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Local AnestheticsLocal Anesthetics

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Brendan Astley MDBrendan Astley MDOctober 2008October 2008



Local AnestheticsLocal Anesthetics

Used at multiple sites throughout the body:Used at multiple sites throughout the body:

EpiduralEpidural

SpinalSpinal Peripheral nerve blocksPeripheral nerve blocks

IV (Bier Block)IV (Bier Block)

Skin sites locallySkin sites locally



Amides and EstersAmides and Esters

ChloroprocaineChloroprocaine

(Nesacaine)(Nesacaine)

Cocaine (crack)Cocaine (crack)

ProcaineProcaine

Tetracaine (Pontocaine)Tetracaine (Pontocaine)

Lidocaine (Xylocaine)Lidocaine (Xylocaine)

Bupivacaine (Marcaine)Bupivacaine (Marcaine)

Etidocaine (Duranest)Etidocaine (Duranest) MepivacaineMepivacaine

(Carbocaine)(Carbocaine)

Prilocaine (Citanest)Prilocaine (Citanest) RopivacaineRopivacaine



Mechanism of ActionMechanism of Action

Local anesthetics work in general by binding toLocal anesthetics work in general by binding to

sodium channel receptors inside the cell and therebysodium channel receptors inside the cell and thereby

inhibiting action potentials in a given axon. Theyinhibiting action potentials in a given axon. They

work the best when the axon is firing.work the best when the axon is firing.

The Cell membrane consists of ion pumps, mostThe Cell membrane consists of ion pumps, most

notably the Na/K pump that create a negative 70mVnotably the Na/K pump that create a negative 70mV

resting potential by pumping 2 K+ intracellular for resting potential by pumping 2 K+ intracellular for

every 3 Na+ it pumps extracellular.every 3 Na+ it pumps extracellular.



Mechanism of Action (cont¶d)Mechanism of Action (cont¶d)

If the resting potential encounters the proper If the resting potential encounters the proper chemical, mechanical or electrical stimuli to reducechemical, mechanical or electrical stimuli to reducethe membrane potential to less thanthe membrane potential to less than --55 mV then an55 mV then an

action potential is produced that allows the influx of action potential is produced that allows the influx of sodium ions. LA act here to block the Na influx.sodium ions. LA act here to block the Na influx.

The influx allows the membrane potential to further The influx allows the membrane potential to further increase to +35mV temporarily.increase to +35mV temporarily.

Sodium and potassium channels along with theSodium and potassium channels along with thesodium/potassium pump eventually returning a givensodium/potassium pump eventually returning a givenaxon back to it¶s resting membrane potential after anaxon back to it¶s resting membrane potential after anaction potential.action potential.



Mechanism of ActionMechanism of Action

Benzocaine«.Benzocaine«.

Does not exist in a charged form how does itDoes not exist in a charged form how does it

work?work?

Most likely by expanding the lipid membrane of Most likely by expanding the lipid membrane of

the axon and therefore inhibiting the transportthe axon and therefore inhibiting the transport

mechanisms of Na and K ions.mechanisms of Na and K ions.



General StructureGeneral Structure

A lipophilic group«usually a benzene ringA lipophilic group«usually a benzene ring

A Hydrophilic group«usually a tertiary amineA Hydrophilic group«usually a tertiary amine

These are connected by an intermediate chainThese are connected by an intermediate chainthat includes an ester or amide linkagethat includes an ester or amide linkage

LAs are weak basesLAs are weak bases



Lipid solubilityLipid solubility

Most lipid soluble:Most lipid soluble: TetracaineTetracaine

BupivicaineBupivicaine

RopivacaineRopivacaine

EtidocaineEtidocaine

Increased lipid solubility also equals greater potency andIncreased lipid solubility also equals greater potency andlonger duration of action.longer duration of action. Why?Why?

Because it has less of a chance of being cleared by blood flowBecause it has less of a chance of being cleared by blood flow

Decreased lipid solubility means a faster onset of action.Decreased lipid solubility means a faster onset of action.

What else effects onset of action???What else effects onset of action???



pKapKa

Local anesthetics with a pKa closest to physiologicalLocal anesthetics with a pKa closest to physiological

pH will have a higher concentration of nonionized pH will have a higher concentration of nonionized

base that can pass through the nerve cell membrane, base that can pass through the nerve cell membrane,

and generally a more rapid onset.and generally a more rapid onset.

