Managing Patients with Local Anesthetics Complication

Dr. Zulkarnain Hamzah , Sp An.The 6 th National Symposium of Aesthetic Medicine and Cosmetic Surgery

December 15 th- 16 th , 2012 Jakarta

Various surveys indicate the number of deaths attributed to local anesthesia range from 1:1,500,000 to 1:4,000,000

This occurs despite clinicians' attention to patient medical histories, aspiration of the local anesthetic syringe during injections, and minimizing the dosage of local anesthetic solutions.

Managing complications of local anesthesia would be more difficult, therefore it would be necessary to identify patients who may be a complication.

Moreover, patients requiring community aesthetic surgery are people who expect to be perfect so that the results will lead to complications that complicate lawsuits.

So all this surgery should be pedestrianized basis of competence, periodic examination organized by an official authority collegiums.

Of course, the principle of prioritizing patient safety

History of Local Anesthetics

Cocaine isolated 18561884 cocaine used in occular surgery1880’s Regional anesthesia plexus1898 cocaine used in spinal anesthesia1905 1st synthetic LA (procaine) introduced1943 lidocaine synthesizedMepivacaine (1957), Bupiv (’63), Ropiv (’96)

Differences in structure of local anesthetics

Esters versus Amides1) Affect metabolism2) Affect toxicity3) Allergic potential

Types of Local Anesthetics

Types of Local Anesthetics

EstersProcainechloroprocainetetracainecocaine

Mechanism of Action for Local Anesthetics

•Block propagation of action potential along neuron

prevent depolarization through blockade of Na Channel

voltage gated K channels also blocked by LA but the affinity of receptor much lessLido 4-10x less Bupiv 10-80x lessNB K channel involved in repolarization

Voltage gated Na and Ca channels in DRG are similar

Ty

Mechanism of Action for Local Anesthetics

FIGURE 1. Model of the fourth homologous domain (D4) of the human skeletal muscle sodium channel (hNaV1.4) with the S4 segment depicted as a rotating cylinder. Four S4 residues are shown: Arg1451 (R2), Leu1452, Ala1453, and Arg1454 (R3). The positions of the residues around the S4 segment roughly correspond to those of an helical model. A depolarizing rotation transfers R2 and R3 from an intracellularly to an extracellularly accessible crevice, whereas Leu1452 and Ala1453 are translocated in the opposite direction. Coupled Movements in Voltage-gated Ion Channels Richard Horn Journal of General Physiology, Volume 120, Number 4, October 2002 449-453

Local Anesthetics

Activity of local anesthetics is a function of :Activity of local anesthetics is a function of : Lipid solubility Lipid solubility DiffusibilityDiffusibilityAffinity for protein bindingAffinity for protein bindingPercent ionization at physiologic pHPercent ionization at physiologic pHVasodilating properties. Vasodilating properties.

Local Anesthetics

Lipid solubility is an important characteristic. Potency is related to lipid solubility, because 90% of the nerve cell membrane is composed of lipid. This improve transit into the cell membrane

Local Anesthetics

Diffusibility (how well the LA diffuses diffuses through tissue to its site of action) will also influences the speed of action onset.

Local Anesthetics

Protein binding is related to the duration of Protein binding is related to the duration of action. The site of action (the Na channel) is action. The site of action (the Na channel) is primarily protein in a lipid environment. primarily protein in a lipid environment. Binding affinity will thus affect duration of Binding affinity will thus affect duration of action.action.

Protein binding also plays a part in the Protein binding also plays a part in the availability of the drug as LA binds to availability of the drug as LA binds to lipoproteins in the blood stream.lipoproteins in the blood stream.

And transfer to fetusesAnd transfer to fetuses

Summary

Clinical Pharmacology The potency of Local Anesthetics, their onset and duration of

action are primary determined by physicochemical properties of various agents and their inherent vasodilator activity of same local anesthetics.

Lipid solubility is the primary determinant of anesthetic potency and it is expressed as lipid: water Partition Coefficient

Protein binding influences the duration of action pKa of Local anesthetics determines the onset of action The addition of vasoconstrictors, such as epinephrine or

phenylephrine can prolong duration of action of local anesthetics, decrease their absorption (and the peak plasma level) and enhance the blockade.

