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HISTORY AND EPIDEMIOLOGY
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Local anesthetics block excitation of and transmission along a nerve axon in a predictable and reversible manner. In contrast to the nonselective effects of a general anesthetic, the anesthesia produced is selective to the chosen body part. Because local anesthetics do not require the circulation as an intermediate carrier and usually are not transported to distant organs, their actions are largely confined to the structures with which they come into direct contact. Local anesthetics are used to provide analgesia in various parts of the body by topical application, injection in the vicinity of peripheral nerve endings and major nerve trunks, or via instillation within the ophthalmic, epidural or subarachnoid spaces. The various local anesthetics differ with regard to their potency, duration of action, and degree of effects on sensory and motor nerve fibers. Toxicity is either local or systemic. With systemic toxicity, central nervous system (CNS) and cardiovascular effects are of greatest concern.
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Until the 1880s, the only available analgesics were centrally acting depressants such as alcohol and opioids, which blunted the perception of pain rather than addressing the underlying cause. In 1860, the chemist Albert Niemann extracted the active alkaloid cocaine (Chap. 75) from the leaves of the coca shrub (Erythroxylon coca). Over the next 2 decades, the local anesthetic properties of the drug were identified. In 1884, Koller performed glaucoma surgery with only topical cocaine anesthesia.54
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Although the clinical benefits of cocaine anesthesia were significant, so were its toxic and addictive potential. At least 13 deaths were reported in the first 7 years after the introduction of cocaine in Europe, and within 10 years after the introduction of cocaine as a regional anesthetic, reviews of “cocaine poisoning” appeared in the literature.89,111 The toxicity of cocaine, coupled with the tremendous advantages it provided for surgery, led to a search for less toxic substitutes.
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After the elucidation of the chemical structure of cocaine (the benzoic acid methyl ester of the alkaloid ecgonine) in 1895, other amino esters were examined. Synthetic compounds with local anesthetic activity were introduced but were highly toxic or irritating or had an impractically brief clinical effect. In 1904, Einhorn synthesized procaine, but its short duration of action limited its clinical utility. Research turned to focus on synthesis of local anesthetics with more prolonged durations of action.
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The potent, long-acting local anesthetics dibucaine and tetracaine were synthesized in 1925 and 1928, respectively, and were introduced into clinical practice shortly thereafter. These anesthetics were not safe for regional anesthetic techniques because of potential systemic toxicity secondary to the combination of high potency, delayed metabolism, and the larger volumes of drug required for regional anesthesia compared with local anesthesia. On the other hand, these anesthetics were very useful for spinal anesthesia, which required much smaller volumes.
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Lofgren synthesized lidocaine in 1943 from a series of aniline derivatives. This amino amide combined high tissue penetrance and a moderate duration of action with acceptably low systemic toxicity. Additionally, unlike amino ester anesthetics, the metabolites of lidocaine did not include para-aminobenzoic acid (PABA), responsible for allergic reactions. Subsequent to the release of lidocaine in 1944, several other amino amide compounds were introduced into clinical practice including mepivacaine (1956), prilocaine (1959), bupivacaine (1963), etidocaine (1971), and ropivacaine (1996).
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Considering the frequency of local anesthetic use, both within and outside health care facilities, clinically significant toxic reactions are relatively uncommon. In reports of fatalities resulting from toxic exposures reported to US poison control centers, local anesthetics are rarely implicated, representing fewer than 0.5% of cases (Chap. 130). Iatrogenic poisonings result from inadvertent injection of a therapeutic dose into a blood vessel, repeated use of a therapeutic dose, or unintentional administration of a toxic dose. The amide local anesthetics have largely replaced the esters in clinical use because of their increased stability and relative absence of hypersensitivity reactions (see Pharmacology later). Poisoning from topical benzocaine is relatively common because of the large number of nonprescription products available for treatment of teething and hemorrhoids. With nonprescription use, toxic effects after exposure are typically mild, and death rarely occurs. Toxicity usually occurs as a therapeutic misadventure, the potential for child abuse or neglect should be evaluated if the patient is younger than 2 years, and potential suicide should be evaluated in older children and adults.
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Benzocaine spray is the most important cause of severe acquired methemoglobinemia in the hospital setting (Chap. 124).33 Between November 1997 and March 2002, the US Food and Drug Administration (FDA) received 198 reported adverse events secondary to benzocaine products. A total of 132 cases (66.7%) involved definite or probable methemoglobinemia; most were serious adverse events, and 2 deaths occurred.98 In these cases, a single spray of unspecified duration of 20% benzocaine was the dose most commonly reported. In 2003 and again in 2006, the FDA issued advisories regarding the use of benzocaine spray for topical mucosal anesthesia before intubation, upper endoscopy, and transesophageal echocardiography. In 2006, the US Veterans Health Administration halted the use of benzocaine spray for topical anesthesia. At this point in time, any continued use of topical benzocaine spray should be undertaken with extreme caution after careful assessment of risks, benefits, and alternatives, with antidotal therapy readily available.
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Local anesthetics fall into one of two chemically distinct groups: amino esters and amino amides (Fig. 64–1). The basic structure of all local anesthetics consists of three major components: a lipophilic, aromatic ring connected by an ester or amide linkage to a short alkyl intermediate chain that in turn is bound to a hydrophilic tertiary (or less commonly, secondary) amine. The amine group acts as a base, accepting protons and becoming charged at a higher pH.
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The proportion of charged molecules is dependent upon the pKa of the specific local anesthetic.
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All local anesthetics function primarily by reversibly binding to specific receptor proteins within the membrane-bound sodium channels of conducting tissues. These receptors are reached only via the cytoplasmic (intracellular) side of the cell membrane. Blockade of ion conductance through the sodium channel eventually leads to failure to initiate and propagate action potentials (Fig. 64–2). The analgesic effect results from inhibiting axonal transmission of the nerve impulse in small-diameter myelinated Aδ (“fast pain”) and unmyelinated C (“slow pain”) nerve fibers carrying pain and temperature sensation. Conduction block of these fibers occurs at lower local anesthetic concentrations than required for the larger fibers responsible for touch, motor function, and proprioception.30 This likely occurs in myelinated nerves because smaller fibers have closer spacing of the nodes of Ranvier. Given that a fixed number of nodes must be blocked for conduction failure to occur, the shorter critical length of nerve is reached sooner by the locally placed anesthetic in small fibers.46 For unmyelinated fibers, the smaller diameter limits the distance that such fibers can passively propagate the electrical impulse. Differential nerve blockade is also related to voltage- and time-dependent affinity of local anesthetics to the sodium channels.
