treated. Patients with cardiovascular collapse from bupivacaine, ropivacaine, and levo-bupivacaine may be especially difficult to resuscitate.INTRODUCTION Local anesthetics block the generation, propagation, and oscillations of electrical impulses in electrically excitable tissue. Use of local anesthetics in clinical anesthesia is varied andincludes direct injection into tissues, topical application, and intravenous administration toproduce clinical effects at varied locations including the central neuraxis, peripheral nerves,mucosa, skin, heart, and airway. Detailed knowledge of pertinent anatomy and pharmacology willaid in optimal therapeutic use of local anesthetics. Care should be taken to avoid potential centralnervous system (CNS) and cardiovascular toxicity from local anesthetics.MECHANISMS OF ACTION OF LOCAL ANESTHETICSAnatomy of NervesLocal anesthetics are often used to block nerves either peripherally or centrally. Peripheral nervesare mixed nerves containing afferent and efferent fibers that may be myelinated or unmyelinated.Each axon within the nerve fiber is surrounded by endoneurium composed of nonneural glial cells.Individual nerve fibers are gathered into fascicles and surrounded by perineurium composed ofconnective tissue. Finally, the entire P.454peripheral nerve is encased by epineurium composed of dense connective tissue (Fig. 17-1). Thus,several layers of protective tissue surround individual axons, and these layers act as barriers tothe penetration of local anesthetics. 1 In addition to the enveloping connective tissue, allmammalian nerves with a diameter greater than 1 µm are myelinated. Myelinated nerve fibers aresegmentally enclosed by Schwann cells forming a bilayer lipid membrane that is wrapped severalhundred times around each axon. 2 Thus, myelin accounts for over half the thickness of nervefibers >1 µm (Fig. 17-2). Separating the myelinated regions are the nodes of Ranvier wherestructural elements for neuronal excitation are concentrated (Fig. 17-3). 3 The nodes are coveredby interdigitations from nonmyelinating Schwann cells 4 and by negatively charged glycoproteins.Although axonal membranes are not freely in contact with their environment at the nodes, theseareas do allow passage of drugs and ions. 5 Furthermore, the negatively charged proteins may bindbasic local anesthetics and thus act as a depot. Unmyelinated nerve fibers (diameter <1 µm) areencased by a Schwann cell that simultaneously insulates several (5 to 10) axons (Fig. 17-2).These fibers are continuously encased by Schwann cells and do not possess interruptions (nodes ofRanvier). The existence of multiple protective layers around both myelinated and unmyelinatednerve fibers presents a substantial barrier to the entry of clinically used local anesthetics. Forexample, animal models suggest that only 1.6% of an injected dose of local anesthetic penetratesinto the nerve following performance of peripheral nerve blocks. 6
FIGURE 17-1. Schematic cross section of typical peripheral nerve. The epineurium,consisting of collagen fibers, is oriented along the long axis of the nerve. The perineurim is adiscrete cell layer, whereas the endoneurium is a matrix of connective tissue. Both afferentand efferent axons are shown. Sympathetic axons (not shown) are also present in mixedperipheral nerves. (Adapted with permission from Strichartz GR: Neural physiology and localanesthetic action. In Cousins MJ, Bridenbaugh PO [eds]: Neural Blockade in ClinicalAnesthesia and Management of Pain, p 35. Philadelphia, Lippincott–Raven, 1998.)FIGURE 17-2. Schwann cells form myelin around one myelinated axon or encompass several