Properties of Local Anesthetic Agents

PROPERTIES AMINOESTERS AMINOAMIDES

Metabolism rapid by plasma cholinesterase slow, hepatic

Systemic toxicity less likely more likely

Allergic reaction possible - PABA derivatives form very rare

Stability in solution breaks down in ampules (heat,sun) very stable chemically

Onset of action slow as a general rule moderate to fast

pKa's higher than PH = 7.4 (8.5-8.9) close to PH = 7.4 (7.6-8.1)

pKa

Understanding LA as they relate to pKa

The pH of the tissue and pKa of the agent

The pH and pKa are the most important factors. The pH of the tissue determines the ratio of ionized to non-ionized drug. This ratio, in turn, depends on the pKa of the drug. Understanding the ionization is necessary to understanding the drug's pharmacological characteristics, such as onset, duration and pharmacodynamics.

Henderson Hasselbalch equation

The basis for understanding this equation is knowing the pKa of the agents, remembering that pKa equals the pH where the ionized and non-ionized forms are at equilibrium. In other words, 50% of each form is present. Local anaesthetics are weak bases. For bases, the pKa - pH relationship is described by the Henderson Hasselbalch equation, as follows:

  pKa - pH= log_ionized  non-ionized

Effect of pH, and pKa

The pKa of amides ranges from 7.6 to 8.1. At physiologic pH (7.4), most of the local anaesthetic is in the ionized state (a charged base). For example, lidocaine has a pKa of 7.9. The above formulat determines that at physiologic pH, lidocaine exists in a ratio of 3:1 ionized to non-ionized:

7.9 - 7.4=log [ionized/non-ionized]0.5 =log [ionized/non-ionized]100.5=ionized/non-ionized3ionized~ 1non-ionized

Low pH

The pH of the tissue becomes relevant in conditions of infection or inflammation, in which the natural pH may be more acidic. This acidity results in a greater proportion of the ionized (charged) form of the anaesthetic, thereby delaying or preventing the onset of action. For example, if lidocaine (pKa 7.9) is administered into an area of infection (pH 4.9) emanating from a dental abscess, then:

            7.9 - 4.9 = log [ionized/non-ionized]            103 = ionized/non-ionized

The resulting ratio of 1,000:1 ionized to non-ionized indicates a poorer penetration into the nerve tissue and therefore a less effective nerve block

AGENT Pot. Onset pKa %PBP.

coef

Procaine 0.5-1% (Novocain) 1 Rap 8.9 5.8 0.02

Chloroprocaine 2-3% (Nesacain) 4 Rap 8.7 ? 0.14

Tetracaine 0.1-0.5% (Pontocain) 16 Slow 8.5 75.6 4.1

Lidocaine 1-5% (Xylocaine) 1 Rap 7.9 64.3 2.9

Mepivacaine 1.5% (Carbocaine) 1 Mod 7.6 77.5 0.8

Bupivacaine 0.25-0.75% (Marcainesensorcaine)

4 Slow 8.1 95.6 27.5

Etidocaine 0.5-1.5% (Duranest) 4 Rap 7.7 94 141

Prilocaine 1 7.9 55 0.9

Ropivacaine 0.75% (Naropin) 4 Mod 8.1 94 2.9

Duration of Local anesthetics

Dependent on 1)agent 2)site 3)adjuvant 4)route 5)vascularity

Duration of Local anesthetics

ExamplesLidocaine bupivacaine

local infiltration 30-60 min 120-240minor nerve block 60-120 180-360major nerve block 120-240 360-720Epidural 30-90 180-300addition of epi improved improved

From NYSORA web site

Local Anesthetic Time Line (minutes)

Infiltration plain sol'n With

Epinephrine

Spinal plain With Epinephrine

Epidural plain sol'n With Epinephrine

Chloroprocaine30-4545-60

Lidocaine60-12090-180

Hyperbaric60

60-90

80-120120-180

Mepivacaine90-140

140-200

TetracaineHyperbaric

120-180180-400

Ropivacaine140-200160-220

Bupivacaine180-360300-480

Hyperbaric120-360120-360

180-360120-240

Safety Issues Related to Local Anesthetics

Related to 1) Drug2) Dose3) Site of administration

4) Condition of the patient

CNS Toxicity

Tends to occur first (relative to CVS toxicity)See excitatory signs and symptoms firstFollowed by depressant signs

