Local Anesthetic Toxicity:Prevention and Treatment

John W. Wolfe, M.D.Staff Anesthesiologist

Indiana University School of MedicineIndianapolis, Indiana

John F. Butterworth, M.D.Chairman, Department of Anesthesia

Indiana University School of MedicineIndianapolis, Indiana

LESSON OBJECTIVESUpon completion of this lesson, the readershould be able to:1. List the signs and symptoms of local

anesthetic toxicity.2. Discuss the concept of "maximum safe

doses of a local anesthetic."3. Describe methods for reducing the risk of

local anesthetic toxicity.4. Explain the treatment of local anes-

thetic-related neurologic symptoms andtoxic side effects.

5. Discuss the effects of epinephrine, cloni-

dine, and the site of injection on peaklocal anesthetic concentrations in blood.

6. Describe the mechanism of local anes-thetic central nervous system toxicity.

7. Identify the risk factors for local anes-thetic toxicity.

8. Plan the treatment of local anesthetic-induced cardiac arrhythmias and cardiacarrest.

9. Describe the mechanism of local anes-thetic cardiovascular toxicity.

10. Explain the dosage and proposed mech-anism of lipid emulsion therapy.

Current Reviews for Nurse Anesthetists designates this lessonfor 1 CE contact hour in Clinical pharmacology/therapeutics.

IntroductionCardiac and central nervous system (CNS) toxic

side effects of local anesthetics are relatively rare butpotentially catastrophic complications of local andregional anesthesia. Fortunately, the likelihood of alocal anesthetic toxic event can be reduced by ad-herence to good technique. These reactions are inmost cases readily treatable. This lesson will reviewthe pharmacology, risk factors, presentation, andtreatment of local anesthetic toxicity.

Mechanism ofLocal Anesthetic Toxicity

Local anesthetics normally produce their desiredeffects on peripheral nerves by binding and inhibit-ing voltage-gated sodium channels in neural cellmembranes. When a sufficient fraction of thesesodium channels are inhibited, the neuron cannotdepolarize and cannot generate or conduct actionpotentials.

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Local anesthetic molecules are weak bases. Atphysiologic pH, they exist in solution as a mixture ofneutral, more lipid-soluble molecules and protonated,relatively lipid-insoluble molecules. In order toapproach the local anesthetic binding site on Nachannels, local anesthetic molecules must penetrateto the inner surface of the plasmalemma. Theuncharged fraction of a local anesthetic molecule mixis therefore considered to be the fraction that mostreadily produces both desired and undesired drugactions. Curiously, once the molecule gains entryinto the cytoplasm, it is the charged form that hasgreater potency. The different properties of the lipid-soluble and lipid-insoluble fractions are importantwhen one considers treatments for local anesthetictoxicity.

There are three principal routes for entryof local anesthetic into the plasma: directinjection into an artery or vein, absorptionfrom a depot dose in other tissues, andtranscutaneous or transmucosal absorp-tion.

In the plasma, all local anesthetics are bound toproteins to varying degrees, primarily to aracidglycoprotein (AAG) and albumin. Plasma proteinlevels are affected by disease states and age. Thelong-duration local anesthetics (bupivacaine andropivacaine) are bound by plasma proteins to agreater extent than the less potent, shorter durationlocal anesthetics. Bupivacaine is approximately 95%protein-bound. Intermediate-duration local anes-thetics (lidocaine and mepivacaine) have a smallerprotein-bound fraction (60-70%). Protein bindinghelps to reduce the likelihood that local anestheticsin blood will enter brain or cardiac tissue causingeither CNS or cardiac toxicity.

Local anesthetics may bind a wide variety ofchannels and enzymes in cardiac muscle and in theCNS, and increased blood concentrations of localanesthetics can cause toxic effects in these tissues.Possible mechanisms by which local anesthetics canproduce cardiovascular collapse include depression ofcardiac contractility, potentiation of cardiac arrhyth-mias, and peripheral vasodilation. The balance of

these effects likely varies among local anestheticagents. Lidocaine tends to produce vasodilation andnegative inotropy while rarely producing arrhyth-mias. In contrast, bupivacaine has a greater ten-dency to produce ventricular arrhythmias in additionto vasodilation and negative inotropy.