unmyelinated axons. (Adapted with permission from Carpenter RL, Mackey DC: Local anesthetics. In Barash PG, Cullen BF, Stoelting RF [eds]: Clinical Anesthesia, p 413. Philadelphia, Lippincott–Raven, 1996.) FIGURE 17-3. Diagram of node of Ranvier displaying mitochondria (M), tight junctions in paranodal area (P), and Schwann cell (S) surrounding node. (Adapted with permission from Strichartz GR: Mechanisms of action of local anesthetic agents. In Rogers MC, Tinker JH, Covino BG, et al [eds]: Principles and Practice of Anesthesiology, p 1197. St. Louis, Mosby Year Book, 1993.)Nerve fibers are commonly classified by size, conduction velocity, and function (Table 17-1). Ingeneral, increasing myelination and nerve diameter lead to increased conduction velocity. Thepresence of myelin accelerates conduction velocity because of increased electrical insulation ofnerve fibers and saltatory conduction. Increased nerve diameter accelerates conduction velocityboth by increased myelination and by improved electrical cable conduction properties of the nerve.Myelinated and unmyelinated nerves carry out both afferent and efferent functions. TABLE 17-1 Classification of Nerve Fibers ▪CLASSIFICATION ▪DIAMETER ▪MYELIN ▪CONDUCTION ▪LOCATION ▪FUNCTION (µ) (m/sec) A-alpha 6–22 + 30–120 Afferents/efferents Motor and A-beta for muscles and propriocepti joints A-gamma 3–6 + 15–35 Efferent to muscle Muscle tone spindle A-delta 1–4 + 5–25 Afferent sensory Pain
nerve Touch Temperature B <3 + 3–15 Preganglionic Autonomic sympathetic function C 0.3–1.3 - 0.7–1.3 Postganglionic Autonomic sympathetic function Afferent sensory Pain nerve TemperatureElectrophysiology of Neural ConductionIonic disequilibria across semipermeable membranes form the basis for neuronal resting potentialsand for the potential energy needed to initiate and maintain electrical impulses. The restingpotential of neural membranes averages -60 to -70 mV, with the cell interior being negative to thecell exterior. This resting potential is predominantly maintained by a potassium gradient with a 10times greater concentration of potassium within the cell. This gradient is maintained by an activeprotein pump that transports potassium into the cell and sodium out of the cell through voltage-gated potassium channels that are open at resting potentials. 7 Potassium equilibrium is not theonly factor in resting potential, as a resting potential of approximately -90 mV is predicted by theNernst equation if only potassium is considered. In addition to P.455potassium channels, voltage-independent channels that allow “leak” currents of sodium, chloride,and other ions affect the resting potential.In contrast to the dependence of resting membrane potential on potassium disequilibria,generation of action potentials is primarily a result of activation of voltage-gated sodiumchannels. 7 These channels are protein structures spanning the bilayer lipid membrane composed ofstructural elements, an aqueous pore, and voltage-sensing elements that control passage of ionsthrough the pore (Fig. 17-4). 8 Sodium channels exist in several conformations depending onmembrane potential and time. At resting membrane potential, sodium channels predominantlyexist in a resting (closed) conformation. 7 , 9 During membrane depolarization, channels open withina few hundred microseconds and allow passage of 10 7 ions/sec - 1 . Sodium channels are relativelyselective, but other monovalent ions can also gain passage through the channel. For example,lithium traverses about as well as sodium, whereas potassium only about one-tenth as well.Following activation (opening) of the sodium channel and depolarization, the channel willspontaneously close into an inactivated state in a time-dependent fashion to allow repolarizationand then revert to a resting conformation. 1 0 Thus, a three-state kinetic scheme (Fig. 17-5)conceptualizes the changes in sodium channel conformation that account for changes in sodiumconductance during depolarization and repolarization.