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The sodium channel exists in three classes (Chap. 15 and Fig. 15–2). At resting membrane potential or in the hyperpolarized membrane, the channel is closed to sodium conductance. With an appropriate activating stimulus, the channel opens, allowing rapid sodium influx and membrane depolarization. Milliseconds later, the channel is inactivated, terminating the fast sodium current. Local anesthetic blockade is much stronger for channels that are activated (open) or inactivated than for channels that are resting. Analogous to the use-dependent kinetics of class I antidysrhythmics, pain fibers have a higher firing rate and longer action potential (ie, more time with the sodium channel open or inactivated) than other fiber types and therefore are more susceptible to local anesthetic action.62
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These effects also occur in conductive tissues in the heart and brain that rely on sodium current. Although sodium channel blockade initially was believed to be the sole cause of systemic toxicity, mechanisms are more complex, especially in the heart, and occur at systemic concentrations lower than previously thought.91 Recent proteomics analyses suggest that phosphatidyl-3-kinase (PI3K) plays a central role in pathways associated with bupivacaine-associated neurotoxicity.145
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Growing evidence indicates that local anesthetics directly affect many other organ systems and functions such as the coagulation, immune, and respiratory systems, all at concentrations much lower than those required to achieve sodium channel blockade.20,61,62 For example, lidocaine inhibited muscarinic signaling in Xenopus oocytes at less than 50% of the concentration required for sodium channel blockade.62 Study of these less well-described effects may help elucidate both therapeutic and toxic phenomena that are incompletely explained.
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The primary determinant of the onset of action of a local anesthetic is its pKa, which affects its lipophilicity (Table 64–1). All local anesthetics are weak bases, with a pKa between 7.8 and 9.3. At physiologic pH (7.4), xenobiotics with a lower pKa have more uncharged molecules capable of crossing nerve cell membranes, producing a faster onset of action than xenobiotics with a higher pKa. The onset of action also is influenced by the total dose of local anesthetic administered, which effects the concentration responsible for diffusion.
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Local anesthetic potency is highly correlated with the lipid solubility of the xenobiotic. Therefore, the aromatic side of the anesthetic is the primary determinant of potency. The hydrophilic amine is important in occupying the sodium channel, which involves an ionic interaction with the charged form of the tertiary amine. The length of the intermediate chain is another determinant of local anesthetic activity, with three to seven carbon equivalents providing maximal activity.30 Shorter or longer intermediate chain lengths are associated with rapid loss of local anesthetic action, suggesting that a critical length of physical separation between the aromatic group and the tertiary amine is required for sodium channel blockade to occur.
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The degree of protein binding influences the duration of action of a local anesthetic. Anesthetics with greater protein binding remain associated with the neural membrane for a longer time interval and therefore have longer durations of action.30 When high serum concentrations are achieved, a higher degree of protein binding increases the risk for cardiac toxicity.
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A distinction must be made between local disposition (distribution and elimination) and systemic disposition of the anesthetic. Local distribution is influenced by several factors, including spread of local anesthetic by bulk flow, diffusion, transport via adjacent blood vessels, and binding to proximate tissues. Local elimination occurs through systemic absorption, transfer into the general circulation, and local hydrolysis of amino ester anesthetics. Systemic absorption decreases the amount of local anesthetic that is available for anesthetic effect, thereby limiting the duration of the block. Systemic absorption depends on the avidity of binding of local anesthetics to tissues near the site of injection and on local perfusion. Both these factors vary with the site of injection. In general, areas with greater blood flow will have more rapid and complete systemic uptake of local anesthetic; for example, intravenous (IV) > tracheal > intercostal > paracervical > epidural > brachial plexus > sciatic > subcutaneous.
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Because of their lipophilicity, local anesthetics readily cross cell membranes, the blood–brain barrier, and the placenta. After being absorbed, systemic tissue distribution is highly dependent on tissue perfusion. After local anesthetics enter the venous circulation, they pass through the lungs, where significant uptake occurs, thereby lowering peak arterial concentrations. Thus, the lungs serve as a buffer against systemic toxicity, but the capacity of the lungs to accumulate drug is saturable.80 Part of the reason why most local anesthetic–induced seizures result from unintentional intravascular bolus injection rather than absorptive uptake is that lung uptake of these drugs exceeds 90%. The very high peak venous concentrations produced by rapid injection usually are necessary to produce toxic arterial concentrations.