For purposes of this lesson, we have made noassumptions as to the mechanism by which localanesthetics actually produce either CNS or cardio-vascular toxicity. It is possible that these toxic sideeffects occur through binding to sodium channels; itis equally possible that another mechanism is oper-ative.

Routes for Entry ofLocal Anesthetic into the

Systemic Circulation

There are three principal routes for entry of localanesthetic into the blood: direct injection into anartery or vein, absorption from a depot dose in othertissues, and transcutaneous or transmucosal absorp-tion.

Intravascular InjectionIntravascular injection of local anesthetic agents

is possible with most regional anesthetic techniquesdue to the proximity of vascular structures to ner-vous tissue. For example, accidental injection oflocal anesthetic into the epidural venous plexus canoccur when dosing an epidural catheter, and injec-tion into the femoral artery or vein can occur duringan attempted femoral nerve block.

Injection into an artery feeding the brain mustbe considered when performing regional anestheticsin the neck, such as interscalene brachial plexusblocks. With accidental injection of local anestheticinto a carotid or vertebral artery, a bolus dose of localanesthetic at a relatively high plasma concentra-tion is delivered directly to the brain. In this case,one should expect rapid onset of CNS toxic sideeffects, with rapid onset of seizures after even a verysmall intravascular injection. Fortunately, due tothe typically small dose of local anesthetic injected,these seizures are generally short-lived and usuallynot accompanied by cardiac toxicity.

Slower Absorption Faster AbsorptionSubcutaneous Sciatic Brachial plexus Epidural Caudal Intercostal Trachea! Intravenous

Figure 1. Relative Absorption Rates of Local Anesthetic at Various Locations

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Table 1Factors Increasing Risk

of Local Anesthetic Toxicity

Administration in a site with rapidabsorptionYoung ageLarge total dose of local anestheticRenal dysfunctionHepatic dysfunctionHeart failurePregnancy

Absorption from TissuesWhen local anesthetic is injected into perineural

connective tissue (as in a peripheral nerve block) orthe epidural space, the nerve-blocking action isterminated by gradual absorption from the nerveinto the systemic circulation. Local anestheticmetabolism has almost no effect on the duration ofnerve blocks. Injecting a given dose of local anes-thetic into highly vascular tissue will lead to greaterplasma drug concentrations than placing the samedose of local anesthetic into a poorly vascularizedsite. Epinephrine is effective in retarding the rate ofabsorption of local anesthetic and reducing peakplasma levels of local anesthetic. The effect ofclonidine is less clear, with some studies showingincreased plasma local anesthetic concentrationswhen clonidine is included in local anestheticsolutions. Figure 1 shows the relative absorptionrates for local anesthetics after injection into varioussites.

Tumescent liposuction techniques present ascenario in which large amounts of local anestheticsolution may be absorbed into the systemic circu-lation in an unpredictable manner. Typically, dilutelidocaine with epinephrine is injected through theliposuction cannula. Dangerously elevated plasmalidocaine levels have been reported when large vol-umes of injectate are used.

Transcutaneous and Transmucosal AbsorptionLocal anesthetics can be absorbed across cutan-

eous and mucosal surfaces, most commonly in theoral, nasal, and tracheo-bronchial mucosa. Topicallocal anesthetic formulations may contain concen-trated local anesthetic and introduce the possibilityof delivering many milligrams of drug in a smallvolume.

Toxic blood concentrations are possible followingtranscutaneous absorption of local anesthetic creamsor gels, particularly in small children. There havebeen several deaths reported after patients appliedlarge amounts of topical local anesthetic products toprovide anesthesia for hair removal procedures.

Risk Factors for LocalAnesthetic Toxicity

(see Table 1)

Route of AdministrationThe location of local anesthetic injection affects

its absorption rate and peak plasma concentration.The local anesthetic dose may need to be reducedwhen it is placed into an area with especially rapidabsorption, such as the airway or in intercostal nerveblocks, as compared to sites with relatively slowabsorption, such as subcutaneous injections or sciaticnerve blocks.

Young AgeInfants, particularly those aged 0-3 months,

have reduced concentrations of plasma proteins towhich local anesthetics bind, such as AAG. Thisleads to greater peak levels of free (unbound) localanesthetic after single injections, such as caudal epi-dural blocks. The unbound form is largely respon-sible for toxic side effects. Infants also have a re-duced capacity to metabolize local anesthetic drugs,with lower plasma clearance rates than adults Thismay lead to greater plasma levels when continuousinfusions of local anesthetics are given. Due to thesefactors, both bolus doses and infusion rates of localanesthetics should be reduced in infants.