FIGURE 17-4. Diagram of bilayer lipid membrane of conductive tissue with sodium channel(cross-hatching) spanning the membrane. Tertiary amine local anesthetics exist as neutralbase (N) and protonated, charged form (NH + ) in equilibrium. The neutral base (N) is morelipid soluble, preferentially partitions into the lipophilic membrane interior, and easily passesthrough the membrane. The charged form (NH + ) is more water soluble and binds to thesodium channel at the negatively charged membrane surface. Both forms can affect functionof the sodium channel. The N form can cause membrane expansion and closure of the sodiumchannel. The NH + form will directly inhibit the sodium channel by binding with a localanesthetic receptor. The natural “local anesthetic” tetrodotoxin (TTX) binds at the externalsurface of the sodium channel and has no interaction with clinically used local anesthetics.(Adapted with permission from Strichartz GR: Neural physiology and local anesthetic action.In Cousins MJ, Bridenbaugh PO [eds]: Neural Blockade in Clinical Anesthesia andManagement of Pain, p 35. Philadelphia, Lippincott–Raven, 1998.)FIGURE 17-5. Illustration of dominant form of sodium channel during generation of anaction potential. R = resting form, O = open form, I = inactive form. Figure A demonstrates
the concurrent generation of an action potential, as the membrane depolarizes from resting potential. Figure B demonstrates concurrent changes in ion flux, as inward sodium current (I N a + ) and outward potassium current (I K + ) together yield the net ionic current across the membrane (I i ). (Adapted with permission from Strichartz GR: Neural physiology and local anesthetic action. In Cousins MJ, Bridenbaugh PO [eds]: Neural Blockade in Clinical Anesthesia and Management of Pain, p 35. Philadelphia, Lippincott–Raven, 1998.)An action potential will be generated by depolarization when the impulse-firing threshold of theaxon is reached. That is the point at which no further depolarization is required for local processesto generate a complete action potential. This threshold is not an absolute voltage, but ratherdepends on the dynamics of the sodium and potassium channels. For example, a brief maximallydepolarizing stimulus will not generate an P.456action potential because there is insufficient time for sodium channels to open. Nor will adepolarizing stimulus that increases too slowly create an action potential. As the stimulus slowlyincreases, initially activated sodium channels will spontaneously inactivate, so there will never beenough open channels at one time to generate an action potential. Furthermore, voltage-sensitivepotassium channels would begin to increase potassium conductance that would further inhibitgeneration of an action potential. Thus, successful generation of an action potential requires adepolarizing stimulus of correct intensity and duration.Once an action potential is generated, propagation of the potential along the nerve fiber isrequired for information to be transmitted. Both impulse generation and propagation are “all ornothing” phenomena. In the case of impulse propagation, either the locally generated actionpotential reaches the threshold potential of adjacent segments and causes propagation along thenerve, or the local depolarization ends. Nonmyelinated fibers require achievement of thresholdpotential at the immediately adjacent membrane, whereas myelinated fibers require generation ofthreshold potential at a subsequent node of Ranvier.Repolarization after action potential generation and propagation rapidly follows owing toincreasing equilibria of internal and external sodium ions, a time-controlled decrease in sodiumconductance, and a voltage-controlled increase in potassium conductance. 1 1 In addition, activeinternal concentration of potassium occurs via the membrane-bound enzyme Na + /K + /ATPase thatextrudes three sodium ions for every two potassium ions absorbed. Although many mammaliannonmyelinated nerve fibers develop a period of hyperpolarization after the action potential,myelinated nerve fibers return directly to resting membrane potential. 1 1Molecular Mechanisms of Action of Local Anesthetics The sodium channel is the key target of local anesthetic activity. The wide variety of compounds that exhibit local anesthetic activity combined with the different effects of neutraland charged local anesthetics suggest that local anesthetics may act on the sodium channel eitherby modification of the lipid membrane surrounding it or by direct interaction with its proteinstructure.Previous studies have demonstrated that anesthetics can reduce sodium conductance throughsodium channels by interacting with the surrounding lipid membrane. 1 2 Alterations in neuronalmembranes by local anesthetics can occur by altering the fluidity of the membrane that causesmembrane expansion and subsequent closure of the sodium channel. Furthermore, alterations inmembrane composition may lower the probability of occurrence of the open sodium channel state.Such observations can account for local anesthetic actions of neutral and lipophilic localanesthetics, but do not explain the different activity of clinically used, tertiary amine localanesthetics (e.g., lidocaine).Instead, the mechanisms of action of these local anesthetics are best explained by direct