The charged cation form more avidly binds to theThe charged cation form more avidly binds to the

Na+ channel receptors inside the cell membrane. Na+ channel receptors inside the cell membrane.

pKa > 7.4 more cations, pKa < 7.4 more anions pKa > 7.4 more cations, pKa < 7.4 more anions



Not all Axons are equalNot all Axons are equal

AAKK-- motor (muscle spindle) smaller diameter motor (muscle spindle) smaller diameter

33--6mm, slower conduction 156mm, slower conduction 15--30m/s same LA30m/s same LA

sensitivity as type Ia and Ib fiberssensitivity as type Ia and Ib fibers

%H%H-- Type III fibers, pain, cold temperature andType III fibers, pain, cold temperature and

touch, smaller diameter 2touch, smaller diameter 2--5mm, 125mm, 12--30m/s,30m/s,

more sensitive to LA than the above fibers andmore sensitive to LA than the above fibers and

myelinated.myelinated.



Not all Axons are equalNot all Axons are equal

B fibersB fibers-- Preganglionic autonomic fibers, <3mm diameter, 3Preganglionic autonomic fibers, <3mm diameter, 3--14m/s conduction speed and very sensitive to LA. Some14m/s conduction speed and very sensitive to LA. Somemyelination.myelination.

C fibersC fibers-- Type IV fibers in the dorsal root, pain warm and coldType IV fibers in the dorsal root, pain warm and cold

temp. and touch, .4temp. and touch, .4--1.2mm in diameter, slow conduction again1.2mm in diameter, slow conduction againat .5at .5--2m/s, very sensitive to LA, not myelinated.2m/s, very sensitive to LA, not myelinated.

C fibersC fibers-- Postganglionic sympathetic fibers, smaller diametersPostganglionic sympathetic fibers, smaller diametersat .3at .3--1.3mm, slow conduction at .71.3mm, slow conduction at .7--2.3m/s, very sensitive to2.3m/s, very sensitive toLA and no myelination.LA and no myelination.

In general this all means that the autonomic nerves are blockedIn general this all means that the autonomic nerves are blocked before the sensory nerves which are blocked before the motor before the sensory nerves which are blocked before the motor nerves.nerves.



AMIDESAMIDES

Bupivacaine, Etidocaine and RopivacaineBupivacaine, Etidocaine and Ropivacaine--

very high potency and lipid solubility, veryvery high potency and lipid solubility, very

long duration and protein binding also.long duration and protein binding also.

Lidocaine, Prilocaine and MepivacaineLidocaine, Prilocaine and Mepivacaine-- havehave

intermediate potency and lipid solubility andintermediate potency and lipid solubility and

intermediate duration of action and proteinintermediate duration of action and protein

binding. binding.



ESTERSESTERS

Chloroprocaine and ProcaineChloroprocaine and Procaine-- have lowhave low potency and lipid solubility and also low potency and lipid solubility and also lowduration and protein binding.duration and protein binding.

CocaineCocaine-- has intermediate potency andhas intermediate potency andsolubility and intermediate duration andsolubility and intermediate duration and protein binding protein binding

TetracaineTetracaine-- has high potency and lipidhas high potency and lipidsolubility along with a long duration of actionsolubility along with a long duration of actionand high protein bindingand high protein binding



Plasma protein bindingPlasma protein binding

What protein are LAs bound???What protein are LAs bound???

MostlyMostly EE11--acid glycoproteinacid glycoprotein

To a lesser degree albuminTo a lesser degree albumin



AbsorptionAbsorption

Mucous membranes easily absorb LAMucous membranes easily absorb LA

Skin is a different story«Skin is a different story«

It requires a high water conc. for penetration and aIt requires a high water conc. for penetration and a

high lipid concentration for analgesiahigh lipid concentration for analgesia

Which LAs can we use for this?Which LAs can we use for this?

EMLA creamEMLA cream-- 5% lidocaine and 5% prilocaine in an oil5% lidocaine and 5% prilocaine in an oil--

water emulsionwater emulsion An occlusive dressing placed for 1 hour will penetrate 3An occlusive dressing placed for 1 hour will penetrate 3--

5mm and last about 15mm and last about 1--2 hours.2 hours.