Local anesthetic toxicity symptoms arecaused by the free fraction of the localanesthetic drug (the fraction not bound toplasma proteins). Any condition that re-duces plasma protein levels may increasea patient's risk of local anesthetic toxicity.

Total Dose of Local Anesthetic AdministeredAll other factors being equal, administering lar-

ger doses of local anesthetic will lead to increasedplasma concentrations. Patient size should be con-sidered when determining a local anesthetic dose. Ofnote, it is the product of the concentration and thevolume of the local anesthetic solution that isimportant, not either in isolation; plasma levels oflocal anesthetic correlate with the total mass of druggiven. For example, in most cases 20 ml of a 0.25%ropivacaine solution and 10 ml of a 0.5% ropivacainesolution will produce the same peak plasma concen-tration.

Presence of EpinephrineAddition of epinephrine to local anesthetic solu-

tions will normally reduce the rate of absorptionand peak plasma levels. Epinephrine 1:400,000 to1:200,000 (2.5-5 fig/ml) is as effective as more con-centrated solutions, while having a reduced riskof epinephrine side effects such as hypertension,tachycardia, and arrhythmias. Less data exist on

Curr Rev Nurs Anesth 34(2):13-24, 2011 17

the effect of clonidine on local anesthetic absorption,and some studies suggest that clonidine may in-crease rather than decrease peak plasma levels oflocal anesthetics.

Renal DysfunctionPatients with uremia have a hyperdynamic cir-

culatory state, and they have a more rapid absorp-tion of local anesthetic, with higher peak plasmalevels than in non-uremic patients. Many authorshave assumed that these two are causally related.Partially offsetting this effect, uremic patients havegreater levels of AAG than non-uremic patients. TheAAG tends to bind local anesthetic in the plasma,reducing the concentration of free drug. It hasbeen recommended that a dose reduction of 10-20% be applied when administering regionalanesthetics to patients with renal dysfunction.

Liver DysfunctionWhile mild hepatic dysfunction appears to have

a minimal effect on local anesthetic levels, patientswith end-stage liver dysfunction (ESLD) may havesignificantly reduced hepatic clearance rates for localanesthetics. In ESLD, patients have an increasedvolume of distribution for local anesthetics. This,plus the continued presence of AAG in the plasmaeven in ESLD, leads to a recommendation thatnormal doses of local anesthetic may be used forsingle-dose techniques in patients with liver dys-function.

Continuous infusions of local anesthetics, how-ever, must be significantly reduced in patients withhepatic dysfunction due to their lower rate of clear-ance of these drugs. Dose reductions of 10-50% havebeen suggested based on the severity of the hepaticdysfunction.

The addition of epinephrine to local anes-thetic solutions will generally slow therate of absorption and reduce peak localanesthetic concentrations in blood.

Heart FailurePatients with mild, well-controlled heart failure

may not require any reduction in local anestheticdosing. In patients with severe heart failure, how-ever, clearance of local anesthetic drugs may besubstantially reduced due to decreased hepatic bloodflow and clearance.

PregnancyPregnant patients have increased sensitivity to

local anesthetics, allowing dose reductions. Theyalso have a reduced degree of protein binding of localanesthetics. Because of the increased sensitivity andhigher risk of toxic effects, local anesthetic dosesshould be reduced in pregnant patients. Otherfactors, including the reduced spinal CSF volume in

Table 2Early and Late Signs and Symptoms

of Local Anesthetic CNS Toxicity

Early• Perioral or tongue numbness or

tinglingAltered or metallic taste sensationLightheadedness or vertigoAnxiety or panicConfusionSomnolence

Late• Seizure activity (generally tonic-

clonic)• Depressed level of consciousness

or coma• Respiratory depression or arrest

,

pregnancy, lead to an exaggerated spread of spinaland epidural local anesthetics.

Signs and Symptoms ofLocal Anesthetic Toxicity

CNS Signs and SymptomsAfter an accidental intravenous injection, local

anesthetics produce signs and symptoms of CNStoxicity at lower doses and earlier than signs andsymptoms of cardiovascular toxicity. However, thelonger-acting local anesthetics (particularly bupiva-caine) may produce toxicity in the CNS and myo-cardium simultaneously, and there are even reportsof cardiovascular toxicity without any CNS sideeffects. One should also keep in mind that drugscommonly given for sedation (e.g., midazolam orpropofol) may increase the seizure threshold.