interaction with the sodium channel (modulated receptor theory). 1 3 The commonly used tertiaryamine local anesthetics exist in free equilibrium as both a lipid-soluble neutral form and ahydrophilic, charged form depending on pK a and environmental pH. Although the neutral form mayexert anesthetic actions as described earlier, the cationic species is clearly the more potent form(see Fig. 17-4). 1 3 These tertiary amine local anesthetics also demonstrate greater sodium channelblockade when the neural membrane is repetitively depolarized (1 to 100 Hz), 1 4 , 1 5 whereas neutrallocal anesthetics exhibit little change in activity with increased frequency of stimulation (use-dependent block). Increasing frequency of stimulation increases the probability that sodiumchannels will exist in the open and inactive forms as compared to the unstimulated state. Thus,differences in activity of tertiary amine local anesthetics between use-dependent (repetitivestimulation) and tonic (unstimulated) block are well explained by the existence of a single localanesthetic receptor within the sodium channel that possesses different affinities during differentchannel conformations (resting, open, inactive). Specifically, higher affinities occur during theopen and inactive phases. In support of this theory, when the affinity of inactive channels for localanesthetics is decreased through genetic manipulation, use-dependent block is reduced. 1 6 , 1 7Molecular manipulation of the sodium channel has revealed specifics of the local anestheticreceptor. 8 Binding sites to local anesthetics are located on the intracellular side of the sodiumchannel, may have different binding areas during the open and inactivated conformations of thesodium channel, and possess stereoselectivity with preference for the R isomers. 9 , 1 7 , 1 8Mechanism of Blockade of Peripheral Nerves Local anesthetics may block function of peripheral nerves through several mechanisms. As discussed earlier, sodium channel blockade leads to attenuation of neural action potentialformation and propagation. Although it remains unknown in humans by what percent the neuralaction potential must be decreased before functional block occurs, animal studies suggest that theaction potential must be decreased by at least 50% before measurable loss of function isobserved. 6 Previous studies have examined the differences in susceptibility of nerve fiber to localanesthetic blockade based on size, myelination, and length of fiber exposed to local anesthetic.Clinically, one can often discern a differential pattern of sensory block after application of localanesthetic to a peripheral nerve. 1 9 Classically, the sensation of temperature is lost, followed bysharp pain, then light touch. Thus, an initial assumption was that small, unmyelinated (C) fibersconducting temperature sensation were inherently more susceptible to local anesthetic blockadethan large, myelinated (A) fibers conducting touch. However, experimental studies reveal a morecomplex picture. In vivo studies of sciatic nerve block in rats with lidocaine indicate that larger Afibers are more susceptible to tonic and phasic block than smaller C fibers. 1 5 Differential block oflarge and small nerve fibers is also affected by choice of local anesthetic. Those with an amidegroup, high pK a , and lower lipid solubility are more potent blockers of C fibers. Thus, experimentalstudies indicate that local anesthetic block of nerve fibers will intrinsically depend on type (size)of fiber, frequency of membrane stimulation, and choice of local anesthetic. 1 4 , 2 0During clinical applications, the exposure length of the nerve fiber may explain differentialblock, 2 1 , 2 2 as small nerve fibers require a shorter length of fiber exposed to local anesthetic forblock to occur than do large fibers. It is theorized that this observation is because of decrementalconduction block of a “critical length” of nerve. 