Typically 1Typically 1--2 grams of drug per 10cm2 grams of drug per 10cm22 of skinof skin



Rate of systemic absorptionRate of systemic absorption

IntravenousIntravenous > > trachealtracheal > > intercostalintercostal > > caudalcaudal > >

paracervical paracervical > > epiduralepidural> > brachial plexus brachial plexus > >

sciaticsciatic > > subcutaneoussubcutaneous

Any vasoconstrictor present??Any vasoconstrictor present??

High tissue binding also decreases the rate of High tissue binding also decreases the rate of

absorptionabsorption



MetabolismMetabolism

Amides«Amides«

N N--dealkylation and hydroxylationdealkylation and hydroxylation

PP--450 enzymes, liver, slower process than esterase activity450 enzymes, liver, slower process than esterase activity

Prilocaine>lidocaine>mepivacaine>ropivacaine>bupivacaiPrilocaine>lidocaine>mepivacaine>ropivacaine>bupivacainene

Prilocaine has a metabolite«.Prilocaine has a metabolite«.

oo--toluidinetoluidine

This causes methemoglobin to form (Benzocaine can alsoThis causes methemoglobin to form (Benzocaine can also

cause methemoglobin to form)cause methemoglobin to form)

Treated with methylene blue 1Treated with methylene blue 1--2mg/kg over 5 minutes2mg/kg over 5 minutes Reduces methemoglobin Fe3+ to hemoglobin Fe2+Reduces methemoglobin Fe3+ to hemoglobin Fe2+



MetabolismMetabolism

Esters«Esters«

PseudocholinesterasePseudocholinesterase

Procaine and benzocaine are metabolized to«Procaine and benzocaine are metabolized to« PABA (pPABA (p--aminobenzoic acid) allergy risk aminobenzoic acid) allergy risk

Tetracaine intrathecal has it¶s actionTetracaine intrathecal has it¶s action

terminated by«terminated by«

No esterase activity intrathecally therefore No esterase activity intrathecally therefore

absorption into bloodstream terminates it¶s actionabsorption into bloodstream terminates it¶s action



Clinical UsesClinical Uses

EstersEsters

BenzocaineBenzocaine-- Topical, duration of 30 minutes to 1Topical, duration of 30 minutes to 1hour hour

ChloroprocaineChloroprocaine-- Epidural, infiltration andEpidural, infiltration and peripheral nerve block, max dose 12mg/kg, peripheral nerve block, max dose 12mg/kg,duration 30minutes to 1 hour duration 30minutes to 1 hour

CocaineCocaine-- Topical, 3mg/kg max., 30 minutes to oneTopical, 3mg/kg max., 30 minutes to one

hour hour TetracaineTetracaine-- Spinal, topical, 3mg/kg max., 1.5Spinal, topical, 3mg/kg max., 1.5--66

hours durationhours duration



Clinical UsesClinical Uses

BupivacaineBupivacaine-- Epidural, spinal, infiltration, peripheralEpidural, spinal, infiltration, peripheralnerve block, 3mg/kg max., 1.5nerve block, 3mg/kg max., 1.5--8 hours duration8 hours duration

LidocaineLidocaine-- Epidural, spinal, infiltration, peripheralEpidural, spinal, infiltration, peripheralnerve block, intravenous regional, topical, 4.5mg/kgnerve block, intravenous regional, topical, 4.5mg/kgor 7mg/kg with epi, 0.75or 7mg/kg with epi, 0.75--2 hours duration2 hours duration

MepivacaineMepivacaine-- Epidural, infiltration, peripheral nerveEpidural, infiltration, peripheral nerve block, 4.5mg/kg or 7mg/kg with epi, 1 block, 4.5mg/kg or 7mg/kg with epi, 1--2 hours2 hours

PrilocainePrilocaine-- Peripheral nerve block (dental), 8mg/kg,Peripheral nerve block (dental), 8mg/kg,

30 minutes to 1 hour duration30 minutes to 1 hour duration RopivacaineRopivacaine-- Epidural, spinal, infiltration, peripheralEpidural, spinal, infiltration, peripheral

nerve block, 3mg/kg, 1.5nerve block, 3mg/kg, 1.5--8 hours duration8 hours duration



Systemic ToxicitySystemic Toxicity

Blockage of voltagedBlockage of voltaged--gated Na channel affectsgated Na channel affects

action potential propagation throughout theaction potential propagation throughout the

body«therefore the potential is present for body«therefore the potential is present for

systemic toxicity.systemic toxicity.

