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Home , Local anesthetic

Local Toxicity: Prevention and Treatment

John W. Wolfe, M.D. Staff Anesthesiologist Indiana University School of Medicine Indianapolis, Indiana John F. Butterworth, M.D. Chairman, Department of Indiana University School of Medicine Indianapolis, Indiana

LESSON OBJECTIVES dine, and the site of on peak Upon completion of this lesson, the reader concentrations in . should be able to: 6. Describe the mechanism of local anes- 1. List the signs and symptoms of local thetic central toxicity. anesthetic toxicity. 7. Identify the risk factors for local anes- 2. Discuss the concept of "maximum safe thetic toxicity. doses of a local anesthetic." 8. Plan the treatment of local anesthetic- 3. Describe methods for reducing the risk of induced cardiac and cardiac local anesthetic toxicity. arrest. 4. Explain the treatment of local anes- 9. Describe the mechanism of local anes- thetic-related neurologic symptoms and thetic cardiovascular toxicity. toxic side effects. 10. Explain the dosage and proposed mech- 5. Discuss the effects of epinephrine, cloni- anism of therapy.

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

Introduction Mechanism of Cardiac and (CNS) toxic Local Anesthetic Toxicity side effects of local are relatively rare but potentially catastrophic complications of local and Local anesthetics normally produce their desired regional anesthesia. Fortunately, the likelihood of a effects on peripheral nerves by binding and inhibit- local anesthetic toxic event can be reduced by ad- ing voltage-gated channels in neural cell herence to good technique. These reactions are in membranes. When a sufficient fraction of these most cases readily treatable. This lesson will review sodium channels are inhibited, the cannot the pharmacology, risk factors, presentation, and depolarize and cannot generate or conduct action treatment of local anesthetic toxicity. potentials.

Curr Rev Nurs Anesth 34(2):13-24, 2011 15 Local anesthetic molecules are weak bases. At these effects likely varies among local anesthetic physiologic pH, they exist in solution as a mixture of agents. tends to produce and neutral, more lipid-soluble molecules and protonated, negative inotropy while rarely producing arrhyth- relatively lipid-insoluble molecules. In order to mias. In contrast, has a greater ten- approach the local anesthetic binding site on Na dency to produce ventricular arrhythmias in addition channels, local anesthetic molecules must penetrate to vasodilation and negative inotropy. to the inner surface of the plasmalemma. The For purposes of this lesson, we have made no uncharged fraction of a local anesthetic molecule mix assumptions as to the mechanism by which local is therefore considered to be the fraction that most anesthetics actually produce either CNS or cardio- readily produces both desired and undesired vascular toxicity. It is possible that these toxic side actions. Curiously, once the molecule gains entry effects occur through binding to sodium channels; it into the cytoplasm, it is the charged form that has is equally possible that another mechanism is oper- greater potency. The different properties of the lipid- ative. soluble and lipid-insoluble fractions are important when one considers treatments for local anesthetic toxicity. Routes for Entry of Local Anesthetic into the There are three principal routes for entry Systemic Circulation of local anesthetic into the plasma: direct There are three principal routes for entry of local injection into an artery or vein, absorption anesthetic into the blood: direct injection into an from a depot dose in other tissues, and artery or vein, absorption from a depot dose in other transcutaneous or transmucosal absorp- tissues, and transcutaneous or transmucosal absorp- tion. tion.

In the plasma, all local anesthetics are bound to Intravascular Injection proteins to varying degrees, primarily to aracid Intravascular injection of local anesthetic agents glycoprotein (AAG) and albumin. Plasma protein is possible with most regional anesthetic techniques levels are affected by disease states and age. The due to the proximity of vascular structures to ner- long-duration local anesthetics (bupivacaine and vous tissue. For example, accidental injection of ) are bound by plasma proteins to a local anesthetic into the epidural venous plexus can greater extent than the less potent, shorter duration occur when dosing an epidural catheter, and injec- local anesthetics. Bupivacaine is approximately 95% tion into the femoral artery or vein can occur during protein-bound. Intermediate-duration local anes- an attempted femoral . thetics (lidocaine and ) have a smaller Injection into an artery feeding the brain must protein-bound fraction (60-70%). Protein binding be considered when performing regional anesthetics helps to reduce the likelihood that local anesthetics in the neck, such as interscalene brachial plexus in blood will enter brain or cardiac tissue causing blocks. With accidental injection of local anesthetic either CNS or cardiac toxicity. into a carotid or vertebral artery, a bolus dose of local Local anesthetics may bind a wide variety of anesthetic at a relatively high plasma concentra- channels and enzymes in cardiac muscle and in the tion is delivered directly to the brain. In this case, CNS, and increased blood concentrations of local one should expect rapid onset of CNS toxic side anesthetics can cause toxic effects in these tissues. effects, with rapid onset of after even a very Possible mechanisms by which local anesthetics can small intravascular injection. Fortunately, due to produce cardiovascular collapse include depression of the typically small dose of local anesthetic injected, cardiac contractility, potentiation of cardiac arrhyth- these seizures are generally short-lived and usually mias, and peripheral vasodilation. The balance of not accompanied by cardiac toxicity.