2 2 Decremental conduction describes the decreasedability of successive nodes of Ranvier to propagate an impulse in the presence of local anesthetic(Fig. 17-6). As internodal distances become greater with increasing nerve fiber size, 2 3 largernerve fibers will demonstrate increasing resistance to local anesthetic block. Evidence for thismechanism is conflicting. Sciatic nerve blocks in rats demonstrate greater length of spread alongthe nerve and greater intraneural content of radiolabeled lidocaine with injections of high volumeand low concentrations of lidocaine. However, the use of small volumes and greater concentrationsof lidocaine produced more effective sensory and motor block despite lesser spread andintraneural penetration of lidocaine. 2 4 Further clinical studies on decremental conduction and roleof “critical P.457length” will be needed, especially as nerve blocks in humans typically involve much greater
lengths of affected nerve than animal models. For example, sciatic nerve blocks in humansprobably result in 5 to 10 cm of affected nerve length. 6 FIGURE 17-6. Diagram illustrating the principle of decremental conduction block by local anesthetic at a myelinated axon. The first node of Ranvier at left contains no local anesthetic and gives rise to a normal action potential (solid curve). If the nodes succeeding the first are occupied by a concentration of local anesthetic high enough to block 74 to 84% of the sodium conductance, then the action potential amplitudes decrease at successive nodes (amplitudes are indicated by interrupted bars representing three increasing concentration of local anesthetic). Eventually, the impulse decays to below threshold amplitude if the series of local anesthetic containing nodes is long enough. Propagation of the impulse has then been blocked by decremental conduction, even though none of the nodes are completely blocked. Concentrations of local anesthetic that block more than 84% of the sodium conductance at three successive nodes prevent any impulse propagation at all. (Adapted with permission from Fink BR: Mechanisms of differential axial blockade in epidural and spinal anesthesia. Anesthesiology 70:851, 1989.)A final mechanism whereby local anesthetics may block peripheral nerve function is viadegradation of transmitted electrical patterns. It is theorized that a large part of the sensoryinformation transmitted via peripheral nerves is carried via coding of electrical signals in after-potentials and after-oscillations. 2 5 Evidence for this theory is found in studies demonstrating lossof sensory nerve function after incomplete local anesthetic blockade. For example, sensation oftemperature of the skin can be lost despite unimpeded conduction of small fibers. 2 6 Furthermore,a surgical depth of epidural and peripheral nerve block anesthesia can be obtained with only minorchanges in somatosensory evoked potentials from the anesthetized area. 2 7 , 2 8 Previous studieshave demonstrated that application of sub-blocking concentrations of local anesthetic willsuppress normally occurring after-potentials and after-oscillations without significantly affectingaction potential conduction. 2 9 Thus, disruption of coding of electrical information by localanesthetics may be another mechanism for block of peripheral nerves.Mechanism of Blockade of Central NeuraxisCentral neuraxial block via spinal or epidural administration of local anesthetics involves the samemechanisms at the level of spinal nerve roots, either intra- or extradural, as discussed earlier. Inaddition, central neuraxial administration of local anesthetics allows multiple potential actions oflocal anesthetics within the spinal cord at different sites. For example, within the dorsal horn,local anesthetics can exert familiar ion channel block of sodium and potassium channels in dorsalhorn neurons and inhibit generation and propagation of nociceptive electrical activity. 3 0 Otherspinal cord neuronal ion channels, such as calcium channels, are also important for afferent and
efferent electrical activity. Administration of calcium channel blockers to spinal cord N (neuronal)calcium channels results in hyperpolarization of cell membranes, resistance to electricalstimulation from nociceptive afferents, and intense analgesia. 3 1 Local anesthetics appear to havesimilar actions on calcium channels, which may contribute to analgesic actions of centralneuraxially administered local anesthetics. 3 2In addition to ion channels, multiple neurotransmitters are involved in nociceptive transmission inthe dorsal horn of the spinal cord. 3 3 For example, tachykinins (substance P) are importantneurotransmitters modulating nociception from C fibers. 