Mixtures of LA have additive affectsMixtures of LA have additive affects

i.e. a 50% toxic dose of lidocaine and a 50% toxici.e. a 50% toxic dose of lidocaine and a 50% toxic

dose of bupivicaine have 100% the toxic affect of dose of bupivicaine have 100% the toxic affect of either drugeither drug



Systemic ToxicitySystemic Toxicity

Neurological Neurological

Symptoms include cicumoral numbness, tongueSymptoms include cicumoral numbness, tongue

paresthesia, dizziness, tinnitus, blurred vision, paresthesia, dizziness, tinnitus, blurred vision,

restlessness, agitation, nervousness, paranoia,restlessness, agitation, nervousness, paranoia,

slurred speech, drowsiness, unconsciousness.slurred speech, drowsiness, unconsciousness.

Muscle twitching heralds the onset of tonicMuscle twitching heralds the onset of tonic--clonicclonic

seizures with respiratory arrest to follow.seizures with respiratory arrest to follow.



Local anesthetic toxicityLocal anesthetic toxicity

Seizure treatment:Seizure treatment:

Thiopental 1Thiopental 1--2mg/kg abruptly terminates seizure2mg/kg abruptly terminates seizureactivityactivity

Benzos and hyperventilation«decrease CBF andBenzos and hyperventilation«decrease CBF andtherefore drug exposure. These raise the thresholdtherefore drug exposure. These raise the thresholdof local anestheticof local anesthetic--induced seizuresinduced seizures

Chloroprocaine injected intrathecally canChloroprocaine injected intrathecally can

cause prolonged neurotoxicity. This is likelycause prolonged neurotoxicity. This is likelydue to a preservative no longer used with thisdue to a preservative no longer used with thisagent. (Sodium bisulfate)agent. (Sodium bisulfate)




Repeated doses of 5% lidocaine and .5% tetracaineRepeated doses of 5% lidocaine and .5% tetracaine

may be responsible for cauda equina syndromemay be responsible for cauda equina syndrome

following infusion through small bore catheters infollowing infusion through small bore catheters in

spinal anesthetics.spinal anesthetics. Pooling of drug around the cauda equina resulted inPooling of drug around the cauda equina resulted in

permanent neurological damage permanent neurological damage

Animal studies suggest that neuro damage is:Animal studies suggest that neuro damage is:

Lido=tetracaine>bupivacaine>ropivacaine. AlsoLido=tetracaine>bupivacaine>ropivacaine. Also

perservative free chloroprocaine may be neurotoxic perservative free chloroprocaine may be neurotoxic




TransientNeurological SymptomsTransientNeurological Symptoms

This is associated with dysethesia, burning pain andThis is associated with dysethesia, burning pain andaching in lower ext, buttocks.aching in lower ext, buttocks.

Follows spinal anesthesia with variety of agentsFollows spinal anesthesia with variety of agents(lido), attributed to radicular irritation and resolves in(lido), attributed to radicular irritation and resolves in1 week usually1 week usually

Risk factors includeRisk factors include Lidocaine intrathecallyLidocaine intrathecally

Lithotomy positionLithotomy position ObesityObesity

Outpatient statusOutpatient status



Local anesthestic toxicityLocal anesthestic toxicity

Respiratory center may be depressedRespiratory center may be depressed

(medullary)«postretrobulbar apnea syndrome(medullary)«postretrobulbar apnea syndrome

Lidocaine depresses hypoxic respiratory driveLidocaine depresses hypoxic respiratory drive(PaO2)(PaO2)

Direct paralysis of phrenic or intercostalDirect paralysis of phrenic or intercostal

nervesnerves



LA cardio toxicityLA cardio toxicity

All LA¶s depress spontaneous Phase IVAll LA¶s depress spontaneous Phase IVdepolarization and reduce the duration of thedepolarization and reduce the duration of therefractory periodrefractory period

Myocardial contractility and conductionMyocardial contractility and conductionvelocity are depressed at higher concentrationsvelocity are depressed at higher concentrations

All LA¶s except cocaine cause smooth muscleAll LA¶s except cocaine cause smooth muscle

relaxation and therefore vasodilation (art)relaxation and therefore vasodilation (art)whick can lead to brady, heart block andwhick can lead to brady, heart block andhypotension«cardiac arrest.hypotension«cardiac arrest.