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All local anesthetics, except cocaine, cause peripheral vasodilation by direct relaxation of vascular smooth muscle. Vasodilation enhances vascular absorption of the local anesthetic. Addition of epinephrine (5 mcg/mL or 1:200,000) to the local anesthetic solution decreases the rate of vascular absorption, thereby improving the depth and prolonging the duration of local action, and mitigating risk of systemic toxicity. Local anesthetic mixed with epinephrine also decreases bleeding into the surgical field and serves as a marker for inadvertent intravascular injection (by producing tachycardia) when a test dose of the mixture is injected through a needle or catheter.95 Significant drawbacks to epinephrine use include uncomfortable side effects such as palpitations and tremors, local tissue ischemia, and life-threatening systemic adverse reactions in susceptible patients (eg, myocardial ischemia and hypertensive crises). Inadvertent intravascular injection of local anesthetics mixed with epinephrine can be fatal, although generally the epinephrine in these mixtures is very dilute.86
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The two classes of local anesthetics undergo metabolism by different routes (Chap. 75). The amino esters are rapidly metabolized by plasma cholinesterase to the major metabolite, PABA. The amino amides are metabolized more slowly in the liver to a variety of metabolites that do not include PABA.29 Patients with enzymatic mutations or low or absent concentrations of plasma cholinesterase (pseudocholinesterase) are at increased risk for systemic toxicity from amino ester local anesthetics. Factors that decrease hepatic blood flow or impair hepatic function increase the risk for toxic reactions to the amino amides and make management of serious reactions more difficult. Patient age, as it relates to liver enzyme activity and plasma protein binding, influences the rate of metabolism of local anesthetics. Whereas lidocaine’s terminal half-life after IV administration averaged 80 minutes in volunteers aged 22 to 26 years, the half-life was 138 minutes in those aged 61 to 71 years (Chap. 32).103 Newborns with immature hepatic enzyme systems have prolonged elimination of amino amides, which is associated with seizures when high continuous infusion rates are used.1,92 Lidocaine elimination is reduced by congestive heart failure or coadministration of xenobiotics that reduce hepatic blood flow, thus explaining the increased risk of toxicity with cimetidine and propranolol.117 Propranolol and cimetidine also potentially decrease lidocaine clearance by inhibiting hepatic CYP450 enzymes, including CYP1A2 and CYP3A4 involved in lidocaine N-deethylation and 3-hydroxylation in humans.137
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Local anesthetics are often mixed to take advantage of desirable pharmacokinetics. In theory, rapid-acting, relatively short-duration local anesthetics such as chloroprocaine and lidocaine can be combined with the longer latency, long-acting tetracaine or bupivacaine to enable an immediate and prolonged anesthetic response. In practice, the advantages of the mixtures are small, and toxicities are additive.6 Administration of one local anesthetic increases the free plasma fraction of another by displacement from protein-binding sites.67
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Local anesthetics usually cannot penetrate intact skin in sufficient quantities to produce reliable anesthesia.14 Efficient skin penetration requires the combination of a high water content and a high concentration of the water-insoluble base form of the local anesthetic. This combination of properties is achieved by mixing lidocaine and prilocaine in their base forms in a 1:1 ratio (eutectic mixture of local anesthetics {EMLA}).18 Application for at least 45 minutes is required to achieve adequate dermal analgesia. Local anesthetic uptake continues for several hours during application. A liposomal formulation of 4% lidocaine (ELA-Max) facilitates skin absorption.49 It is as effective as lidocaine–prilocaine base for topical anesthesia.40,71 In addition, a 4% tetracaine gel preparation is used in children for topical skin anesthesia with an onset of action and efficacy at least as good as lidocaine–prilocaine base without any systemic side effects
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The low molecular weight of local anesthetics is associated with rapid absorption and subsequent elimination and therefore relatively short duration of action. Recently, a liposomal bupivacaine formulation was introduced as a long acting postsurgical anesthetic.22,85 After local infiltration, the product has a terminal half-life 9.8-fold greater than that of plain bupivacaine. Significantly elevated plasma bupivacaine concentrations were observed for 96 hours after local infiltration of the liposomal formulation but do not correlate with local efficacy.3,64 Current manufacturer recommendations warn against use of all local anesthetics within 96 hours of liposomal bupivacaine administration because local infiltration has the potential to precipitate an immediate release of local anesthetic from the liposomal formulation, with subsequent systemic toxicity.
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CLINICAL MANIFESTATIONS OF TOXICITY
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Although the most common adverse reactions to local anesthetics are vasopressor syncopal events associated with injection, the following sections focus on their local and systemic toxicity.134
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Regional Side Effects and Tissue Toxicity
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At a sufficient concentration, all local anesthetics are directly cytotoxic to nerve cells. However, in clinically relevant doses, they rarely produce localized nerve damage.73,102 Significant direct neurotoxicity results from intrathecal injection or infusion of local anesthetics for spinal anesthesia. In this setting, lidocaine has an increased risk for both persistent lumbosacral neuropathy and a syndrome of painful but self-limited postanesthesia buttock and leg pain or dysesthesia referred to as transient neurologic symptoms.66 Nerve damage often is attributed to the use of excessively concentrated solutions or inappropriate formulations. Several reports of cauda equina syndrome are associated with use of hyperbaric 5% lidocaine solutions for spinal anesthesia. Hyperbaric solutions are denser than cerebrospinal fluid. This neurotoxicity appears to be a phenomenon that occurs when the anesthetic is injected through narrow-bore needles or through continuous spinal catheters. This process results in very high local concentrations of the anesthetic that might pool around the sacral roots because of inadequate mixing.118 The mechanism of this neurotoxicity is unknown but is believed to be independent of sodium channel blockade.66 Because an equally effective block can be achieved with injection of larger volumes of lower concentration, 5% lidocaine is generally avoided and bupivacaine used instead. There is a significant (up to 10-fold) increase in the development of new neurologic dysfunction after receiving a neuraxial block in patients with preexisting peripheral neuropathy, a fact emphasizing the importance of informed consent and risk communication.57
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Similar severe neurotoxic reactions occur after massive subarachnoid injection of chloroprocaine during attempted epidural anesthesia.115 The neurotoxicity initially was attributed to use of the antioxidant sodium bisulfite and the low pH of the commercial solution rather than use of the anesthetic itself.136 Despite reformulation without bisulfite, subsequent animal data suggest that chloroprocaine itself is responsible for the neurotoxicity.131 Skeletal muscle changes are observed after intramuscular injection of local anesthetics, especially the more potent, longer acting local anesthetics. The effect is reversible, and muscle regeneration is complete within 2 weeks after injection of local anesthetics.10
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Although rare, after peripheral nerve or plexus block, transient or prolonged postoperative neuropathy is well recognized. Likely mechanisms include direct injury of the nerve related to intraneuronal injection and local anesthetic neurotoxicity. The frequency of peripheral neuropathies reported after peripheral nerve blockade varies from 0% to more than 5%.15 Direct visualization of peripheral nerves via ultrasonography reduces this complication, avoiding traumatic injury and allowing for injection of less local anesthetic to produce adequate nerve block.80,126 In one study, intraneural injection occurred in 17% of supraclavicular or interscalene blocks, but ultrasonographic identification prevented further injection.8 Analysis of 12,668 ultrasound-guided nerve blocks for peripheral regional anesthesia found that the incidences of postoperative neurologic symptoms lasting longer than 5 days and 6 months were 0.18% and 0.008%, respectively.126 Visualization of the target site via ultrasound guidance also decreases local anesthetic systemic toxicity, likely because of reduced incidence of inadvertent vascular puncture.8
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Systemic Side Effects and Toxicity
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Allergic reactions to local anesthetics are extremely rare. Fewer than 1% of all adverse drug reactions caused by local anesthetics are immunoglobulin (Ig) E mediated.49 In one study designed to determine the prevalence of true local anesthetic allergy in patients referred to an allergy clinic for suspected hypersensitivity, skin prick and intradermal testing results were negative for all 236 participants tested.11 As noted, the amino esters are responsible for the majority of true allergic reactions. When hydrolyzed, the amino ester local anesthetics produce PABA, a known allergen (Chap. 46). Cross-sensitivity to other amino ester anesthetics is common. Some multidose commercial preparations of amino amides contain the preservative methylparabens (Chap. 46), chemically related to PABA, and most likely the cause of the much rarer allergic reactions attributed to amino amides. Preservative-free amino amides, including lidocaine, are appropriate for use in patients who have reactions to drug preparations containing methylparabens unless the patient is specifically sensitive to lidocaine. If the patient with a history of allergic reaction to a particular anesthetic requires a local anesthetic, a paraben preservative-free drug from the opposite class can be chosen because there is no cross-reactivity between the amides and esters.
