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Table 45-5 shows categories of the toxic effects of local anesthetics.
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True allergic reactions are associated with amino ester–linked local anesthetics, not amino amide–linked ones. In a study of anaphylactic and anaphylactoid reactions (n = 789) occurring during anesthesia, Mertes et al91 found no such reactions to local anesthetics. However, Mackley et al92 reported that of 183 patients who were patch tested, 4 had positive reactions to lidocaine, 2 of whom had histories of sensitivity to local injections of lidocaine manifested by dermatitis. They concluded that contact-type IV sensitivity to lidocaine might occur more frequently than previously thought. It is common, but inappropriate, to refer to all adverse events as "allergic reactions."
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Tissue toxicity, primarily myotoxicity and neurotoxicity, can be produced by all local anesthetics if "high" concentrations are used. Signs and symptoms of varying degrees of neuropathy (eg, transient neurologic symptoms, cauda equina syndrome) have been reported after spinal anesthesia with, for example, 2% and 5% lidocaine. In a systematic review, Zaric et al93 compared the frequency of transient neurologic symptoms and neurologic complications after spinal anesthesia with lidocaine with that after other local anesthetics. The results showed that the risk for developing transient neurologic symptoms after spinal anesthesia with lidocaine was higher with lidocaine than with bupivacaine, prilocaine, procaine, or mepivacaine.
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A variety of local anesthetics reportedly may produce methemoglobinemia. Prilocaine is the local anesthetic for which there appears to be greatest risk for this to occur. A dose–response relationship exists between the amount of prilocaine administered epidurally and the degree of methemoglobinemia. In general, doses of prilocaine of 600 mg are required for the development of clinically significant levels of methemoglobinemia.94 The formation of methemoglobinemia is believed to be related to prilocaine's chemical structure. This agent lacks a methyl group in the benzene ring. The metabolism of prilocaine in the liver results in the formation of O-toluidine, which is responsible for the oxidation of hemoglobin to methemoglobin.95 The methemoglobinemia associated with prilocaine is spontaneously reversible or may be treated by IV methylene blue.
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Cardiovascular and Central Nervous System
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As concentration of local anesthetic in systemic circulation increases, various cardiovascular system and central nervous system (CNS) signs and symptoms appear (Fig. 45-20). The relative CNS and cardiovascular toxicity of local anesthetics has been of interest, especially after Albright96 reported unexpected cardiovascular toxicity of bupivacaine. Most animal studies show that the ratio of doses of bupivacaine that produced convulsive activity and cardiovascular collapse are lower than for other local anesthetics.97 Human volunteer studies of doses required to produce early features of CNS and cardiovascular system toxicity by ropivacaine and levobupivacaine demonstrated the doses were about equal and higher than for bupivacaine.98-100
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Brown et al101 reviewed records of patients who had seizures while undergoing brachial plexus, epidural, and caudal regional anesthetics. No adverse cardiovascular, pulmonary or nervous system events were associated with any of the seizures, including in 16 patients who received bupivacaine blocks. Clinically, which of the usual features of systemic local anesthetic toxicity occurs, the order in which they occur and how soon after local anesthetic administration are quite variable (Fig. 45-21).102 This is not surprising given what is known about how various health conditions, other drugs, and rate of increase of local anesthetic concentration in systemic circulation influence the manifestation and progression of signs and symptoms of local anesthetic toxicity.
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In dogs, the relative CNS toxicity of bupivacaine, etidocaine, and lidocaine is 4:2:1,103 which is similar to the relative potency of these agents for the production of regional anesthesia in humans. The convulsant doses of bupivacaine and ropivacaine are similar.104 IV infusion studies in human volunteers have also demonstrated an inverse relationship between the intrinsic anesthetic potency of various agents and the dosage required to induce CNS toxicity.105,106
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The rate of IV administration alters the toxicity of local anesthetic agents.106 In human volunteers, an average dose of 236 mg of etidocaine and a venous blood concentration of 3.0 μg/mL resulted in CNS symptoms when 10 mg/min was infused. When the infusion rate was increased to 20 mg/min, an average of 161 mg of etidocaine, which produced a venous plasma concentration of approximately 2 μg/mL, caused symptoms of CNS toxicity.
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Acid–base status can alter the CNS activity of local anesthetic agents. In cats, the convulsive threshold of various local anesthetics is inversely related to the arterial CO2 tension (Paco2)107 (Fig. 45-22). An increase in Paco2 from 25 to 40 mm Hg to a range of 65 to 81 mm Hg decreases the convulsive threshold of procaine, mepivacaine, prilocaine, lidocaine, and bupivacaine by approximately 50%. A decrease in arterial pH also decreases the convulsant threshold of these agents. Respiratory acidosis, with a resultant increase in Paco2 and a decrease in arterial pH, consistently decreases the convulsant threshold of local anesthetic agents. However, an elevation in both Paco2 and arterial pH, as may occur during metabolic alkalosis, does not increase CNS toxicity to the same degree.