The effects of elevated systemic levels of localanesthetics are generally divided into early and latesigns and symptoms, as shown in Table 2.

Cardiovascular Signs and SymptomsThere is evidence from animal studies that

bupivacaine and lidocaine cardiotoxicity may takedifferent forms. Lidocaine tends to decrease myo-cardial contractility and cause peripheral vasodila-tion, leading to hypotension as a prominent sign oflidocaine toxicity. In animal studies, animals re-ceiving lidocaine to the point of cardiovascular col-lapse will almost never demonstrate cardiacarrhythmias. In contrast, bupivacaine tends to pro-duce aberrant conduction and arrhythmias (inaddition to producing vasodilation and myocardialdepression) leading to cardiac arrest.

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In general, cardiac signs of local anesthetic in-toxication include:• Transient hypertension and tachycardia (espec-

ially if epinephrine is present)• Hypotension• Bradycardia• Cardiac arrhythmias, including premature ven-

tricular contractions, ventricular tachycardia,ventricular fibrillation, pulseless electrical ac-tivity, and cardiac arrest.

Techniques for Reducingthe Likelihood of Injury from

Local Anesthetic Toxicity(see Table 3)

Basic PreparationsWhenever one administers local anesthetic to a

patient in doses sufficient to produce toxicity, oneshould apply appropriate monitors (pulse oximetryand non-invasive blood pressure at a minimum)and be certain that emergency resuscitation drugsand equipment are available. The latter shouldinclude airway management devices, an electricaldefibrillator, and a lipid emulsion solution.

The long-acting local anesthetics (partic-ularly bupivacaine) may produce toxicityin the CNS and myocardium simultan-eously.

Use of Lowest Effective DosesThe lowest practical dose or volume of local

anesthetic solution that will produce the intendedtherapeutic effect should be used. In patients withmedical conditions that predispose them to localanesthetic toxicity, one should choose the peripheralnerve block locations and techniques that permitreduced doses of local anesthetic. For example,studies suggest that ultrasound guidance permitsthe use of significantly lower doses of local anestheticfor supraclavicular blocks compared with nervestimulator-guided axillary blocks.

Ultrasound ImagingThe use of ultrasound guidance for peripheral

nerve blocks may reduce the risk of local anesthetictoxicity in several ways. As mentioned above, theuse of ultrasound guidance may allow the use oflower volumes of local anesthetic solutions whilemaintaining acceptable surgical anesthesia. Unlikenerve stimulator or landmark techniques, the nerveblock needle is visualized during positioning andinjection, potentially reducing the risk of accidentalvascular puncture and potentially reducing thevolume needed to detect an accidental intravascularinjection.

Fractionated Doses with Multiple AspirationsNerve block needles and epidural catheters can

move, and an initially well-positioned needle orcatheter may become intravascular. Doses of localanesthetic should be divided into aliquots s 5 ml,with aspiration between injections. Always observethe patient's condition and vital signs duringinjection because negative aspiration for blood doesnot guarantee that local anesthetic is not entering avein. This is especially important if a small gaugeneedle is utilized.

Slow Injection SpeedFast, forceful injection of local anesthetic may

increase the risk of local anesthetic channeling intoveins or other vascular structures. It also mayincrease the risk of pressure injuries to nervesduring peripheral nerve blocks. We normally injectlocal anesthetic no faster than 5 mL at a time andwill usually not administer more than three suchincrements per minute.

Use of Test DosesAccurate placement of a needle in the epidural

space or perineurally does not guarantee that acatheter passed through it will not enter a vascularstructure. Dilute epinephrine (2.5 to 5 ng/mL) maybe used as a marker for intravascular injection. Testdoses of medication (generally containing epine-phrine) should be given when initiating use of anepidural or nerve block catheter and should berepeated if there is any indication that the catheterposition may have changed.

Table 3Techniques for Reducing

Local Anesthetic Toxicity Risk

Have appropriate monitors andresuscitation equipment availablewhenever regional anesthetics areplacedUse the lowest effective dose toachieve the desired anestheticendpointUse ultrasound guidance when itwill facilitate the use of lowerdoses of local anestheticInject local anesthetic slowly,with frequent aspirationsUse test doses to verify placementof epidural and nerve blockcathetersAvoid redosing of local anestheticswhenever possible

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Avoidance of Repeated DosingWhen repeating nerve block injections (e.g., after

a failed block) over a short time interval, one must beaware of the cumulative dose of local anesthetic thathas been administered.