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

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

16 Current Reviews for Nurse Anesthetists Table 1 Risk Factors for Local Factors Increasing Risk Anesthetic Toxicity of Local Anesthetic Toxicity (see Table 1)

Administration in a site with rapid Route of Administration absorption The location of local anesthetic injection affects Young age its absorption rate and peak plasma concentration. Large total dose of local anesthetic The local anesthetic dose may need to be reduced Renal dysfunction when it is placed into an area with especially rapid Hepatic dysfunction absorption, such as the airway or in intercostal nerve failure blocks, as compared to sites with relatively slow Pregnancy absorption, such as subcutaneous injections or sciatic nerve blocks.

Young Age Infants, particularly those aged 0-3 months, Absorption from Tissues have reduced concentrations of plasma proteins to When local anesthetic is injected into perineural which local anesthetics bind, such as AAG. This connective tissue (as in a peripheral nerve block) or leads to greater peak levels of free (unbound) local the epidural space, the nerve-blocking action is anesthetic after single injections, such as caudal epi- terminated by gradual absorption from the nerve dural blocks. The unbound form is largely respon- into the systemic circulation. Local anesthetic sible for toxic side effects. Infants also have a re- has almost no effect on the duration of duced capacity to metabolize local anesthetic , nerve blocks. Injecting a given dose of local anes- with lower plasma clearance rates than adults This thetic into highly vascular tissue will lead to greater may lead to greater plasma levels when continuous plasma drug concentrations than placing the same infusions of local anesthetics are given. Due to these dose of local anesthetic into a poorly vascularized factors, both bolus doses and infusion rates of local site. Epinephrine is effective in retarding the rate of anesthetics should be reduced in infants. absorption of local anesthetic and reducing peak plasma levels of local anesthetic. The effect of Local anesthetic toxicity symptoms are clonidine is less clear, with some studies showing caused by the free fraction of the local increased plasma local anesthetic concentrations anesthetic drug (the fraction not bound to when clonidine is included in local anesthetic plasma proteins). Any condition that re- solutions. Figure 1 shows the relative absorption duces plasma protein levels may increase rates for local anesthetics after injection into various a patient's risk of local anesthetic toxicity. sites. Tumescent liposuction techniques present a scenario in which large amounts of local anesthetic Total Dose of Local Anesthetic Administered solution may be absorbed into the systemic circu- All other factors being equal, administering lar- lation in an unpredictable manner. Typically, dilute ger doses of local anesthetic will lead to increased lidocaine with epinephrine is injected through the plasma concentrations. Patient size should be con- liposuction cannula. Dangerously elevated plasma sidered when determining a local anesthetic dose. Of lidocaine levels have been reported when large vol- note, it is the product of the concentration and the umes of injectate are used. volume of the local anesthetic solution that is important, not either in isolation; plasma levels of Transcutaneous and Transmucosal Absorption local anesthetic correlate with the total mass of drug Local anesthetics can be absorbed across cutan- given. For example, in most cases 20 ml of a 0.25% eous and mucosal surfaces, most commonly in the ropivacaine solution and 10 ml of a 0.5% ropivacaine oral, nasal, and tracheo-bronchial mucosa. Topical solution will produce the same peak plasma concen- local anesthetic formulations may contain concen- tration. trated local anesthetic and introduce the possibility of delivering many milligrams of drug in a small Presence of Epinephrine volume. Addition of epinephrine to local anesthetic solu- Toxic blood concentrations are possible following tions will normally reduce the rate of absorption transcutaneous absorption of local anesthetic creams and peak plasma levels. Epinephrine 1:400,000 to or gels, particularly in small children. There have 1:200,000 (2.5-5 fig/ml) is as effective as more con- been several deaths reported after patients applied centrated solutions, while having a reduced risk large amounts of topical local anesthetic products to of epinephrine side effects such as , provide anesthesia for hair removal procedures. 