Circumoral and tongue numbnessLightheadedness and tinnitusVisual disturbanceMuscle twitchingConvulsions

COMARespiratory arrestCVS depression

CVS Toxicity

Alteration in the excitatory mechanismslower depolarization

decreased HRprolonged PR intervalwidened QRS

Arrythmiasbradycardiaectopic beatsventricular fibrillation

Decreased cardiac output on the basis ofHRcontractility

Treatment of Toxicity

Identify the problemsigns and symptomstemporal relationshipIV injection40-60 min post for peak plasma levels

CNStreatment with benzodiazepines

Treatment of Toxicity

CVS signs and symptomsCNS effectsCVS effects

arrythmiaQRS changesigns of collapse fall in BP

With CVS toxicity The agent is an important consideration

Treatment of Toxicity

When there is CVS collapse

ACLSA B C’s

defibrillationEpinephrineVasopressinLidocaine?Bretylium?Amiodarone

Lipid Rescue

Relatively new concept

NanoparticlesScavenging Nanoparticles: An Emerging Treatment for Local

Anesthetic Toxicity The authors of the lipid-based studies speculated that four

mechanisms may play a role in the success of resuscitation. In their primary hypothesis, the lipid infusion may create plasma lipid droplets capable of segregating uncharged bupivacaine molecules from plasma, which makes them unavailable for interaction at their target sites. The authors supported this theory by showing that bupivacaine molecules preferentially segregated from plasma to their lipid infusion in a 1:12 ratio. 29 In two of the other proposed mechanisms, the lipid acts within tissue. Here, lipid or its component fatty acids either interact in a clinically significant way with tissue bupivacaine molecules or directly overcome bupivacaine’s inhibitory effect on cellular metabolism by supplying substrate for cellular energy production.30,31 [ 30, 31] Finally, the lipid infusion may act on nitric oxide pathways and reverse bupivacaine’s inhibitory effects. 29 Building on this work and assuming that sequestration of bupivacaine is an important aspect of resuscitation in the aforementioned lipid-based studies, some investigators have hypothesized even greater segregation of bupivacaine into lipid may occur with large reductions in particle size to the dimension of the nanometer. Regional Anesthesia andPMJuly - May, 2005 pp: 380-384 July - May, 2005 pp: 380-384 Renehan,Renehan,

Regional Anesthesia andPMJuly - May, 2005 pp: 380-384 July - May, 2005 pp: 380-384 RenehanRenehan,,

Regional Anesthesia andPMJuly - May, 2005 pp: 380-384 Renehan,

Toxicty

Email

 

Reported adverse event cases of methemoglobinemia associated with benzocaine products     .      The researchers identified 198 cases that described unique adverse events linked to the use of benzocaine. Of these, 132 cases (66.7%) were either definitely or probably episodes of MHb. Spray products containing benzocaine accounted for 123 (93.2%) of the adverse events. In every one of these cases in which a tissue type was

specified, benzocaine was applied to mucosal tissue. Of the 132 episodes of MHb, there were 107 episodes that were considered serious and two deaths. In neither case that resulted in death was benzocaine considered the principle suspect cause.

MDNews 6/18/2004. Arch Intern Med. 2004;164:1192-6 Moore

Special preparations

EMLA lidocaine 2.5% prilocaine 2.5%requires 45-60 application on intact skin

TAC tetracaine 0.5% epi 1 in 2000 cocaine 10%application into woundmaximum dose for kids 0.05ml/Kgtoxicity due to cocaine

Tumescent Anesthesia lidocaine dilute epiliposuctiondose 35-55mg/KgPeak levels 8-12h later

IontophoresisIontophoresis is a method of delivering a topical

anesthetic with a mild electric current. Lidocaine-soaked sponges are applied to intact skin, and electrodes are placed on top of the anesthetic. A DC current is then applied to the skin (Figure 2). The anesthetic effect occurs within 10 minutes and lasts approximately 15 minutes. The depth of anesthesia can reach up to 1 to 2 cm.12

Although the effectiveness of iontophoresis has been compared favorably to that of EMLA, it remains underused. Some patients find the mild electrical sensation uncomfortable. The apparatus is expensive and bulky, and cannot be used over large surface areas of the body.8 Other applications using iontophoresis are still being developed. Principles of Office Anesthesia: Part II. Topical AnesthesiaPrinciples of Office Anesthesia: Part II. Topical AnesthesiaSURITI KUNDU, M.D.,

Iontophoresis

Iontophoresis

Comparison of EMLA and lidocaine iontophoresis for cannulation analgesia.