3 4 Administration of local anesthetics inconcentrations that occur after spinal and epidural anesthesia inhibits postsynaptic depolarizationsdriven by substance P and may decrease nociception via this inhibitory mechanism. 3 5 Otherneurotransmitters that are important for nociceptive processing in the spinal cord, such asacetylcholine, γ-aminobutyric acid (GABA), and N-methyl-D-aspartate (NMDA), can all be affectedby local anesthetics either pre- or postsynaptically. 8 , 3 5 These studies suggest that antinociceptiveeffects of central neuraxial local anesthetic block may be mediated via complex interactions atneural synapses in addition to ion channel blockade.PHARMACOLOGY AND PHARMACODYNAMICSChemical Properties and Relationship to Activity and PotencyThe clinically used local anesthetics consist of a lipid-soluble, substituted benzene ring linked toan amine group (tertiary or quaternary depending on pK a and pH) via an alkyl chain containingeither an amide or ester linkage (Fig. 17-7). The type of linkage separates the local anestheticsinto either aminoamides, metabolized in the liver, or aminoesters, metabolized by plasmacholinesterases. Several chemical properties of local anesthetics will affect their efficacy andpotency. FIGURE 17-7. General struture of clinically used local anesthetics. (Adapted with permission from Carpenter RL, Mackey DC: Local anesthetics. In Barash PG, Cullen BF, Stoelting RF [eds]: Clinical Anesthesia, p 413. Philadelphia, Lippincott–Raven, 1996.)All clinically used local anesthetics are weak bases that can exist as either the lipid-soluble,neutral form or as the charged, hydrophilic form. The combination of pH of the environment andpK a , or dissociation constant, of a local anesthetic determines how much of the compound exists ineach form (Table 17-2). As previously discussed, the primary site of action of local anestheticsappears to exist on the intracellular side of the sodium channel, and the charged form appears tobe the predominantly active form. 1 3 Penetration of the lipid-soluble form through the lipid neuralmembrane appears to be the primary form of access of local anesthetic molecules, although some
access by the charged form can be gained via the aqueous sodium channel pore (see Fig. 17-4). 3 9Thus, decreasing pK a for a given environmental pH will increase the percentage of lipid-solubleforms in existence, hastening penetration of neural membranes and onset of action. TABLE 17-2 Physicochemical Properties of Clinically Used Local Anesthetics ▪LOCAL ▪pKa ▪% IONIZED ▪PARTITION ▪% PROTEIN ANESTHETIC (at pH 7.4) COEFFICIENT (LIPID BINDING SOLUBILITY) ▪AMIDES Bupivacaine a 8.1 83 3,420 95 Etidocaine 7.7 66 7,317 94 Lidocaine 7.9 76 366 64 Mepivacaine 7.6 61 130 77 Prilocaine 7.9 76 129 55 Ropivacaine 8.1 83 775 94 ▪ESTERS Chloroprocaine 8.7 95 810 N/A Procaine 8.9 97 100 6 Tetracaine 8.5 93 5,822 94 N/A, not available. a Levo-bupivacaine has same physicochemical properties as racemate. Data from Liu SS. Local anesthetics and analgesia. In Ashburn MA, Rice LJ (eds): The Management of Pain, pp 141–170. New York, Churchill Livingstone Inc., 1997. P.458 Lipid solubility is another important determinant of activity. Although increasing lipid solubility may hasten penetration of neural membranes, increasing solubility may also resultin increased sequestration of local anesthetic in myelin and other lipid-soluble compartments.Thus, increasing lipid solubility usually slows the rate of onset of action. 4 0 Similarly, duration of
action is increased as absorption of local anesthetic molecules into myelin and surrounding neuralcompartments creates a depot for slow release of local anesthetics. 4 0 Finally, increased lipidsolubility increases potency of the local anesthetic. 1 2 , 1 3 This observation may be explained by acorrelation between lipid solubility and both sodium channel receptor affinity and ability to altersodium channel conformation by direct effects on lipid cell membranes.Degree of protein binding also affects activity of local anesthetics, as only the unbound form isfree for pharmacologic activity. In general, the more lipid soluble and longer acting agents haveincreased protein binding. 4 1 Although the sodium channel is a protein structure, it does not appearthat degree of local anesthetic protein binding correlates with binding to the local anestheticreceptor. Studies suggest that dissociation of local anesthetic molecules from the sodium channeloccurs in a matter of seconds regardless of degree of protein binding of the local anesthetic. 4 2Thus, prolongation in duration of action associated with an increased degree of protein bindingmust involve other extracellular or membranous proteins. A final physical property of interest is stereoisomeric mixture of the commercially available local anesthetics. All currently available local anesthetics are racemic mixtures with theexception of lidocaine (achiral), ropivacaine (S), and levo-bupivacaine (l = S). 