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- Table 2 crease rather than decrease peak plasma levels of Early and Late Signs and Symptoms local anesthetics. of Local Anesthetic CNS Toxicity , Renal Dysfunction Early Patients with uremia have a hyperdynamic cir- • Perioral or tongue numbness or culatory state, and they have a more rapid absorp- tingling tion of local anesthetic, with higher peak plasma Altered or metallic taste sensation levels than in non-uremic patients. Many authors Lightheadedness or vertigo have assumed that these two are causally related. Anxiety or panic Partially offsetting this effect, uremic patients have Confusion greater levels of AAG than non-uremic patients. The Somnolence AAG tends to bind local anesthetic in the plasma, reducing the concentration of free drug. It has Late been recommended that a dose reduction of 10- • activity (generally tonic- 20% be applied when administering regional clonic) anesthetics to patients with renal dysfunction. • Depressed level of consciousness or Liver Dysfunction • Respiratory depression or arrest While mild hepatic dysfunction appears to have a minimal effect on local anesthetic levels, patients with end-stage liver dysfunction (ESLD) may have significantly reduced hepatic clearance rates for local anesthetics. In ESLD, patients have an increased pregnancy, lead to an exaggerated spread of spinal volume of distribution for local anesthetics. This, and epidural local anesthetics. plus the continued presence of AAG in the plasma even in ESLD, leads to a recommendation that normal doses of local anesthetic may be used for Signs and Symptoms of single-dose techniques in patients with liver dys- Local Anesthetic Toxicity function. Continuous infusions of local anesthetics, how- CNS Signs and Symptoms ever, must be significantly reduced in patients with After an accidental intravenous injection, local hepatic dysfunction due to their lower rate of clear- anesthetics produce signs and symptoms of CNS ance of these drugs. Dose reductions of 10-50% have toxicity at lower doses and earlier than signs and been suggested based on the severity of the hepatic symptoms of cardiovascular toxicity. However, the dysfunction. longer-acting local anesthetics (particularly bupiva- caine) may produce toxicity in the CNS and myo- cardium simultaneously, and there are even reports The addition of epinephrine to local anes- of cardiovascular toxicity without any CNS side thetic solutions will generally slow the effects. One should also keep in mind that drugs rate of absorption and reduce peak local commonly given for (e.g., or anesthetic concentrations in blood. propofol) may increase the seizure threshold. The effects of elevated systemic levels of local Heart Failure anesthetics are generally divided into early and late Patients with mild, well-controlled heart failure signs and symptoms, as shown in Table 2. may not require any reduction in local anesthetic dosing. In patients with severe heart failure, how- Cardiovascular Signs and Symptoms ever, clearance of local anesthetic drugs may be There is evidence from animal studies that substantially reduced due to decreased hepatic blood bupivacaine and lidocaine cardiotoxicity may take flow and clearance. different forms. Lidocaine tends to decrease myo- cardial contractility and cause peripheral vasodila- Pregnancy tion, leading to as a prominent sign of Pregnant patients have increased sensitivity to lidocaine toxicity. In animal studies, animals re- local anesthetics, allowing dose reductions. They ceiving lidocaine to the point of cardiovascular col- also have a reduced degree of protein binding of local lapse will almost never demonstrate cardiac anesthetics. Because of the increased sensitivity and arrhythmias. In contrast, bupivacaine tends to pro- higher risk of toxic effects, local anesthetic doses duce aberrant conduction and arrhythmias (in should be reduced in pregnant patients. Other addition to producing vasodilation and myocardial factors, including the reduced spinal CSF volume in depression) leading to .