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Methemoglobinemia is a frequent adverse effect of topical and oropharyngeal benzocaine and is occasionally reported with lidocaine, tetracaine, or prilocaine use. Most reports of methemoglobinemia associated with local anesthetics are the result of an excessive dose or a break in the normal mucosal barrier for topical anesthetics (Chap. 124).
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Benzocaine is initially metabolized to aniline and then further metabolized to phenylhydroxylamine and nitrobenzene, which are both potent oxidizing agents (Chap. 124). Although reports describe methemoglobinemia resulting from standard doses of benzocaine topical oropharyngeal spray given for laryngoscopy or gastrointestinal upper endoscopy, affected patients commonly have abnormal mucosal integrity as occurs with thrush or mucositis.38,98 Prilocaine is an amino ester local anesthetic primarily used in obstetric anesthesia because of its rapid onset of action and low systemic toxicity in both the mother and fetus. Use of large doses of prilocaine lead to the development of methemoglobinemia.59,82 An aniline derivative, prilocaine undergoes hepatic metabolism to produce ortho-toluidine, another oxidizing agent.59 A direct relationship exists between the amount of epidural prilocaine administered and the incidence of methemoglobinemia. A dose greater than approximately 8 mg/kg is generally necessary to produce effects and symptoms, which are often not apparent until several hours after epidural administration of the drug. Lidocaine–prilocaine cream, often used in the outpatient setting for minor dermal procedures, is associated with significant methemoglobinemia, more commonly in children than in adults.53 Standard doses of lidocaine–prilocaine cream used for circumcision in term neonates are associated with minimal production of methemoglobin, but risks may be increased in neonates with metabolic disorders.129 The diagnosis of methemoglobinemia is suggested by cyanosis unresponsive to oxygen in individuals with normal cardiopulmonary examinations and known oxidant exposure and presence of chocolate brown blood. It is confirmed by direct measurement of methemoglobin with a cooximeter. When clinically indicated, we recommend treating affected patients with symptomatic methemoglobinemia with IV methylene blue (Chap. 124 and Antidotes in Depth: A43).
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Local Anesthetic Systemic Toxicity
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Systemic toxicity for all local anesthetics correlates with serum concentrations. Factors that determine the concentration include dose; rate of administration; site of injection (absorption occurs more rapidly and completely from vascular areas, such as with neck and intercostal blocks); the presence or absence of a vasoconstrictor; and the degree of tissue–protein binding, fat solubility, and pKa of the local anesthetic.97 The brain and heart are the primary target organs for systemic toxicity because of their rich perfusion, moderate tissue–blood partition coefficients, lack of diffusion limitations, and presence of cells that rely on voltage-gated sodium channels to produce an action potential.
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Recommendations for maximal local anesthetic doses designed to minimize the risk for systemic toxic reactions were developed but remain controversial.127 These maximal recommended doses aim to prevent infiltration of excessive drug. However, because most episodes of systemic toxicity from local anesthetics, with the exception of methemoglobinemia from topical drug, occur secondary to unintentional intravascular injection rather than from overdosage, limiting the maximal dose will not prevent most toxic systemic reactions.123
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Toxicity is also related to the metabolism of a given local anesthetic. The rapidity of elimination from the plasma influences the total dose delivered to the CNS or heart. The amino esters are rapidly hydrolyzed in the plasma and eliminated, explaining their relatively low potential for systemic toxicity. The amino amides have a much greater potential for producing systemic toxicity because termination of the therapeutic effect of these drugs is achieved through redistribution and slower metabolic inactivation.45 Another factor that creates difficulty in specifying the minimal toxic plasma concentration of lidocaine results from the fact that its N-dealkylated metabolites are pharmacologically active and monoethylglycylxylide has a prolonged half life (Chap. 57 and Fig. 57-3). Although these factors make it difficult to establish safe doses of local anesthetics, Table 64–2 summarizes the estimates of minimal toxic IV doses of various local anesthetics.