Major cardiovascular toxicity usually resultsMajor cardiovascular toxicity usually results

from 3 times the blood concentration of LAfrom 3 times the blood concentration of LA

that causes seizures.that causes seizures.

Therefore cardiac collapse is usually theTherefore cardiac collapse is usually the

presenting sign under GA. presenting sign under GA.

R isomer of bupivacaine avidly blocks cardiacR isomer of bupivacaine avidly blocks cardiac

sodium channels and dissociates very slowly.sodium channels and dissociates very slowly.

Making resuscitation prolonged and difficult.Making resuscitation prolonged and difficult.




LevoLevo--bupivacaine (S isomer) is no longer bupivacaine (S isomer) is no longer avaliable in the US but had a cardiovascular avaliable in the US but had a cardiovascular profile similar to ropivacaine. profile similar to ropivacaine.

Ropivacaine has a larger therapeutic index andRopivacaine has a larger therapeutic index andit is 70% less likely to cause severe cardiacit is 70% less likely to cause severe cardiacdsyrhythmias than bupivacainedsyrhythmias than bupivacaine

Also ropviacaine has greater C NS toleranceAlso ropviacaine has greater C NS tolerance

The improved safety profile is due to a lower The improved safety profile is due to a lower lipid solubilitylipid solubility



LA toxicity treatmentLA toxicity treatment

Supportive care: intubation, vasopressors, appropriateSupportive care: intubation, vasopressors, appropriatedefibrillation, fluids, stop injection of LA, anythingdefibrillation, fluids, stop injection of LA, anythingelse«.else«.

Intralipid«Bolus 1cc/kg of 20% intralipid,Intralipid«Bolus 1cc/kg of 20% intralipid,0.25cc/kg/min of 20% intralipid for 10 minutes0.25cc/kg/min of 20% intralipid for 10 minutes

Bolus can be repeated every 5 minutes up to aBolus can be repeated every 5 minutes up to amaximum of 8cc/kg of 20% intralipidmaximum of 8cc/kg of 20% intralipid

Cardiac support should be continued as ACLSCardiac support should be continued as ACLS

dictatesdictates Epi and vasopresin should likely both be used in theEpi and vasopresin should likely both be used in the

resusitation efforts (animal model data from A & A)resusitation efforts (animal model data from A & A)



Lipid, Not Propofol, TreatsBupivacaine OverdoseLipid, Not Propofol, TreatsBupivacaine Overdose

Guy Weinberg, MD, Paul Hertz, MD, and Janet Newman, MD Guy Weinberg, MD, Paul Hertz, MD, and Janet Newman, MD Department of Anesthesiology, University of Illinois, Chicago, IL, [email protected] of Anesthesiology, University of Illinois, Chicago, IL, [email protected]

To the Editor:To the Editor:

Mayr et al.Mayr et al. (1)(1) recently reported the comparative efficacies of epinephrine, vasopressin, and a combination of the two drugs in a porcine modrecently reported the comparative efficacies of epinephrine, vasopressin, and a combination of the two drugs in a porcine modelel of bupivacaine overdose. They used a single 5of bupivacaine overdose. They used a single 5mg/kg IV bolus of bupivacaine, applied advanced cardiac life support 1 min after asystole, and administered drugs 2 min later mg/kg IV bolus of bupivacaine, applied advanced cardiac life support 1 min after asystole, and administered drugs 2 min later anand at 5d at 5--min intervals thereafter. Monophasic countershocksmin intervals thereafter. Monophasic countershockswere applied as dictated by rhythm disturbance. Rates of survival were 5/7 for vasopressin, 4/7 for epinephrine, 7/7 in the cwere applied as dictated by rhythm disturbance. Rates of survival were 5/7 for vasopressin, 4/7 for epinephrine, 7/7 in the combombined treatment group, and 0/7 in controls.ined treatment group, and 0/7 in controls.