CONCLUSIONS: Although lidocaine iontophoresis is effective more quickly than the eutectic mixture of local anaesthetic cream, the superior quality of analgesia produced by the eutectic mixture in this study should be borne in mind if these treatments are used electively

Eur J Anaesthesiol. 2004 Mar;21(3):210-3. Moppett

LiposomesLiposomes are comprised of lipid layers

surrounded by aqueous layers. They are able to penetrate the stratum corneum because they resemble the lipid bilayers of the cell membrane. A liposomal delivery system recently became available as an over-the-counter product called ELA-Max. It contains 4 percent lidocaine cream in a liposomal matrix and is FDA-approved for the temporary relief of pain resulting from minor cuts and abrasions. ELA-Max is applied to intact skin for 15 to 40 minutes without occlusion.15-17 In limited studies, ELA-Max has also proved effective in providing dermal analgesia before chemical peeling.18 The safety of its application to mucous membranes has not been evaluated.5 Despite a paucity of data and lack of an FDA indication, clinicians are be

ginning to use ELA-Max for topical anesthesia before other dermatologic procedures.

Liposome

www.bioteach.ubc.ca

Liposomal Bupivacaine

A Novel Liposomal Bupivacaine Formulation to Produce Ultralong-Acting Analgesia

Conclusions: This novel liposomal formulation had a favorable drug-to-phospholipid ratio and prolonged the duration of bupivacaine analgesia in a dose-dependent manner. If these results in healthy volunteers can be duplicated in the clinical setting, this formulation has the potential to significantly impact the management of pain.

Anesthesiology: Volume 101(1) July 2004 pp 133-137 Anesthesiology: Volume 101(1) July 2004 pp 133-137 Grant,

Liposomal Bupivacaine The median duration of analgesia with 0.5% standard

bupivacaine was 1 h. The median durations of analgesia after 0.5, 1.0, and 2.0% liposomal bupivacaine were 19, 38, and 48 h, respectively.

Although the data presented with this novel LMVV formulation are very encouraging because we found that LMVV bupivacaine was well tolerated and that it significantly prolonged the duration of analgesia compared to standard bupivacaine, there are a number of issues that must be resolved before the

formulation can be introduced for clinical use. Stability of the formulation during prolonged storage, batch-to-batch variability in physicochemical characteristics, and adaptability of the method for upscaling for large batch sizes remain to be determined. The primary objective of the current study was to establish proof of concept regarding the efficacy of LMVV bupivacaine in humans. The dose of LMVV bupivacaine administered in this study was low—only 17.5 mg. Before the efficacy of LMVV bupivacaine in various painful conditions can be evaluated, a study to determine its maximum tolerated dose in humans is necessary.

Liposomes Liposomal Drug Delivery for Postoperative Pain

Management Translational vignette Although the plasma concentration versus time curve is flatter for the Although the plasma concentration versus time curve is flatter for the

extended-release formulation, overall bioavailability is similar.extended-release formulation, overall bioavailability is similar. Although Although the exact mechanism of the exact mechanism of in vivoin vivo drug release from MVL drug release from MVL particles is not known, it is believed to be the result of particles is not known, it is believed to be the result of a gradual erosion or reorganization of the lipid a gradual erosion or reorganization of the lipid membranesmembranes

Summary and Conclusions Liposomes are effective drug delivery systems to improve the

therapeutic efficacy of drugs by increasing drug circulation times, facilitating targeting of drugs, and enhancing stability without compromising safety or tolerability. Extended-release MVL preparation has proved to be an effective drug delivery vehicle for morphine sulfate; extended-release MVL morphine sulfate exhibits an extended duration of pain relief for up to 48 hours postoperatively without compromising safety or tolerability, according to initial clinical studies.

Regional Anesthesia and PM Regional Anesthesia and PM Sept - May, 2005 pp: 491-496 Sept - May, 2005 pp: 491-496 EugeneEugene

Encapsulation of mepivacaineEncapsulation of mepivacaine Encapsulation of mepivacaine prolongs the analgesia Encapsulation of mepivacaine prolongs the analgesia

provided by sciatic nerve blockade in mice.provided by sciatic nerve blockade in mice.