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Central Nervous System Toxicity
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Systemic toxicity in humans usually presents initially with CNS abnormalities. Intravenous infusion studies in volunteers demonstrate an inverse relationship between anesthetic potency and dose required to induce signs of CNS toxicity.125 A similar relationship exists between the convulsive concentration and the relative anesthetic potency. In humans, seizures are reported at serum concentrations of approximately 2 to 4 mcg/mL for bupivacaine and etidocaine. Concentrations in excess of 10 mcg/mL are usually required for production of seizures when less potent drugs such as lidocaine are administered. Despite the strong relationship between local anesthetic potency and CNS toxicity, several other factors influence the CNS effects, including the rate of injection, drug interactions, and acid–base status.32
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The rapidity with which a particular serum concentration is achieved influences anesthetic toxicity. Volunteers tolerated an average dose of 236 mg of etidocaine and a serum concentration of 3 mcg/mL before onset of CNS effects and symptoms when the anesthetic was infused at a rate of 10 mg/min. However, when the infusion rate was increased to 20 mg/min, the same individuals only tolerated an average of 161 mg which produced a serum concentration of approximately 2 mcg/mL.124
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Both metabolic and respiratory acidoses increase local anesthetic induced CNS toxicity. Acidemia decreases plasma protein binding, increasing the amount of free drug available for CNS diffusion despite promoting the charged form of the amine group. The convulsive threshold of various local anesthetics is inversely related to arterial PCO2.34,41,42 Hypercarbia lowers the seizure threshold by several mechanisms: (1) increased cerebral blood flow, which increases drug delivery to the CNS; (2) increased conversion of the drug base to the active cation in the presence of decreased intracellular pH; and (3) decreased plasma protein binding, which increases the amount of free drug available for diffusion into the brain.19,34,41,42 In general, CNS depressants minimize the signs and symptoms of CNS excitation and increase the threshold for local anesthetic–induced seizures. Flumazenil increases the sensitivity of the CNS to the amino amide anesthetics.17
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A gradually increasing serum lidocaine concentration usually produces a stereotypical pattern of signs and symptoms (Fig. 64–3). In an awake patient, the initial effects include tinnitus, lightheadedness, circumoral numbness, disorientation, confusion, auditory and visual disturbances, and lethargy. Subjective side effects occur at serum concentrations between 3 and 6 mcg/mL. Significant psychological effects of local anesthetics are also reported. Near-death experiences and delusions of actual death are described as specific symptoms of local anesthetic toxicity.87 Thus, the appearance of psychological symptoms during administration of local anesthetics should not be disregarded as unrelated nervous reactions or effects of sedatives given as premedication but rather as a possible early sign of CNS toxicity.
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Clinical signs, usually excitatory, then develop, and include shivering, tremors, and ultimately generalized tonic–clonic seizures.106 Objective CNS toxicity usually is evident at lidocaine concentrations between 5 and 9 mcg/mL. Seizures typically occur at concentrations above 10 mcg/mL, with higher concentrations producing coma, apnea, and cardiovascular collapse. The excitatory phase has a wide range of intensity and duration, depending on the chemical properties of the local anesthetic. With the highly lipophilic, highly protein-bound local anesthetics, the excitement phase is brief and mild. Toxicity from large IV boluses of bupivacaine often present without CNS excitement, with bradycardia, cyanosis, and coma as the first signs.120 Rapid intravascular injection of lidocaine produces a brief excitatory phase followed by generalized CNS depression with respiratory arrest. Seizures are reported after even small doses injected into the vertebral or carotid artery (as rarely occurs during stellate ganglion block).72 A relative overdose produces a slower onset of effects (usually within 5–15 minutes of drug injection), with irritability progressing to seizures.
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The mechanism of the initial CNS excitation involves selective sodium channel blockade of cerebral cortical inhibitory pathways in the amygdala.130,135 The resulting increase in unopposed excitatory activity leads to seizures. As the concentration increases further, both inhibitory and excitatory neurons are blocked, and generalized CNS depression ensues. Levobupivacaine causes increased neuronal excitation and neurotoxicity by inhibition of KCNQ2/3 channels, an effect reversed by the channel activator retigabine.25
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Cardiovascular Toxicity
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Cardiovascular side effects are the most feared manifestations of local anesthetic toxicity. Shock and cardiovascular collapse are related to effects on vascular tone, inotropy, and dysrhythmias related to indirect CNS and direct cardiac and vascular effects of the local anesthetic. Animal studies and clinical observations clearly demonstrate that for most local anesthetics, CNS toxicity develops at significantly lower serum concentrations than those needed to produce cardiac toxicity. With the exception of bupivacaine, local anesthetics have a high cardiovascular: CNS toxicity ratio.72,100,101,120
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Some of the discrepancy between the incidence of CNS and cardiac toxicity result from a detection bias. Not only can the treating physicians fail to recognize cardiac effects because of preoccupation with CNS manifestations of toxicity, but early cardiac toxicity is often quite subtle. An experimental study attempting to identify early warning signs of bupivacaine-induced cardiac toxicity in pigs evaluated bupivacaine induced changes in cardiac output, heart rate, blood pressure, and electrocardiogram (ECG).108 A 40% reduction in cardiac output was not associated with significant change in heart rate or blood pressure, the latter secondary to a direct vasoconstrictive effect of bupivacaine at the concentrations produced.23 If cardiac toxicity develops, management is exceedingly difficult.
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Changes in systemic vascular tone induced by local anesthetics are mediated by direct effect on vascular smooth muscle or indirectly via effects on spinal cord sympathetic outflow. Predictably, sympathetic blockade after spinal anesthesia or epidural anesthesia above the T5 dermatome results in peripheral venodilation and arterial dilation. Shock results when high doses of anesthetic are used in hypovolemic patients. Local anesthetics have a biphasic effect on peripheral vascular smooth muscle. Whereas lower doses produce direct vasoconstriction, higher doses are associated with severe cardiovascular toxicity and cause vasodilation, contributing to cardiovascular collapse.