Treatment of SystemicLocal Anesthetic Toxicity

(see Tables 4 and 5)

Treatment for systemic local anesthetic toxicityshould be guided by the form of toxicity the patientis experiencing (CNS vs. cardiovascular vs. allergy)and the local anesthetic agent used (bupivacaineand related drugs appear to require a differentapproach to cardiac resuscitation than the lesspotent local anesthetics). In general, milder symp-toms should be treated with more conservativeactions. Nevertheless, mild CNS symptoms mayrapidly progress into local anesthetic cardiotoxicitywith arrhythmias and cardiac arrest, and one shouldfrequently re-evaluate whether more aggressivetherapies are required.

Table 4Treatments for

Local Anesthetic Toxicity

• Mild neurologic symptoms (tinnitus,lightheadedness, confusion) may betreated with observation andreassurance if they are expected tobe brief in duration.

• Local anesthetic-induced seizuresshould be treated with small dosesof benzodiazepines, barbiturates,or propofol. Phenytoin andphosphenytoin should be avoided.

• When treating local anesthetic-induced arrhythmias, lidocaine,beta blockers, and calcium channelblockers should be omitted.

• When local anesthetic cardiotoxicityhas been caused by bupivacaine,levobupivacaine, or ropivacaine,doses of epinephrine and vaso-pressin should be reduced duringresuscitation.

• Lipid emulsion therapy should beinitiated as soon as possible in casesof local anesthetic cardiotoxicity.

• Cardiopulmonary bypass should beconsidered as a treatment of lastresort when other therapies havefailed.

Treatment of Local Anesthetic CNS ToxicityIf a patient exhibits mild-to-moderate symptoms

and signs of local anesthetic toxicity (e.g., tinnitus,lightheadedness, tremulousness, myoclonic jerks, orconfusion) without seizure activity or signs of cardiactoxicity, it may be appropriate to provide conserva-tive treatment in the form of reassurance and mildsedation and anxiolysis with benzodiazepines. Aconservative approach is most appropriate withtoxicity symptoms due to intermediate-duration localanesthetics (lidocaine, mepivacaine), and when thesymptoms are expected to be brief and of limitedseverity, such as occurs commonly after release of aBier block.

When the CNS symptoms and signs include lossof consciousness or seizures, standard resuscitationmeasures should begin including control of theairway and breathing. Medications that are usefulfor treatment of local anesthetic-induced seizuresinclude benzodiazepines, barbiturates, and propofol.Small doses of these drugs are recommended (e.g.,midazolam 2-4 mg, propofol 0.5-1 mg/kg). Propofoldoses in particular should be kept low due to propo-fol's cardiodepressant activity, which may worsenany subsequent local anesthetic cardiotoxicity.Phenytoin and fosphenytoin have generally beenavoided in the treatment of local anesthetic toxicitybecause they share the sodium channel blockingactions of local anesthetics and may potentiate theirtoxicity.

Lidocaine (and related agents with mod-erate potency and duration) tends to de-crease myocardial contractility and causeperipheral vasodilation, leading to hypo-tension as a prominent sign of lidocainetoxicity. In contrast, bupivacaine willoften produce aberrant conduction andarrhythmias leading to cardiac arrest.

Treatment of Local Anesthetic Cardiac Toxi-city: Antiarrhythmics

If unexplained hypotension, bradycardia, orarrhythmias are detected, treatment for suspectedlocal anesthetic cardiac toxicity should begin withoutdelay. Resuscitation of a patient with local anes-thetic-induced cardiovascular collapse can requireprolonged and extensive resuscitative efforts, par-ticularly with bupivacaine-induced toxicity, and mayprove unsuccessful. Treatment may begin withstandard advanced cardiac life support (ACLS)methods, but we recommend some minor changes tothe standard protocols.

We omit lidocaine from resuscitation of patientswith local anesthetic-induced arrhythmias due to itspotential to produce an additive effect with the"intoxicating" local anesthetic agent. While wesuspect that amiodarone may be a better choice fortreatment of ventricular arrhythmias, conclusivedata are lacking.