PURPOSE: Liposomal formulations of local anesthetics (LA) are PURPOSE: Liposomal formulations of local anesthetics (LA) are able to control drug-delivery in biological systems, prolonging able to control drug-delivery in biological systems, prolonging their anesthetic effect. This study aimed to prepare, characterize their anesthetic effect. This study aimed to prepare, characterize and evaluate in vivo drug-delivery systems, composed of large and evaluate in vivo drug-delivery systems, composed of large unilamellar liposomes (LUV), for bupivacaine (BVC) and unilamellar liposomes (LUV), for bupivacaine (BVC) and mepivacaine (MVC). mepivacaine (MVC).

CONCLUSION: MVC(LUV) provided a LA effect CONCLUSION: MVC(LUV) provided a LA effect comparable to that of BVC. We propose MVC(LUV) comparable to that of BVC. We propose MVC(LUV) drug delivery as a potentially new therapeutic option drug delivery as a potentially new therapeutic option for the treatment of acute pain since the formulation for the treatment of acute pain since the formulation enhances the duration of sensory blockade at lower enhances the duration of sensory blockade at lower concentrations than those of plain MVC.concentrations than those of plain MVC. Can J Anaesth. 2004 Jun-Jul;51(6):566-72. Can J Anaesth. 2004 Jun-Jul;51(6):566-72. de Araujo de Araujo

Uses of Local Anesthetics

TopicalLocal infiltrationMinor peripheral nerve blockadeMajor peripheral nerve blockadeNeuraxial blockadeTumescent anesthesiaChronic pain

IV Local anesthetics

Perioperative Intravenous Lidocaine Has Perioperative Intravenous Lidocaine Has Preventive Effects on Postoperative Pain and Preventive Effects on Postoperative Pain and Morphine Consumption After Major Morphine Consumption After Major Abdominal Surgery Abdominal Surgery IMPLICATIONS: The perioperative administration of IMPLICATIONS: The perioperative administration of

systemic small-dosesystemic small-dose lidocaine reduces pain during lidocaine reduces pain during surgery associated with the developmentsurgery associated with the development of of pronounced central hyperalgesia, presumably by pronounced central hyperalgesia, presumably by affectingaffecting mechanoinsensitive nociceptors, because mechanoinsensitive nociceptors, because these have been linkedthese have been linked to the induction of central to the induction of central sensitization and were shown tosensitization and were shown to be particularly be particularly sensitive to small-dose lidocainesensitive to small-dose lidocaine lidocaine 2%lidocaine 2% (bolus injection of 1.5 mg/kg in 10 min (bolus injection of 1.5 mg/kg in 10 min

followed by an IV infusionfollowed by an IV infusion of 1.5 mg · kgof 1.5 mg · kg-1-1 · h · h-1-1),),

Anesth Analg 2004;98:1050-1055 Koppert

Tumescent AnesthesiaPlasma lidocaine levels and risks after liposuction Plasma lidocaine levels and risks after liposuction

with tumescent anaesthesia.with tumescent anaesthesia.

Background: It is common today to use tumescent Background: It is common today to use tumescent anaesthesia with large doses of lidocaine for anaesthesia with large doses of lidocaine for liposuction. liposuction. The purpose of the present study was to evaluate The purpose of the present study was to evaluate lidocaine plasma levels and objective and subjective symptoms lidocaine plasma levels and objective and subjective symptoms during 20 h after tumescent anaesthesia with approximately 35 during 20 h after tumescent anaesthesia with approximately 35 mg per kg bodyweight of lidocaine for abdominal liposuction. mg per kg bodyweight of lidocaine for abdominal liposuction. Methods: Three litres of buffered solution of 0.08% lidocaine with Methods: Three litres of buffered solution of 0.08% lidocaine with epinephrineepinephrine. . Results: Lidocaine 33.2 +/- 1.8 mg/kg was given at a Results: Lidocaine 33.2 +/- 1.8 mg/kg was given at a rate of 116 +/- 11 ml/min. Peak plasma levels (2.3 +/- 0.63 rate of 116 +/- 11 ml/min. Peak plasma levels (2.3 +/- 0.63 microg/ml) of lidocaine occurred after 5-17 hmicrog/ml) of lidocaine occurred after 5-17 h