By comparison, we reported that injecting a 20% lipid emulsion in combination with ca rdiac massage leads to successful returnBy comparison, we reported that injecting a 20% lipid emulsion in combination with card iac massage leads to successful return of of normal hemodynamics in 9/9 dogs after a bolus injectionnormal hemodynamics in 9/9 dogs after a bolus injectionof 10 mg/kg bupivacaineof 10 mg/kg bupivacaine (2)(2). Lipid infusion in 6 of these dogs was delayed for 10 min to approximate a clinical scenario. A normal rhythm was establishe. Lipid infusion in 6 of these dogs was delayed for 10 min to approximate a clinical scenario. A normal rhythm was established id in all 9 dogs within 5 min; non all 9 dogs within 5 min; noelectrical counter shock was required. No control animal demonstrated return of BP or HR.electrical counter shock was required. No control animal demonstrated return of BP or HR.

Dogs and pigs may differ in terms of susceptibility to bupivacaine cardiac toxicity; the porcine and canine models may not beDogs and pigs may differ in terms of susceptibility to bupivacaine cardiac toxicity; the porcine and canine models may not be cocompletely comparable for this and other reasons. However,mpletely comparable for this and other reasons. However,we and otherswe and others (3)(3) believe the rapid return of normal rhythm and hemodynamics in both dogs and rats following massive bupivacaine overdose (twic believe the rapid return of normal rhythm and hemodynamics in both dogs and rats following massive bupivacaine overdose (twicee the dose used in Mayr¶s study),the dose used in Mayr¶s study),indicates superior efficacy of lipid rescue for bupivacaine toxicity to drugs, such as epinephrine and vasopressin tha t are cindicates superior efficacy of lipid rescue for bupivacaine toxicity to drugs, such as epinephrine and vasopressin tha t are compomponents of the generic ACLS protocol for cardiopulmonaryonents of the generic ACLS protocol for cardiopulmonaryarrestarrest (4)(4). Perhaps Dr. Mayr will consider comparing combined epinephrine/vasopressin with lipid rescue in the porcine model of bupivac. Perhaps Dr. Mayr will consider comparing combined epinephrine/vasopressin with lipid rescue in the porcine model of bupivacainaine cardiac toxicity.e cardiac toxicity.

Mayr et al.Mayr et al. (1)(1) also incorrectly cite us as indicating that "....a lipid infusion such as propofol increases the dose of bupivacaine requiredalso incorrectly cite us as indicating that "....a lipid infusion such as propofol increases the dose of bupivacaine required tto induce cardiac arrest, and, therefore, this strategyo induce cardiac arrest, and, therefore, this strategyhas been suggested as a potential means to improve outcomes from such toxicity." We havehas been suggested as a potential means to improve outcomes from such toxicity." We have never never recommended use of propofol for treating bupivacaine overdose, and strongly suspect thatrecommended use of propofol for treating bupivacaine overdose, and strongly suspect thatits use in cardiac arrest will impede resus citation.its use in cardiac arrest will impede resus citation.

We have recommended treating bupivacaineWe have recommended treating bupivacaine--associated cardiac arrest by injecting a 1 mL/kg bolus of 20% lipid emulsion (such as Iassociated cardiac arrest by injecting a 1 mL/kg bolus of 20% lipid emulsion (such as Intr alipid) and starting an infusion of 0 .25 mL/kg/min for ntralipid) and starting an infusion of 0.25 mL/kg/min for 10 min, while continuing basic life support10 min, while continuing basic life support (5)(5). The bolus could be repeated every 5 min, two or three times if needed. The upper dose limit of 20% lipid emulsion is not kn. The bolus could be repeated every 5 min, two or three times if needed. The upper dose limit of 20% lipid emulsion is not knownown, but a total, but a totalof more than 8 mL/kg is not likely to be needed, nor successful if lower doses are not. Note that this protocol will deliver of more than 8 mL/kg is not likely to be needed, nor successful if lower doses are not. Note that this protocol will deliver a sa significant volume load (several hundred mL in an adult). Theignificant volume load (several hundred mL in an adult). Thestandard formulation of propofol is 10% lipid and 1% propofol. Therefore, gram quantities of propofol would accompany our recstandard formulation of propofol is 10% lipid and 1% propofol. Therefore, gram quantities of propofol would accompany our recommommended regimen and only half the dose of lipid, theended regimen and only half the dose of lipid, thenecessary ingredient, would be delivered.necessary ingredient, would be delivered.