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All local anesthetics directly produce a dose dependent decrease in cardiac contractility, with the effects roughly proportional to their peripheral anesthetic effect. Although the classic anesthetic action of sodium channel blockade in heart muscle accounts in large part for the negative inotropy by affecting excitation–contraction coupling, it does not explain the entire difference in myocardial depression produced by different anesthetics.36 Poorly understood effects on calcium handling or effects of the intracellular drug directly on contractile proteins or mitochondrial function underlie these effects.36,43 Bupivacaine impairs regulation of glucose homeostasis through inhibition of protein kinase B (Akt) and activation of 5′-adenosine monophosphate activated protein kinase (AMPK) activities: interacts with peripheral δ- and κ-opioid receptors; and inhibits myosin phosphatase target subunit I (MYPTI), protein kinase C (PKC), and phosphorylation-dependent inhibitory protein of myosin phosphatase (CPI-17).27,109
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Blockade of the fast sodium channels of cardiac myocytes decreases maximum upstroke velocity (Vmax) of the action potential (Chaps. 15 and 16 and Fig. 15–2). This effect slows impulse conduction in the sinoatrial and atrioventricular (AV) nodes, the His-Purkinje system, and atrial and ventricular muscle.28 These changes are reflected on ECG by increases in PR interval and QRS complex duration. At progressively higher anesthetic concentrations, hypotension, sinus arrest with junctional rhythm, and eventually cardiac arrest occur.5 Asystole is described in patients who received unintentional IV bolus injections of 800 to 1,000 mg of lidocaine.5,44 Cardiovascular toxicity of local anesthetics usually occurs after a sudden increase in serum concentration, as in unintentional intravascular injection. Cardiovascular toxicity is rare in other circumstances because high serum concentrations are necessary to produce this effect and because CNS toxicity precedes cardiovascular events, providing a warning. Cardiac toxicity usually is not observed with lidocaine use in humans until the serum lidocaine concentration greatly exceeds 10 mcg/mL unless the patient is also receiving xenobiotics that depress sinus and AV nodal conduction such as calcium channel blockers, β-adrenergic antagonists, or cardioactive steroids. Intravascular lidocaine injection used to diminish pain associated with IV propofol injection was associated with episodes of bradycardia (heart rate <30 beats/min) and sinus arrest in a 69-year-old man later diagnosed with sick sinus syndrome.69
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Animal studies compared the dose or serum concentrations of local anesthetics required to produce irreversible circulatory collapse with those necessary to produce seizures.33,100,101 The cardiovascular collapse:CNS toxicity (CC:CNS) ratio for lidocaine is approximately 7; therefore, CNS toxicity should become evident well before potentially cardiotoxic concentrations are reached. In contrast, bupivacaine is significantly more cardiotoxic than most other local anesthetics commonly used, with a CC:CNS ratio of 3:7. Inadvertent intravascular injection produces near simultaneous signs of CNS and cardiovascular toxicity. Bupivacaine produces myocardial depression out of proportion to its anesthetic potency and, more importantly, causes refractory ventricular dysrhythmias.122 The enhanced cardiovascular toxicity of bupivacaine relates to enhanced CNS effects at cardiovascular centers, direct effects on myocyte metabolism, and important differences related to sodium channel blockade.132 Although lidocaine and bupivacaine both block sodium channels in the open or inactivated states, lidocaine quickly dissociates from the channel at diastolic potentials, allowing rapid recovery from block during diastole (known as fast on–fast off kinetics). Therefore, sodium channel blockade with lidocaine is much more pronounced at rapid heart rates (accounting for the antidysrhythmic effects for ventricular tachycardia).86 In contrast, at high concentrations, bupivacaine rapidly binds to and slowly dissociates from sodium channels (fast on–slow off kinetics), with significant block accumulating at all physiologic heart rates.28 Accordingly, at heart rates of 60 to 150 beats/min, approximately 70 times more lidocaine is needed than bupivacaine to produce an equal effect on Vmax of the action potential. Enhanced conduction block in Purkinje fibers and ventricular muscle cells sets up a reentrant circuit responsible for the ventricular tachydysrhythmias induced by bupivacaine.93
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Bupivacaine is problematic both in terms of having the highest potential for cardiovascular toxicity and for the refractoriness of its toxicity to conventional therapy. Bupivacaine has an asymmetrically substituted carbon, and the kinetics of sodium channel binding are stereospecific.75 The S (levo)-enantiomer levobupivacaine is significantly less cardiotoxic than the R (dextro)-enantiomer despite having similar anesthetic properties.7,91 Consequently, bupivacaine, the racemic mixture of both enantiomers, is more cardiotoxic than levobupivacaine, which contains only the levo-enantiomer.52 The stereospecific effect on sodium channels seems to differ between the heart and the peripheral nerves because the local anesthetic potency of levobupivacaine is the same as, or perhaps even greater than, that of bupivacaine.39,104 Ropivacaine is a pure enantiomer and is less cardiotoxic than bupivacaine, but it is also slightly less potent as an anesthetic.112,113
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Effects other than sodium channel blockade contribute to cardiotoxicity. Lipophilic local anesthetics such as bupivacaine directly impair mitochondrial energy transduction via two mechanisms: (1) uncoupling of oxygen consumption and adenosine triphosphate (ATP) synthesis and (2) inhibition of complex I in the respiratory chain.122 These effects are related to the lipophilic properties of the drug rather than to stereospecific effects on ion channels. Lidocaine has no effect on mitochondrial respiration, and ropivacaine has less effect than bupivacaine.142 There is no difference between the two bupivacaine enantiomers. These effects occur with higher concentrations of the local anesthetic, as occur after unintentional intravascular injection.
++
Low-dose bupivacaine-induced cardiotoxic effects are described in humans under certain circumstances and at concentrations that are not associated with seizures in pigs.68,140 Severe cardiac toxicity is described after injection of a small subcutaneous dose of bupivacaine in a patient with secondary carnitine deficiency.140 Myocytes are highly dependent on oxidation of free fatty acids for energy. Interference with this mechanism via bupivacaine-induced inhibition of carnitine–acylcarnitine translocase contributes to the cardiotoxicity of lipophilic local anesthetics (Chap. 48, Fig. 48–3, and Antidotes in Depth: A10).141 Bupivacaine produce dysrhythmias by blocking GABAergic neurons that tonically inhibit the autonomic nervous system.59 In addition to its other effects on the heart, bupivacaine induces a marked decrease in cardiac contractility by altering Ca2+ release from sarcoplasmic reticulum.84
++
In a large series of patients receiving bupivacaine, systemic toxicity occurred in only 15 of 11,080 nerve blocks.96 Of these patients, 80% manifested seizures; the other 20% had milder symptoms. Bupivacaine use, particularly at 0.75% concentration, is associated with severe cardiovascular depression, ventricular dysrhythmias, and even death.116 Pregnant women were disproportionately affected. Some of these patients required prolonged resuscitation, and restoration of adequate spontaneous circulation proved exceedingly difficult.116 In 1983, 49 incidents of cardiac arrest or ventricular tachycardia occurring over a 10-year period were presented to the FDA Anesthetic and Life Support Advisory Committee. Among these cases, 0.75% bupivacaine was used in 27 obstetric patients with 10 deaths, and 0.5% bupivacaine was used in 8 obstetric patients with 6 deaths. Among the 14 nonobstetric patients, 5 died. The overall mortality rate was 43% (21 of 49). Partly as a result of these reports, in 1984, the FDA withdrew approval of bupivacaine 0.75% for use as obstetric anesthesia.116
++
Acid–base and electrolyte status influence the cardiac toxicity of a given drug because all depressant properties are potentiated by acidosis, hypoxia, or hypercarbia.16 Table 64–3 outlines the spectrum of acute local anesthetic reactions.