18 Current Reviews for Nurse Anesthetists' In general, cardiac signs of local anesthetic in- Fractionated Doses with Multiple Aspirations toxication include: Nerve block needles and epidural catheters can • Transient hypertension and tachycardia (espec- move, and an initially well-positioned needle or ially if epinephrine is present) catheter may become intravascular. Doses of local • Hypotension anesthetic should be divided into aliquots s 5 ml, • Bradycardia with aspiration between injections. Always observe • Cardiac arrhythmias, including premature ven- the patient's condition and vital signs during tricular contractions, ventricular tachycardia, injection because negative aspiration for blood does ventricular fibrillation, pulseless electrical ac- not guarantee that local anesthetic is not entering a tivity, and cardiac arrest. vein. This is especially important if a small gauge needle is utilized. Techniques for Reducing Slow Injection Speed the Likelihood of Injury from Fast, forceful injection of local anesthetic may Local Anesthetic Toxicity increase the risk of local anesthetic channeling into (see Table 3) veins or other vascular structures. It also may increase the risk of pressure injuries to nerves Basic Preparations during peripheral nerve blocks. We normally inject Whenever one administers local anesthetic to a local anesthetic no faster than 5 mL at a time and patient in doses sufficient to produce toxicity, one will usually not administer more than three such should apply appropriate monitors (pulse oximetry increments per minute. and non-invasive blood pressure at a minimum) and be certain that emergency resuscitation drugs Use of Test Doses and equipment are available. The latter should Accurate placement of a needle in the epidural include devices, an electrical space or perineurally does not guarantee that a defibrillator, and a lipid emulsion solution. catheter passed through it will not enter a vascular structure. Dilute epinephrine (2.5 to 5 ng/mL) may The long-acting local anesthetics (partic- be used as a marker for intravascular injection. Test ularly bupivacaine) may produce toxicity doses of (generally containing epine- in the CNS and myocardium simultan- phrine) should be given when initiating use of an ^ eously. epidural or nerve block catheter and should be repeated if there is any indication that the catheter position may have changed. Use of Lowest Effective Doses The lowest practical dose or volume of local anesthetic solution that will produce the intended therapeutic effect should be used. In patients with Table 3 medical conditions that predispose them to local Techniques for Reducing anesthetic toxicity, one should choose the peripheral Local Anesthetic Toxicity Risk nerve block locations and techniques that permit reduced doses of local anesthetic. For example, Have appropriate monitors and studies suggest that ultrasound guidance permits resuscitation equipment available the use of significantly lower doses of local anesthetic whenever regional anesthetics are for supraclavicular blocks compared with nerve placed stimulator-guided axillary blocks. Use the lowest effective dose to achieve the desired anesthetic Ultrasound Imaging endpoint The use of ultrasound guidance for peripheral Use ultrasound guidance when it nerve blocks may reduce the risk of local anesthetic will facilitate the use of lower toxicity in several ways. As mentioned above, the doses of local anesthetic use of ultrasound guidance may allow the use of Inject local anesthetic slowly, lower volumes of local anesthetic solutions while with frequent aspirations maintaining acceptable surgical anesthesia. Unlike Use test doses to verify placement nerve stimulator or landmark techniques, the nerve of epidural and nerve block block needle is visualized during positioning and catheters injection, potentially reducing the risk of accidental Avoid redosing of local anesthetics vascular puncture and potentially reducing the volume needed to detect an accidental intravascular whenever possible injection.

Curr Rev Nars Anesth 34(2): 13-24, 2011 19 Avoidance of Repeated Dosing Treatment of Local Anesthetic CNS Toxicity When repeating nerve block injections (e.g., after If a patient exhibits mild-to-moderate symptoms a failed block) over a short time interval, one must be and signs of local anesthetic toxicity (e.g., , aware of the cumulative dose of local anesthetic that lightheadedness, tremulousness, myoclonic jerks, or has been administered. confusion) without seizure activity or signs of cardiac toxicity, it may be appropriate to provide conserva- tive treatment in the form of reassurance and mild Treatment of Systemic sedation and anxiolysis with benzodiazepines. A Local Anesthetic Toxicity conservative approach is most appropriate with (see Tables 4 and 5) toxicity symptoms due to intermediate-duration local anesthetics (lidocaine, mepivacaine), and when the Treatment for systemic local anesthetic toxicity symptoms are expected to be brief and of limited should be guided by the form of toxicity the patient severity, such as occurs commonly after release of a is experiencing (CNS vs. cardiovascular vs. ) Bier block. and the local anesthetic agent used (bupivacaine When the CNS symptoms and signs include loss and related drugs appear to require a different of consciousness or seizures, standard resuscitation approach to cardiac resuscitation than the less measures should begin including control of the potent local anesthetics). In general, milder symp- airway and breathing. that are useful toms should be treated with more conservative for treatment of local anesthetic-induced seizures actions. Nevertheless, mild CNS symptoms may include benzodiazepines, barbiturates, and propofol. rapidly progress into local anesthetic cardiotoxicity Small doses of these drugs are recommended (e.g., with arrhythmias and cardiac arrest, and one should midazolam 2-4 mg, propofol 0.5-1 mg/kg). Propofol frequently re-evaluate whether more aggressive doses in particular should be kept low due to propo- therapies are required. fol's cardiodepressant activity, which may worsen any subsequent local anesthetic cardiotoxicity. Phenytoin and fosphenytoin have generally been avoided in the treatment of local anesthetic toxicity because they share the sodium channel blocking Table 4 actions of local anesthetics and may potentiate their Treatments for toxicity. Local Anesthetic Toxicity