Propofol is not an acceptable treatment for bupivacaine overdose.Propofol is not an acceptable treatment for bupivacaine overdose.

ReferencesReferences

Mayr VD, Raedler C, Wenzel V, et al. A comparison of epinephrine and vasopressin in a porcine model of cardiac arrest after r Mayr VD, Raedler C, Wenzel V, et al. A comparison of epinephrine and vasopressin in a porcine model of cardiac arrest after rapiapid intravenous injection of bup ivacaine. Anesth Analgd intravenous injection of bupivacaine. Anesth Analg2004; 98: 14262004; 98: 1426± ±31.31.[Abstract/Free[Abstract/FreeFullFull Text]Text]

Weinberg G, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaineWeinberg G, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaine--induced cardiac toxicity. R induced cardiac toxicity. Reg Anesth Pain Med 2003; 28: 198eg Anesth Pain Med 2003; 28: 198± ± 202.202.[ISI][ISI][Medline][Medline]

Groban L, Butterworth J. Lipid reversal of bupivacaine toxicity: has the silver bullet been identified? Reg Anesth Pain Med 2Groban L, Butterworth J. Lipid reversal of bupivacaine toxicity: has the silver bullet been identified? Reg Anesth Pain Med 2003003; 28: 167; 28: 167± ±9.9.[ISI][ISI][Medline][Medline]

Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 8: advanced challenges in resuscitaGuidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 8: advanced challenges in resuscitatiotion: section 2: toxicology in ECC. The American Heartn: section 2: toxicology in ECC. The American Heart

Association in collaboration with the International Liaison Committee on Resuscitation. Circulation 2000; 102 (suppl 8): I223Association in collaboration with the International Liaison Committee on Resuscitation. Circulation 2000; 102 (suppl 8): I223± ±8.8.[Medline][Medline] Weinberg G. Lipid rescue: caveats and recommendations for the "Silver Bullet" [letter]. Reg Anesth Pain Med 2004; 29: 74Weinberg G. Lipid rescue: caveats and recommendations for the "Silver Bullet" [letter]. Reg Anesth Pain Med 2004; 29: 74± ±5.5.

ResponseResponse

ViktoriaD. Mayr,MD, Claus Raedler, MD, Volker Wenzel, MD, Karl H. Lindner, MD, and HansViktoriaD. Mayr,MD, Claus Raedler, MD, Volker Wenzel, MD, Karl H. Lindner, MD, and Hans--Ulrich Strohmenger, MD Ulrich Strohmenger, MD Univ. Klinik f. Anaesthesie u. Allg. Intensivmedezin,Univ. Klinik f. Anaesthesie u. Allg. Intensivmedezin,Innsbruck, Austria, [email protected], Austria, [email protected]

In Response:In Response:

We would like to thank Weinberg et al. for their interest in our work, as well a s for their constructive comments. First, weWe would like to thank Weinberg et al. for their interest in our work, as well a s for their constructive comments. First, we sinsincerely apologize for having incorrectly cited Weinberg et al. bycerely apologize for having incorrectly cited Weinberg et al. byconfounding propofol and intralipid; we completely agree with their statement that propofol administrat ion cannot be recommenconfounding propofol and intralipid; we completely agree with their statement that propofol administrat ion cannot be recommendedded for managing a bupivacaine overdose. When indicatingfor managing a bupivacaine overdose. When indicatingin the Discussion section that "... a lipid infusion such as propofol increases the dose of bupivacaine required to induce cain the Discussion section that "... a lipid infusion such as propofol increases the dose of bupivacaine required to induce cardirdiac arrest, and therefore, this stra tegy has been suggested as aac arrest, and therefore, this strategy has been suggested as a potential means to improve outcomes from such toxicity," we did not suggest to use propofol for treating bupivacaine toxicity potential means to improve outcomes from such toxicity," we did not suggest to use propofol for treating bupivacaine toxicity, n, nor that Dr. Weinberg et al. used propofol for treatingor that Dr. Weinberg et al. used propofol for treating bupivacaine toxicity. We share the same opinion that usage of propofol in cardiac arr est may impede resuscitation. With our s bupivacaine toxicity. We share the same opinion that usage of propofol in cardiac arr est may impede resuscitation. With our stattatement about a "lipid infusion such as propofol...", we onlyement about a "lipid infusion such as propofol...", we onlywanted to state the reason why we did not u se propofol but isoflurane and nitrous oxide to maintain anesthesia in our experimwanted to state the reason why we did not u se propofol but isoflurane and nitrous oxide to maintain anesthesia in our experimentent. Instead of saying "... a lipid infusion such as propofol...", it. Instead of saying "... a lipid infusion such as propofol...", itwould have been better to state "... as p ropofol is a lipid infusion which may increase the dose of bupivacaine required to iwould have been better to state "... as p ropofol is a lipid infusion which may increase the dose of bupivacaine required to indunduce cardiac arrest..." Second, beneficial lipid effects duringce cardiac arrest..." Second, beneficial lipid effects duringmassive bupivacaine overdose as described by Weinberg et al. resulted in impressive outcome data. However, their conclusion dmassive bupivacaine overdose as described by Weinberg et al. resulted in impressive outcome data. However, their conclusion drawrawn in the letter that these results indicate the superiority of n in the letter that these results indicate the superiority of this treatment regime in comparison to advanced card iac life support including epinephrine and vasopressin has not been provethis treatment regime in comparison to advanced card iac life support including epinephrine and vasopressin has not been proven.n. The comparative investigation of theThe comparative investigation of the