++
++
In cases of possible local anesthetic toxicity, the patient should be attached to continuous cardiac monitoring, and an ECG should be obtained to detect dysrhythmias and conduction disturbances. Serum electrolytes, blood urea nitrogen, creatinine, and blood gas analysis should be obtained to help assess the cause of cardiac dysrhythmias. Cooximetry should be obtained in patients in whom methemoglobinemia is suspected clinically. Rapid, sensitive assays are available for measuring concentrations of lidocaine and its monoethylglycinexylidide (MEGX) metabolite. When properly interpreted, the results of these assays are used to prevent lidocaine toxicity and to identify lidocaine toxicity in the nontherapeutic setting (Chap. 57, Fig. 57-3). Assays for determining serum concentrations of other local anesthetics are not routinely available. Treatment should never be delayed while waiting for results of xenobiotic concentration determinations.
++
If toxicity results from ingestion of liquid medications, it is reasonable to give oral activated charcoal within 1 to 2 hours of ingestion, provided airway protective reflexes are intact. Contaminated mucous membranes should be washed off. Neither hemodialysis nor hemoperfusion has proven utility.
+++
Treatment of Local Anesthetic Central Nervous System Toxicity
++
At the first sign of possible CNS toxicity, administration of the drug must be discontinued. One hundred percent oxygen should be supplied immediately, and ventilation should be supported if necessary. Patients with minor symptoms usually do not require treatment, provided adequate respiratory and cardiovascular functions are maintained. The patient must be followed closely so that progression to more severe effects can be detected.
++
Although most seizures caused by local anesthetics are self-limited, they should be treated quickly because the hypoxia and acidemia produced by prolonged seizures increase both CNS and cardiovascular toxicity.99,101 Intubation is not mandatory, and the decision to intubate must be individualized. Maintaining adequate ventilation is of proven value. Modest hyperventilation extracorporeal life support (ECLS) is reasonable to produce respiratory alkalemia. By decreasing CNS extraction of drug, lowering extracellular potassium, and hyperpolarizing the neuronal cell membrane, normalizing (lowering) PCO2 decreases the affinity for, or accelerates separation of, the local anesthetic from the sodium channel. Ultra-short-acting barbiturates and benzodiazepines are recommended for treatment of local anesthetic–induced seizures, but either of these medication groups can also exacerbate circulatory and respiratory depression.32,94 Propofol 1 mg/kg IV was as effective as thiopental 2 mg/kg IV in stopping bupivacaine induced seizures in rats and was used successfully in a patient with uncontrolled muscle twitching secondary to local anesthetic toxicity.13,55 However, propofol causes significant bradydysrhythmias and even asystole, especially when used with other xenobiotics that cause bradycardia. Based on currently available data, benzodiazepines are recommended as the first-line treatment for local anesthetic CNS toxicity. Neuromuscular blockers are proposed as adjunctive treatment for local anesthetic–induced seizures. They block muscular activity, decreasing oxygen demand and lactic acid production. However, neuromuscular blockers should never be used to treat seizures per se because they have no anticonvulsant effect and can make clinical diagnosis of ongoing seizures problematic by abolishing muscle contractions. To avoid this potentially lethal complication, chemical paralysis should be used only to facilitate endotracheal intubation if needed, unless continuous electroencephalography is also used. If used, short-acting neuromuscular blockers are desirable, facilitating subsequent repeated neurologic assessments. Succinylcholine is not routinely recommended because of significant side effects, including hyperkalemia and dysrhythmias. Given less potential for adverse cardiac effects, nondepolarizing neuromuscular blockers such as rocuronium are preferentially recommended (Chap. 66).
++
When severe systemic toxicity occurs, the cardiovascular system must be monitored closely because cardiovascular depression often goes unnoticed while seizures are being treated. Because local anesthetic–induced myocardial depression occurs even with preserved blood pressure, it is important to be aware of early signs of cardiac toxicity, including ECG changes.
+++
Treatment of Local Anesthetic Cardiovascular Toxicity
++
Treatment of cardiovascular toxicity is complicated by the complex effects of local anesthetics on the heart. Initial therapy should focus on correcting the physiologic derangements that potentiate the cardiac toxicity of local anesthetics, including hypoxemia, acidemia, and hyperkalemia.16,119 Prompt support of ventilation and circulation limits hypoxia and acidemia. Early recognition of potential cardiac toxicity is critical to achieving a good outcome because patients with cardiac toxicity that goes unrecognized for any interval are more difficult to resuscitate.9 If a potentially massive intravascular local anesthetic injection is suspected, maximizing oxygenation of the patient before cardiovascular collapse occurs is critical.
++
Standard Advanced Cardiac Life Support (ACLS) protocols should be followed when dealing with most local anesthetic cardiac toxicity. Bupivacaine-induced dysrhythmias often are refractory to cardioversion, defibrillation, and pharmacologic treatment. Lidocaine, phenytoin, magnesium, bretylium, amiodarone, calcium channel blockers, and combined therapy with clonidine and dobutamine were all used in animal models with variable results.37,88,90 Lidocaine competes with bupivacaine for cardiac sodium channels and at high doses may displace it. Anecdotal reports suggest that lidocaine has occasionally helped in this application.31 However, concern exists about additive CNS effects when lidocaine is used to treat bupivacaine cardiac toxicity, and its use in this manner cannot be routinely recommended.
