:545-555 sequelae of this condition seem to be rare. On the Hodgson PS et al. The Neurotoxicity of Drugs Given Intrathecally.
other hand diplopia after cataract surgery is increas- Hogan Q et al. Local Anesthetic Myotoxicity: A Case and Review.
ingly being recognized as a complication of regional techniques - current data indicates an incidence of Horlocker TT, Wedel DJ. Local Anesthetic Toxicity - Does Product 0.25-0.39%. Bupivacaine seems to be responsible for Labeling Reflect Actual Risk? Reg Anesth Pain Med 2002; 27: 562-567 Horlocker TT. One Hundred Years Later, I Can Still Make Your Heart the vast majority of clinically significant complications.
Stop and Your Legs Weak: The Relationship Between RegionalAnesthesia and Local AnestheticToxicity. Reg Anesth Pain Med 200227;6:543-544 Summary:
Liu SS, McDonald SB. Current Issues in Spinal Anesthesia.
Although the toxicity of local anaesthetic agents is Longnecker DE, Tinker JH, Morgan GE. Principles and Practice of unequivocal and often impressive, it should be kept in mind that these drugs have a long track record of Miller RD (Ed.). Anaesthesia 4th Ed. Churchill Livingstone.
safety when used correctly, and may even confer ben- Mulroy MF. Systemic Toxicity and Cardiotoxicity From LocalAnesthetics: Incidence and Preventive Measures. Reg Anesth Pain efits to the patient beyond their immediately apparent pharmacological actions. All local anaesthetic agents Neal JM. Effects of Epinephrine in Local Anesthetics on the Central should however be assumed to have extreme toxic and Peripheral Nervous Systems: Neurotoxicity and Neural BloodFlow. Reg Anesth Pain Med 2002 27;6: 124-134 potential. In order to prevent complications arising Panni M, Segal S. New local anesthetics: Are they worth the cost? from the use of these agents, the following guidelines Polley LS, Santos AC. Cardiac Arrest Following Regional Anesthesiawith Ropivacaine - Here We Go Again! Anesth 2003; 99: 1253-4 Careful consideration of indications and contra- Pollock JE. Transient Neurologic Symptoms: Etiology, Risk Factors, and Management. Reg Anesth Pain Med 2002 27;6:581-586 Rang HP et al (Eds). Pharmacology 5th Ed. Churchill Livingstone.
Do not administer more local anaesthetic agent Tetzlaff JE. The Pharmacology of Local Anesthetics. Anesth Clin Wald JJ. The Effects of Toxins on Muscle. Neurol Clin Aug 2000, Weinberg GL, Hertz PH, Newman J. Local Anesthetic Cardiac Toxicity can Present as Late-onset Hypotension, Bradycardia, and Asystole (Correspondence). Anesthesiology Aug 2004, 102;2 Weinberg GL. Current Concepts in Resuscitation of Patients With Local Anesthetic Cardiac Toxicity. Reg Anesth Pain Med 200227;6:568-575 Maintain contact with your patient during adminis- Zink W et al. The Acute Myotoxic Effects of Bupivacaine and Ropivacaine After Continuous Peripheral Nerve Blockades. AnesthAnalg 2003; 97: 1173-9 Zink W, Graf BM. Local Anesthetic Myotoxicity. Reg Anes Pain Med2004; 29: 333-340

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