Conclusion: Doses of lidocaine up to 35 mg/kg were Conclusion: Doses of lidocaine up to 35 mg/kg were sufficient for abdominal liposuction using the sufficient for abdominal liposuction using the tumescent technique and gave no fluid overload or tumescent technique and gave no fluid overload or toxic symptoms in eight patients, toxic symptoms in eight patients, but with this dose there is but with this dose there is still a risk of subjective symptoms in association with the peak still a risk of subjective symptoms in association with the peak level of lidocaine that may appear after discharge.level of lidocaine that may appear after discharge.

Acta Anaesthesiol Scand. 2005 Nov;49(10):1487-90.Acta Anaesthesiol Scand. 2005 Nov;49(10):1487-90. NordstromNordstrom

Tumescent Anesthesia

Deaths Related to LiposuctionDeaths Related to LiposuctionConclusionsConclusions Tumescent liposuction can be fatal, Tumescent liposuction can be fatal,

perhapsperhaps in part in part because of lidocaine toxicity or because of lidocaine toxicity or lidocaine-related drug interactions.lidocaine-related drug interactions.

In tumescent liposuction, reported doses of lidocaine range

from 10 to 88 mg per kilogram,8 several times higher than the maximal recommended dose of 4.5 mg per kilogram (or up to 7 mg per kilogram with epinephrine) typically used for subcutaneous infiltration.21,22 The 1991 guidelines of the American Academy of Dermatologists for tumescent liposuction suggested a maximal dose of 35 mg of lidocaine per kilogram,23 which was increased to “at least 55 mg per kilogram” in 1997

NEJM V340:1471-1475 NEJM V340:1471-1475 Rama Rama

Myotoxicity 

The long term myotoxic effects of bupivacaine and ropivacaine after continuous peripheral nerve blocks.

IMPLICATIONS: In a period of 4 wk after peripheral nerve block, both long-acting local anesthetics, bupivacaine and ropivacaine, produced calcific myonecrosis suggestive of irreversible skeletal muscle damage. In comparison with ropivacaine, however, the extent of bupivacaine-induced muscle lesions was significantly larger.

Anesth Analg. 2005 Aug;101(2):548-54, Zink W,

CVS Toxicity

Cardiovascular collapse on the basis of malignant rhythmdecreased contractilityvascular dilation

Bob Hoffman New York City Poison Center, NY,

USA

Is Methylene Blue SafeIn Patients With Methemoglobinemia

And Glucose 6-phosphateDehydrogenase (G6PD) Deficiency?

Genetics

> 400 variants describedDifferent electrophoretic mobility, kinetic

properties. 5 classes according to the residual enzyme

activity based (WHO). Mediterranean and African (A-) variants

The most clinically significant.

Activity scarcely detectable in the Mediterranean type but close to normal in the African variant.

Methylene blue

If giving methylene blue to patients with a known or suspected history of G6PD deficiency Keep the first dose small (1 mg/kg) Recheck the MetHb often Do not repeat if unsuccessful Observe closely for hemoylsis

Newer Local anestheticsDirect cardiac effects of intracoronary bupivacaine,

levobupivacaine and ropivacaine in the sheep.In previous preclinical studies we found that central nervous system (CNS) excito-toxicity reversed the cardiac depressant effects

All three drugs produced tachycardia, decreased myocardial contractility and stroke volume and widening of electrocardiographic QRS complexes. Thirteen of 19 animals died of ventricular fibrillation: No significant differences in survival or in fatal doses between these

drugs were found. The findings suggest that ropivacaine, levobupivacaine

and bupivacaine have similar intrinsic ability to cause direct fatal cardiac toxicity when administered by left intracoronary arterial infusion in conscious sheep and do not explain the differences between the drugs found with intravenous dosage

Br J Pharmacol. 2001 Feb;132(3):649-58. Br J Pharmacol. 2001 Feb;132(3):649-58. Chang DH,

Limitations of Local Anesthetics

Amount and complexity of the work to be donePatientArea to be anesthetizedDuration of procedureImmobility

Summary

Anamnesa MonitoringTherapy for complicationCompetention developing

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