4 3 , 4 4 Stereoisomersof local anesthetics appear to have potentially different effects on anesthetic potency,pharmacokinetics, and systemic toxicity. 1 9 , 4 3 , 4 4 For example, R isomers appear to have greater invitro potency for block of both neural and cardiac sodium channels and may thus have greatertherapeutic efficacy and potential systemic toxicity. 1 8 , 4 3 , 4 4 , 4 5Relative in vitro potencies of the clinically used local anesthetics have been identified and varydepending on individual nerve fibers and frequency of stimulation, and overall increasing lipidsolubility of local anesthetic correlates with increasing anesthetic potency (see Table 17-2). 4 6However, clinical use of local anesthetics is complex and in vivo potencies often do not correlatewith in vitro determinants. 4 7 Local factors affecting diffusion and spread of anesthetic will havegreat impact on clinical effects and will vary with different applications (e.g., peripheral nerveblock vs. spinal injection). Furthermore, clinical use may not require absolute suppression of thecompound action potential, but rather a disruption of information coding in the pattern ofdischarges. Few rigorous studies have been performed to evaluate relative clinical potencies oflocal anesthetics, and commonly accepted values are listed in Table 17-3. TABLE 17-3 Relative Potency of Local Anesthetics for Different Clinical Applications ▪BUPIVACAINE ▪CHLORO- ▪LIDOCAINE ▪MEPIVACAINE ▪PRILOCAINE ▪ROP PROCAINE Peripheral 3.6 N/A 1 2.6 0.8 nerve Spinal 9.6 1 1 1 1 Epidural 4 0.5 1 1 1 N/A, not available. Data from Camorcia M. Minimum local analgesic doses of ropivacaine, levobupivacaine, and bupivacain intrathecal labor analgesia. Anesthesiology 2005:102:646. Faccenda KA. A comparison of levobupivaca and racemic bupivacaine 0.5% for extradural anesthesia for caesarean section. Reg Anesth Pain Med
2003;28:394. McDonald SB. Hyperbaric spinal ropivacaine: a comparison to bupivacaine in volunteers. Anesthesiology 1999:90:971. Marsan A. Prilocaine or mepivacaine for combined sciatic-femoral nerve patients receiving elective knee arthroscopy. Minerva Anestesiol 2004;70:763. Casati A. Lidocaine ver ropivacaine for continuous interscalene brachial plexus blockafter open shoulder surgery. Acta Anaesth Scand 2003;47:35. Casati A. A double-blind study of axillary brachial plexus block by 0.75% ropivacai mepivacaine. Eur J Anaesthesiol 1998;15:549. Fanelli G. A double-blind comparison of ropivacaine, bu and mepivacaine during sciatic and femoral nerve blockade. Anesth Analg, 1998;87:597. Yoos JR. Spin chloroprocaine: a comparison with small-dose bupivacaine in volunteers. Anesth Analg 2005 Feb;100:5 ME. Spinal 2-chloroprocaine: a comparison with lidocaine in volunteers. Anesth Analg 2004 Jan:98:75.Tachyphylaxis to Local AnestheticsTachyphylaxis to local anesthetics is a clinical phenomenon whereby repeated injection of thesame dose of local anesthetic leads to decreasing efficacy. Tachyphylaxis has been described aftercentral neuraxial blocks, peripheral nerve blocks, and for different local anesthetics. 4 8 , 4 9 Aninteresting clinical feature of tachyphylaxis to local anesthetics is dependence on dosing interval.If dosing intervals are short enough such that pain does not occur, tachyphylaxis does notdevelop. Conversely, longer periods of patient discomfort before redosing hasten development oftachyphylaxis. 4 8 Both pharmacokinetic and dynamic mechanisms may be involved. A studyexamining repeated sciatic nerve blocks and infiltration analgesia in rats noted tachyphylaxisaccompanied by increased clearance of radiolabeled lidocaine out of nerves and skin. 5 0 Not allstudies support a pharmacokinetic mechanism for tachyphylaxis. For example, with thedevelopment of clinical tachyphylaxis, there is no difference in local anesthetic spread within orclearance from the epidural space. 5 1The observation that pain is important for the development of tachyphylaxis has led to speculationthat there is a pharmacodynamic mechanism for tachyphylaxis via spinal cord sensitization. 5 2 Ratsreceiving repeated sciatic nerve blocks failed to develop tachyphylaxis in the absence of noxiousstimulation. Exposure of the rats to increasingly noxious degrees of thermal stimulationincreasingly hastened development of tachyphylaxis, whereas pretreatment with an NMDAantagonist (MK-801) that prevents spinal cord sensitization also prevented development oftachyphylaxis. Second-messenger effects of nitric oxide for NMDA pathways may be especiallyimportant, as administration of nitric oxide synthetase inhibitors prevented development oftachyphylaxis in a P.459dose-dependent manner in the same model. 