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Hypercarbia increases cerebral blood flow, which probably results in a greater uptake of local anesthetic by the brain. In addition, diffusion of CO2 into neuronal cells decreases intracellular pH and thus increases the intracellular cationic form of the local anesthetic agents. This form does not diffuse well across the nerve membrane, so ion trapping occurs. Hypercarbia and/or acidosis also decrease the plasma protein binding of local anesthetic agents, which will increase the proportion of free drug available for diffusion into the brain.108,109 On the other hand, acidosis also decreases the percentage of the local anesthetic existing in the base form, which should decrease the rate of diffusion into neuronal cells.
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Local anesthetics have a direct effect on both cardiac muscle and vascular smooth muscle.97 These agents alter the heart's electrical and mechanical activity. Studies using the intact, isolated mammalian heart in vitro show that highly lipid-soluble, extensively protein-bound, highly potent local anesthetics (eg, tetracaine, bupivacaine, etidocaine) are much more cardiotoxic than are the less lipid-soluble, protein-bound, potent local anesthetics (eg, lidocaine, mepivacaine, prilocaine).110 Bupivacaine has a potent depressant effect on electrical conduction in the heart primarily via an action on voltage-gated sodium channels that generally govern the initial rapid depolarization (phase 0) of cardiomyocytes. The S forms of bupivacaine are less cardiotoxic than the R form. Bupivacaine actions other than on voltage-gated sodium channels probably also contribute to dose-dependent cardiotoxic effect of this local anesthetic.
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Local anesthetics decrease the maximal rate of depolarization in Purkinje fibers and ventricular muscle because of an inhibition of sodium channels in cardiac membranes.111-113 Action potential duration and the effective refractory period are also decreased by local anesthetics. However, the ratio of effective refractory period to action potential duration is increased both in Purkinje fibers and in ventricular muscle.
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Qualitative differences exist between the various local anesthetic agents. Bupivacaine depresses the rapid phase of depolarization (Vmax) in Purkinje fibers and ventricular muscle to a greater extent than does lidocaine.111-113 In addition, the rate of recovery from a use-dependent block is slower in bupivacaine-treated than in lidocaine-treated papillary muscles.114 This slow rate of recovery results in an incomplete restoration of Vmax between action potentials, particularly at high heart rates. In contrast, recovery from lidocaine is complete, even at rapid heart rates. These differential effects of lidocaine and bupivacaine may explain the antidysrhythmic properties of lidocaine and the dysrhythmogenic potential of bupivacaine.
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Bupivacaine, and to a lesser degree etidocaine and ropivacaine, can produce severe cardiac dysrhythmias, including ventricular fibrillation, in various animal species.97,115-119 Ventricular dysrhythmias are rarely seen with lidocaine, mepivacaine, or tetracaine. Although the dysrhythmogenic action of bupivacaine is probably related primarily to an inhibition of the fast sodium channels in the cardiac membrane, evidence also exists that this agent may block the slow calcium channels.120 These electrophysiologic effects of bupivacaine may result in conduction abnormalities, leading to a reentrant type of dysrhythmia similar to a torsade de pointes dysrhythmia.116
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The dysrhythmogenic activity of bupivacaine is believed to result primarily from a direct cardiac effect. Isolated guinea pig hearts perfused with bupivacaine revealed evidence of conduction block, bigeminy, and trigeminy.121 In addition, ventricular fibrillation occurred in intact pigs in which bupivacaine was injected directly into the left anterior descending coronary artery.118 On the other hand, the injection of bupivacaine directly into certain regions of the brain may result in cardiac dysrhythmias, which may indicate a relationship between the CNS and cardiotoxic effects of bupivacaine.122,123
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Electrophysiologic studies in intact dogs and in people have shown that high blood levels of local anesthetics prolong conduction time through various parts of the heart as indicated by an increase in the PR interval and QRS duration. Extremely high concentrations of local anesthetics depress spontaneous pacemaker activity in the sinus node, resulting in sinus bradycardia and sinus arrest.