epinephrine/vasopressin combination and the lipid rescue protocol in the same animal model of bupivacaine card iac toxicity caepinephrine/vasopressin combination and the lipid rescue protocol in the same animal model of bupivacaine card iac toxicity can on only provide reliable information in this respect.nly provide reliable information in this respect.



True Allergic Reactions to LA¶sTrue Allergic Reactions to LA¶s

Very uncommonVery uncommon

Esters more likely because of pEsters more likely because of p--aminobenzoicaminobenzoic

acid (allergen)acid (allergen) Methylparaben preservative present in amidesMethylparaben preservative present in amides

is also a known allergenis also a known allergen



Local Anesthetic MusculoskeletalLocal Anesthetic Musculoskeletal

Cause myonecrosis when injected directly intoCause myonecrosis when injected directly into

the musclethe muscle

When steroid or epi added the myonecrosis isWhen steroid or epi added the myonecrosis isworsenedworsened

Regeneration usually takes 3Regeneration usually takes 3--4 weeks4 weeks

Ropivacaine produces less sereve muscleRopivacaine produces less sereve muscleinjury than bupivacaineinjury than bupivacaine



Drug InteractionsDrug Interactions

Chloroprocaine epidurally may interfere with the analgesicChloroprocaine epidurally may interfere with the analgesiceffects of intrathecal morphineeffects of intrathecal morphine

Opioids andOpioids and EE22 agonists potentiate LA¶sagonists potentiate LA¶s

Propranolol and cimetidine decrease hepatic blood flow andPropranolol and cimetidine decrease hepatic blood flow anddecrease lidocaine clearancedecrease lidocaine clearance

Pseudocholinesterase inhibitors decrease Ester LA metabolismPseudocholinesterase inhibitors decrease Ester LA metabolism

Dibucaine (amide LA) inhibits pseudocholinesterase used toDibucaine (amide LA) inhibits pseudocholinesterase used todetect abn enzymedetect abn enzyme

Sux and ester LA need pseudochol. for metabolism thereforeSux and ester LA need pseudochol. for metabolism thereforeadminstering both may potentiate their activityadminstering both may potentiate their activity

LA potentiate nondepolarizing muscle relaxant blockadeLA potentiate nondepolarizing muscle relaxant blockade



Other agents with LA propertiesOther agents with LA properties

MeperidineMeperidine

TCAs (amitriptyline)TCAs (amitriptyline)

Volatile anestheticsVolatile anesthetics

KetamineKetamine

Tetrodotoxin (blocks Na channels from theTetrodotoxin (blocks Na channels from theoutside of the cell membrane) Animal studiesoutside of the cell membrane) Animal studies

suggest that when used in low doses withsuggest that when used in low doses withvasoconstrictors it will significantly prolongvasoconstrictors it will significantly prolongduration of action of LA.duration of action of LA.



BibliographyBibliography

Clinical Anesthesiology, Morgan and MikhailClinical Anesthesiology, Morgan and Mikhail

local anesthetics oct

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