• Mild neurologic symptoms (tinnitus, Lidocaine (and related agents with mod- lightheadedness, confusion) may be erate potency and duration) tends to de- treated with observation and crease myocardial contractility and cause reassurance if they are expected to peripheral vasodilation, leading to hypo- be brief in duration. tension as a prominent sign of lidocaine • Local anesthetic-induced seizures toxicity. In contrast, bupivacaine will should be treated with small doses often produce aberrant conduction and of benzodiazepines, barbiturates, arrhythmias leading to cardiac arrest. or propofol. Phenytoin and phosphenytoin should be avoided. Treatment of Local Anesthetic Cardiac Toxi- • When treating local anesthetic- city: Antiarrhythmics induced arrhythmias, lidocaine, If unexplained hypotension, bradycardia, or beta blockers, and calcium channel arrhythmias are detected, treatment for suspected blockers should be omitted. local anesthetic cardiac toxicity should begin without • When local anesthetic cardiotoxicity delay. Resuscitation of a patient with local anes- has been caused by bupivacaine, thetic-induced cardiovascular collapse can require , or ropivacaine, prolonged and extensive resuscitative efforts, par- doses of epinephrine and vaso- ticularly with bupivacaine-induced toxicity, and may pressin should be reduced during prove unsuccessful. Treatment may begin with resuscitation. standard advanced cardiac life support (ACLS) • Lipid emulsion therapy should be methods, but we recommend some minor changes to initiated as soon as possible in cases the standard protocols. of local anesthetic cardiotoxicity. We omit lidocaine from resuscitation of patients • Cardiopulmonary bypass should be with local anesthetic-induced arrhythmias due to its considered as a treatment of last potential to produce an additive effect with the resort when other therapies have "intoxicating" local anesthetic agent. While we failed. suspect that amiodarone may be a better choice for treatment of ventricular arrhythmias, conclusive data are lacking.