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Table 5Recommended Treatment of Severe Local Anesthetic Toxicity

1. Call for help. Initiate a rapid response system ("Code Blue"), if available and adequateassistance cannot otherwise be obtained.

2. Start ACLS treatment:a. Airway + Breathing: Administer 100% oxygen and assure adequate ventilation. Place

advanced airway devices, if appropriate, based on the patient and the circumstances.b. Circulation: Assess blood pressure, heart rate, and cardiac rhythm. Start chest compressions

if indicated.c. Do not administer lidocaine, calcium channel blockers, or beta-blockers.d. If the local anesthetic is bupivacaine, levobupivacaine, ropivacaine, tetracaine, etidocaine, or

cocaine: administer epinephrine (and/or vasopressin) incrementally, in "just sufficient" doses.*e. If the local anesthetic is lidocaine, mepivacaine, or related agents: epinephrine and vasopressin

may be administered in a standard resuscitative fashion with less concern about epinephrine(or vasopressin) interactions with the local anesthetic.*

3. Treat seizures:a. Benzodiazepines are preferred.b. Avoid phenytoin.c. Avoid propofol in patients showing signs of cardiotoxicity.

4. Start lipid emulsion therapy as soon as it is feasible:a. Use a 20% lipid emulsion (such as Intralipid™).b. DO NOT USE PROPOFOL IN PLACE OF LIPID EMULSION.c. Give a bolus dose of 1.5 ml/kg IV over one minute (-100 ml for adult patients).d. When the bolus dose is complete, start an infusion of 0.25 ml/kg/min (-20 ml/min for adult

patients).e. Administer up to two additional bolus doses for continued severe cardiovascular symptoms

(severe hypotension, ventricular arrhythmias).f. Increase the infusion rate to 0.5 ml/kg/min if hypotension persists.g. The lipid infusion should be continued for at least 10 minutes after the cardiac rhythm and

circulation have stabilized.5. If the lipid emulsion therapy fails, contact the nearest facility with cardiopulmonary

bypass capability, and prepare the patient for emergent bypass.

*These recommendations are somewhat speculative. Further research should determine their appropriateness.

_

Local anesthetic cardiac toxicity will often in-clude depressed contractility. One should avoid ad-ministering other negative inotropes in this circum-stance.

Treatment of Local Anesthetic Cardiotoxicity:Epinephrine and/or Vasopressin

Recent animal studies indicate that in cases ofbupivacaine cardiotoxicity, high-dose epinephrinemay exacerbate resuscitation efforts and worsenoutcomes. Based on the available animal and humandata we recommend that epinephrine be admin-istered incrementally (even in resuscitation) startingwith 1 ng/kg and basing additional doses on thepatient's response, rather than immediately giving10-15 M-g/kg as a bolus.

Whether vasopressin should be used routinely incombination with epinephrine (as some animalresults would suggest) or avoided completely due toa propensity for producing pulmonary edema (as itdoes in rodents) remains highly controversial. We

recommend that if vasopressin is used, it should bedosed incrementally rather than as a single largebolus.

Local anesthetic injections should alwaysbe fractionated and frequent aspirationsfor blood should be performed duringinjection. Test doses should always begiven prior to initiating use of an epiduralor peripheral nerve catheter.

Treatment of Local Anesthetic Cardiotoxicity:Lipid Emulsion

Infusion of a 20% lipid emulsion solution (suchas Intralipid™) appears to be a surprisingly effectivetreatment for severe local anesthetic cardiotoxicity.Multiple case reports and animal studies indicate theefficacy of this treatment and its apparent lack ofnoxious side effects. The evidence supporting lipidemulsion therapy is still being gathered, and animal

Curr Rev Nurs Anesth 34(2):13-24, 2011 21

studies and case reports have used a variety of lipiddoses. The regimen described below has been widelyreported, and is based on discussions with inves-tigators and clinicians who have used lipid success-fully for cardiac toxicity. Boluses and short-terminfusions of 20% lipid emulsion appear to havealmost no important side effects. In the setting oflocal anesthetic toxicity, the benefits of fairly liberallipid emulsion dosing will likely outweigh any risksor side effects.