++
With toxicity from the longer acting, highly lipid-soluble, protein-bound amide local anesthetics (bupivacaine and etidocaine), if the patient does not respond promptly to therapy, cardiopulmonary resuscitation is expected to be difficult and prolonged (1–2 hours) before depression of the cardiac conduction system spontaneously reverses as a result of redistribution and metabolism of the drugs.2,114 Vital organ perfusion is seriously compromised during CPR despite optimal chest compression. The significance of this problem increases with the duration of resuscitation; therefore, rapid initiation of is recommended when practical. Cardiopulmonary bypass resulted in successful outcomes in some cases of lidocaine and bupivacaine overdose.47,81 Cardiopulmonary bypass provides circulatory support that is far superior to that provided by closed-chest cardiac massage. The improved perfusion prevents tissue hypoxia and the development of metabolic acidosis, which in turn decreases the binding of local anesthetics to myocardial sodium channel receptors. Hepatic blood flow is better maintained, enhancing local anesthetic metabolism, and increased myocardial blood flow helps redistribute local anesthetics out of the myocardium.81 Increasingly, ECLS using venoarterial extracorporeal membrane oxygenation (VA-ECMO) is being used in the management of critically ill overdose patients in both the emergency department and intensive care unit environments.35
++
Atropine supplemented with electrical pacing is reasonable to treat bradycardia. Cardiac pacing was used successfully for treatment of cardiac arrest after unintentional administration of a 2-g bolus of lidocaine into a cardiopulmonary bypass circuit as the patient was being removed from bypass.107 Pharmacologic therapy was unsuccessful, and resumption of bypass was necessary. Forty-five minutes after the injection, AV pacing restored perfusion and permitted discontinuation of bypass.
++
Use of sodium bicarbonate early in resuscitation to prevent acidemia-mediated potentiation of cardiac toxicity is reasonable.31 Although a canine model of bupivacaine-induced cardiotoxicity demonstrated utility of high dose insulin compared with saline or dextrose, its use cannot be routinely recommended at this time (Antidotes in Depth: A21).26
+++
Intravenous Lipid Emulsion
++
While investigating the relationship between lipid metabolism and bupivacaine toxicity, a rat study of bupivacaine induced asystolic arrest showed that pretreatment with IV lipid emulsion (ILE) increased the toxic dose of bupivacaine by 50%.143 In addition, a dose of bupivacaine that was uniformly fatal in control rats resulted in universal survival in animals that also received fat emulsion.143 Subsequent studies of local anesthetic toxicity demonstrated accelerated return of cardiac function and systemic vascular resistance after ILE both in isolated hearts and in intact animals.21,58,139,140
++
Numerous case reports describe successful use of ILE (in various formulations) to treat patients (including pregnant and pediatric patients) in cardiac arrest after regional anesthesia with various local anesthetics, including bupivacaine, ropivacaine, and levobupivacaine (Antidotes in Depth: A23).12,60
++
The most recent guidelines by the American Society of Regional Anesthesia and Pain Medicine (ASRA) suggest dosing for a patient in cardiac arrest is a 1.5-mL/kg bolus of 20% ILE over 1 minute while continuing chest compressions followed by continuous infusion of 0.25 mL/kg/min.105 For persistent cardiovascular collapse, it is reasonable to repeat the bolus once or twice and double the infusion rate. If there is evidence of recovery, it is reasonable to continue the infusion for at least 10 minutes after stability. After initiating standard ACLS protocols, including ensuring adequate oxygenation and ventilation, we recommend that ILE be given as soon as possible after signs of significant local anesthetic toxicity become manifest (Antidotes in Depth: A23).143 Initiation of VA-ECMO in association with ILE use is associated with fat deposition in the VA-ECMO circuit and increased blood clot formation within the circuit.74 However, given that ILE administration can be accomplished more readily than initiation of VA-ECMO, it is reasonable to administer ILE to the severely intoxicated patient even if the patient eventually is transitioned to VA-ECMO.
+++
Prevention of Systemic Toxicity of Local Anesthetics
++
Despite the development of new, relatively less toxic amino amide local anesthetics such as levobupivacaine and ropivacaine, severe CNS and cardiovascular effects remain a risk. Several cases of ropivacaine-induced cardiac arrest are reported.24,70 In these cases, patients with both asystolic arrest and ventricular fibrillation–associated arrest were successfully resuscitated. Nonetheless, it is clear that prevention is more prudent and effective than treatment of toxicity. The keys to prevention are to use the lowest possible anesthetic concentration and volume consistent with effective anesthesia and to avoid a significant intravascular injection. The latter is accomplished by ensuring extravascular placement demonstrated repetitively by ultrasonographic guidance and by careful, slow aspiration of a needle or catheter before injection; injection of a small test dose of anesthetic mixed with epinephrine to assess a cardiovascular response if injection is intravascular; and use of slow, fractional dosing of large-volume injections with vigilance for early signs of CNS and cardiac toxicity.
++
-
Local anesthetics are frequently used xenobiotics that provide surgical analgesia and acute and chronic pain relief.
-
The analgesic effect of local anesthetics is primarily caused by inhibition of neural conductance secondary to sodium channel blockade.
-
Systemic toxicity, which primarily affects the heart and brain, is also largely related to sodium channel blockade.
-
Severe systemic toxicity usually occurs secondary to inadvertent intravascular injection.
-
If cardiovascular collapse and cardiac arrest occur, especially in the setting of bupivacaine toxicity, resuscitation is difficult and prolonged. In addition to standard ACLS protocols emphasizing maintenance of oxygenation and ventilation, ILE is recommended.
-
Cardiopulmonary bypass is useful because it provides cardiovascular support, limits exacerbating factors such as tissue hypoxia and acidemia, and improves hepatic blood flow, thereby increasing local anesthetic metabolism, but it is difficult to initiate in a timely manner. Although increasingly available, extracorporeal life support will be limited by the use of ILE, which has been noted to clog the VA-ECMO circuit.
++
Brian Kaufman, MD; Staffan Wahlander, MD; and David R. Schwartz, MD, contributed to this chapter in previous editions.
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