20 Current Reviews for Nurse Anesthetists Table 5 Recommended Treatment of Severe Local Anesthetic Toxicity 1. Call for help. Initiate a rapid response system ("Code Blue"), if available and adequate assistance 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, , , or : 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- recommend that if vasopressin is used, it should be clude depressed contractility. One should avoid ad- dosed incrementally rather than as a single large ministering other negative inotropes in this circum- bolus. stance. Local anesthetic injections should always Treatment of Local Anesthetic Cardiotoxicity: be fractionated and frequent aspirations Epinephrine and/or Vasopressin for blood should be performed during Recent animal studies indicate that in cases of injection. Test doses should always be bupivacaine cardiotoxicity, high-dose epinephrine given prior to initiating use of an epidural may exacerbate resuscitation efforts and worsen or peripheral nerve catheter. outcomes. Based on the available animal and human data we recommend that epinephrine be admin- istered incrementally (even in resuscitation) starting Treatment of Local Anesthetic Cardiotoxicity: with 1 ng/kg and basing additional doses on the Lipid Emulsion patient's response, rather than immediately giving Infusion of a 20% lipid emulsion solution (such 10-15 M-g/kg as a bolus. as Intralipid™) appears to be a surprisingly effective _ Whether vasopressin should be used routinely in treatment for severe local anesthetic cardiotoxicity. combination with epinephrine (as some animal Multiple case reports and animal studies indicate the results would suggest) or avoided completely due to efficacy of this treatment and its apparent lack of a propensity for producing pulmonary edema (as it noxious side effects. The evidence supporting lipid does in rodents) remains highly controversial. We emulsion 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 lipid tors and resuscitation equipment available, using the doses. The regimen described below has been widely lowest effective dose of local anesthetic, injecting reported, and is based on discussions with inves- slowly and with multiple aspirations, and using test tigators and clinicians who have used lipid success- doses prior to dosing epidural and peripheral nerve fully for cardiac toxicity. Boluses and short-term catheters. Treatment of CNS toxicity includes infusions of 20% lipid emulsion appear to have suppression of seizures and supportive care. almost no important side effects. In the setting of Treatment of cardiovascular symptoms consists of local anesthetic toxicity, the benefits of fairly liberal ACLS techniques (with omission of lidocaine, calcium lipid emulsion dosing will likely outweigh any risks channel blockers, beta-blockers, and consideration of or side effects. reduced doses of epinephrine and vasopressin). Lipid The mechanism by which 20% lipid emulsion emulsion therapy should be initiated as rapidly negates local anesthetic toxicity is not clear. Most as possible. In cases of refractory cardiovascular likely, microscopic lipid micelles provide a large collapse, Cardiopulmonary bypass should be insti- lipid-rich component in the plasma. Local anesthetic tuted. molecules bind these lipid micelles, and the micelles likely act as a "lipid sink", effectively sequestering the active drug from the circulation. The local anes- References thetic drug is then gradually removed from the blood th stream and metabolized as the lipid micelles are Butterworth, JF 4 : Models and mechanisms of local broken down by the liver. anesthetic cardiac toxicity: a review. Regional Anes- Administration of propofol will NOT provide thesia & Medicine 35(2):167-76, 2010. (Review of sufficient lipid to assist in resuscitation from local the possible mechanisms of local anesthetic toxicity) anesthetic-induced cardiac toxicity. In order to ad- Di Gregorio G, Neal J, Rosenquist R, Weinberg, GL: minister sufficient lipid, cardiotoxic doses of propofol Clinical presentation of local anesthetic systemic would be required. toxicity: a review of published cases, 1979 to 2009. Regional Anesthesia & Pain Medicine 35(2):181-87, Infusion of a 20% lipid emulsion solution 2010. (Retrospective review of reported signs and (such as Intralipid™) appears to be an symptoms of local anesthetic toxicity) effective treatment for severe local anes- thetic cardiotoxicity. Drasner K: Local anesthetic systemic toxicity: a historical perspective. Regional Anesthesia & Pain Medicine 35(2):181-87, 2010. (Interesting review of Treatment of Local Anesthetic Cardiotoxicity: history of local anesthetic toxicity and treatments) Cardiopulmonary Bypass The arrhythmias, hypotension, and cardiac Killer DB, Gregorio GD, Ripper R, Kelly K, Massad M, collapse associated with bupivacaine (and associated Edelman L, Edelman G, Feinstein DL, Weinberg GL: long-acting local anesthetic agents) toxicity have Epinephrine impairs lipid resuscitation from bupiv- been reported to be quite refractory to standard acaine overdose: a threshold effect. 111 ACLS resuscitation methods. Resuscitation efforts (3):498-505, 2009. (Animal study investigating full- may be prolonged, with some patients potentially not dose versus low-dose epinephrine with lipid emulsion responding to standard drugs and therapies. When in severe bupivacaine cardiotoxicity) all other methods have failed, several surviving th patients have been emergently placed on cardio- Neal JM, Bernards CM, Butterworth JF 4 , Di Gre- pulmonary bypass for Cardiopulmonary support and gorio G, Drasner K, Hejtmanek MR, Mulroy MF, to allow time for clearance of a sufficient quantity of Rosenquist RW, Weinberg GL: ASRA Practice Advisory the local anesthetic drugs from target tissues to on Local Anesthetic Systemic Toxicity. Regional Anes- permit survival. There are case reports of successful thesia & Pain Medicine 35(2): 152-61, 2010. (Evidence- resuscitations using Cardiopulmonary bypass after based review article on the subject of local anesthetic toxicity) all other therapies have failed. Rosenberg PH, Veering BT, Urmey WF: Maximum Summary recommended doses of local anesthetics: a multifac- torial concept. Regional Anesthesia & Pain Medicine Local anesthetic toxicity can be a catastrophic 29(6):564-75, 2004. (Review article discussing the complication of regional anesthesia. It may present pharmacokinetics of local anesthetic peak plasma with CNS symptoms, cardiovascular symptoms, or levels) both. Patients' size, age, and comorbidities may in- crease their risk of local anesthetic toxic symptoms. Weinberg GL: http://lipidrescue.org (Dr. Guy Wein- Techniques for reducing the risk of injury from local berg's website focusing on lipid emulsion therapy for anesthetic toxicity include having appropriate moni- local anesthetic toxicity, accessed on 26 May 2010)

22 Current Reviews for Nurse Anesthetists