The mechanism by which 20% lipid emulsionnegates local anesthetic toxicity is not clear. Mostlikely, microscopic lipid micelles provide a largelipid-rich component in the plasma. Local anestheticmolecules bind these lipid micelles, and the micelleslikely act as a "lipid sink", effectively sequesteringthe active drug from the circulation. The local anes-thetic drug is then gradually removed from the bloodstream and metabolized as the lipid micelles arebroken down by the liver.

Administration of propofol will NOT providesufficient lipid to assist in resuscitation from localanesthetic-induced cardiac toxicity. In order to ad-minister sufficient lipid, cardiotoxic doses of propofolwould be required.

Infusion of a 20% lipid emulsion solution(such as Intralipid™) appears to be aneffective treatment for severe local anes-thetic cardiotoxicity.

Treatment of Local Anesthetic Cardiotoxicity:Cardiopulmonary Bypass

The arrhythmias, hypotension, and cardiaccollapse associated with bupivacaine (and associatedlong-acting local anesthetic agents) toxicity havebeen reported to be quite refractory to standardACLS resuscitation methods. Resuscitation effortsmay be prolonged, with some patients potentially notresponding to standard drugs and therapies. Whenall other methods have failed, several survivingpatients have been emergently placed on cardio-pulmonary bypass for Cardiopulmonary support andto allow time for clearance of a sufficient quantity ofthe local anesthetic drugs from target tissues topermit survival. There are case reports of successfulresuscitations using Cardiopulmonary bypass afterall other therapies have failed.

SummaryLocal anesthetic toxicity can be a catastrophic

complication of regional anesthesia. It may presentwith CNS symptoms, cardiovascular symptoms, orboth. Patients' size, age, and comorbidities may in-crease their risk of local anesthetic toxic symptoms.Techniques for reducing the risk of injury from localanesthetic toxicity include having appropriate moni-

tors and resuscitation equipment available, using thelowest effective dose of local anesthetic, injectingslowly and with multiple aspirations, and using testdoses prior to dosing epidural and peripheral nervecatheters. Treatment of CNS toxicity includessuppression of seizures and supportive care.Treatment of cardiovascular symptoms consists ofACLS techniques (with omission of lidocaine, calciumchannel blockers, beta-blockers, and consideration ofreduced doses of epinephrine and vasopressin). Lipidemulsion therapy should be initiated as rapidlyas possible. In cases of refractory cardiovascularcollapse, Cardiopulmonary bypass should be insti-tuted.

References

Butterworth, JF 4th: Models and mechanisms of localanesthetic cardiac toxicity: a review. Regional Anes-thesia & Pain Medicine 35(2):167-76, 2010. (Review ofthe possible mechanisms of local anesthetic toxicity)

Di Gregorio G, Neal J, Rosenquist R, Weinberg, GL:Clinical presentation of local anesthetic systemictoxicity: a review of published cases, 1979 to 2009.Regional Anesthesia & Pain Medicine 35(2):181-87,2010. (Retrospective review of reported signs andsymptoms of local anesthetic toxicity)

Drasner K: Local anesthetic systemic toxicity: ahistorical perspective. Regional Anesthesia & PainMedicine 35(2):181-87, 2010. (Interesting review ofhistory of local anesthetic toxicity and treatments)

Killer DB, Gregorio GD, Ripper R, Kelly K, Massad M,Edelman L, Edelman G, Feinstein DL, Weinberg GL:Epinephrine impairs lipid resuscitation from bupiv-acaine overdose: a threshold effect. Anesthesiology 111(3):498-505, 2009. (Animal study investigating full-dose versus low-dose epinephrine with lipid emulsionin severe bupivacaine cardiotoxicity)

Neal JM, Bernards CM, Butterworth JF 4th, Di Gre-gorio G, Drasner K, Hejtmanek MR, Mulroy MF,Rosenquist RW, Weinberg GL: ASRA Practice Advisoryon Local Anesthetic Systemic Toxicity. Regional Anes-thesia & Pain Medicine 35(2): 152-61, 2010. (Evidence-based review article on the subject of local anesthetictoxicity)

Rosenberg PH, Veering BT, Urmey WF: Maximumrecommended doses of local anesthetics: a multifac-torial concept. Regional Anesthesia & Pain Medicine29(6):564-75, 2004. (Review article discussing thepharmacokinetics of local anesthetic peak plasmalevels)

Weinberg GL: http://lipidrescue.org (Dr. Guy Wein-berg's website focusing on lipid emulsion therapy forlocal anesthetic toxicity, accessed on 26 May 2010)

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