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Local anesthetic agents also depress myocardial contractility. All local anesthetics exert a dose-dependent negative inotropic action on isolated cardiac tissue that is proportional to the conduction blocking potency of the various agents in isolated nerves (Fig. 45-23).124 For example, bupivacaine, tetracaine, and etidocaine produce the greatest degree of myocardial depression. The agents of moderate anesthetic potency (ie, lidocaine, mepivacaine, prilocaine) are intermediate in terms of their negative inotropic action. Procaine and chloroprocaine, which are the least-potent local anesthetics, require the highest concentration to decrease cardiac contractility.
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In dogs, tetracaine is approximately 8 to 10 times more potent than procaine as a local anesthetic and as a myocardial depressant.125 Hemodynamic studies in closed-chest anesthetized dogs have shown that tetracaine, etidocaine, and bupivacaine caused a 50% decrease in cardiac output at doses of 10 to 20 mg/kg, whereas doses of 30 to 40 mg/kg of lidocaine, mepivacaine, prilocaine, and chloroprocaine were required for a similar decrease in cardiac output. A dose of 100 mg/kg of procaine was needed to reduce cardiac output to 50%.
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Most local anesthetic agents exert a biphasic effect on peripheral vascular smooth muscle.56,57 Low concentrations of lidocaine and bupivacaine produced vasoconstriction in the cremaster muscle of rats, whereas high concentrations increased arteriolar diameter, indicative of vasodilatation. In vivo studies also demonstrate that low doses of local anesthetics decrease peripheral arterial flow without any change in blood pressure, whereas higher doses increase blood flow. Cocaine causes vasoconstriction because of its ability to inhibit the uptake of norepinephrine by storage granules.126 Studies indicate that ropivacaine causes cutaneous vasoconstriction, whereas bupivacaine produces vasodilatation.59
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In a review of the cardiotoxicity of modern local anesthetics, Mather and Chang127 concluded that as compared with bupivacaine, although ropivacaine and levobupivacaine may be seen as "safer," they must not be regarded as totally "safe."
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Factors Influencing Cardiovascular Toxicity
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Although the CNS is more susceptible to the toxic effects of local anesthetics than the cardiovascular system, differences exist in the margin between the dose of various agents that causes convulsions and the dose that results in cardiovascular collapse (Fig. 45-24). A cardiovascular collapse (CC)-to-convulsive (CNS) dose ratio of 7.1 + 1.1 was reported for lidocaine in adult sheep, indicating that 7 times as much drug was required to induce irreversible cardiovascular collapse as to cause convulsions.128 The CC:CNS ratio for bupivacaine was 3.7 + 0.5 and for etidocaine, 4.4 + 0.9. The CC:CNS blood level ratio of lidocaine was 3.6 + 0.3, compared with values of 1.6 to 1.7 for bupivacaine and etidocaine. At the time of cardiovascular collapse, high concentrations of bupivacaine and etidocaine were present in the myocardium compared with lidocaine, which suggests that the enhanced cardiac toxicity of these more potent agents may result from a greater myocardial uptake.
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Data regarding the effects of pregnancy on the cardiovascular toxicity of local anesthetic are not conclusive.
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Hypercarbia, acidosis, and hypoxia potentiate the negative chronotropic and inotropic action of lidocaine and bupivacaine in isolated cardiac tissue.129 The combination of hypoxia and acidosis greatly potentiates the cardiodepressant effects of bupivacaine. Hypoxia and acidosis also increase the frequency of cardiac dysrhythmias and the mortality rate in sheep after the IV administration of bupivacaine.130 Hypercarbia, acidosis, and hypoxia occur very rapidly in some patients after seizure activity because of the rapid unintentional intravascular injection of local anesthetic agents.131 Thus the cardiovascular depression observed in some patients after the accidental IV injection of bupivacaine may be related in part to the severe acid–base changes that occur during toxic reactions to this agent.
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Measures to prevent systemic toxic reactions to local anesthetics include following dose recommendations, injecting aliquots over time, avoiding unintentional intravascular injections, and monitoring vital signs during injection. Blanket recommended doses versus block-specific recommended doses were discussed recently.132,133 Drug administration must be stopped should signs or symptoms of toxicity develop. Seizures induced by local anesthetics are usually self-limiting and require maintenance of respiratory gas exchange and control of muscle contractions (eg, intubation, oxygenation, short-acting muscle paralysis). Drugs such as propofol, thiopental, and benzodiazepines are effective against these seizures.
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Cardiovascular toxicity is treated according to American Heart Association guidelines, depending on the nature of the toxicity. Recent evidence suggests that in some instances, lipid emulsion infusion may be beneficial.134 Recently published recommendations by the American Society of Regional Anesthesia and Pain Medicine for treatment of local anesthetic systemic toxicity are summarized in Table 45-6.135
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