5 3 The clinical relevance of these findings needs to beexplored, but the development of a mechanism for tachyphylaxis may lead to clinical means for itsprevention.Additives to Increase Local Anesthetic ActivityEpinephrine Epinephrine has been added to local anesthetics since the early 1890s. Reported benefits of epinephrine include prolongation of local anesthetic block, increased intensity of block, anddecreased systemic absorption of local anesthetic. 5 4 Epinephrines vasoconstrictive effectsaugment local anesthetics by antagonizing inherent vasodilating effects of local anesthetics,decreasing systemic absorption and intraneural clearance, and perhaps by redistributingintraneural local anesthetic. 5 4 , 5 5Direct analgesic effects from epinephrine may also occur via interaction with α-2 adrenergic
receptors in the brain and spinal cord, 5 6 especially because local anesthetics increase the vascularuptake of epinephrine. 5 7 Clinical use of epinephrine is listed in Table 17-4. The smallest dose issuggested, as epinephrine combined with local anesthetics may have toxic effects on tissue, 5 8 thecardiovascular system, 5 9 peripheral nerves, and the spinal cord. 3 3 , 5 4 TABLE 17-4 Effects of Addition of Epinephrine to Local Anesthetics ▪INCREASE ▪DECREASE ▪DOSE/CONCENTRATION OF DURATION BLOOD LEVELS EPINEPHRINE (%) ▪NERVE BLOCK Bupivacaine +- 10–20 1:200,000 Lidocaine ++ 20–30 1:200,000 Mepivacaine ++ 20–30 1:200,000 Ropivacaine -- 0 1:200,000 ▪EPIDURAL Bupivacaine +- 10–20 1:300,000–1:200,000 L-bupivacaine +- 10 1:200,000–400,000 Chloroprocaine ++ 1:200,000 Lidocaine ++ 20–30 1,600,000–1:200,000 Mepivacaine ++ 20–30 1:200,000 Ropivacaine -- 0 1:200,000 ▪SPINAL Bupivacaine +- 0.2 mg Lidocaine ++ 0.2 mg Tetracaine ++ 0.2 mg
++, overall supported; --, overall not supported; +-, inconsistent. Data from Liu SS. Local Anesthetics and Analgesia. In, Ashburn MA, Rice LJ (eds): The Management of Pain. New York: Churchill Livingstone Inc., 1997:141–170 and Kopacz DJ. A comparison of epidural levobupivacaine 0.5% with or without epinephrine for lumbar spine surgery. Anesth Analg 2001;93:755.Alkalinization of Local Anesthetic SolutionSince the late 1800s, local anesthetic solutions have been alkalinized in order to hasten onset ofneural block. 6 0 The pH of commercial preparations of local anesthetics ranges from 3.9 to 6.47 andis especially acidic if prepackaged with epinephrine. 6 1 P.460As the pK a of commonly used local anesthetics ranges from 7.6 to 8.9 (see Table 17-2), less than3% of the commercially prepared local anesthetic exists as the lipid-soluble neutral form. Aspreviously discussed, the neutral form is believed to be the most important for penetration intothe neural cytoplasm, whereas the charged form primarily interacts with the local anestheticreceptor within the sodium channel. Therefore, the rationale for alkalinization was to increase thepercentage of local anesthetic existing as the lipid-soluble neutral form. However, clinically usedlocal anesthetics cannot be alkalinized beyond a pH of 6.05 to 8 before precipitation occurs, 6 1 andsuch pHs will only increase the neutral form to about 10%.Clinical studies that have shown an association between alkalinization of local anesthetics andhastening of block onset have shown a decrease of less than 5 minutes when compared tocommercial preparations. 6 0 , 6 2 In addition, a recent animal study suggests that alkalinization oflidocaine decreases the duration of peripheral nerve blocks if the solution does not also containepinephrine. 6 3 Overall, the value of alkalinization of local anesthetics appears debatable as aclinically useful tool to improve anesthesia.OpioidsAddition of opioids to local anesthetics has gained popularity. Opioids have multiple centralneuraxial and peripheral mechanisms of analgesic action. Supraspinal administration of opioidsresults in analgesia via opiate receptors in multiple sites, 6 4 via activation of descending spinalpathways 6 5 and via activation of nonopioid analgesic pathways. 6 6 Spinal administration of opioidsprovides analgesia primarily by attenuating C fiber nociception 6 7 and is independent of supraspinalmechanisms. 6 8 Coadministration of opioids with central neuraxial local anesthetics results insynergistic analgesia. 6 9 An exception to this analgesic synergy is 2-chloroprocaine, which appearsto decrease the effectiveness of epidural opioids when used for epidural anesthesia. 7 0 Themechanism for this action is unclear but does not appear to involve direct antagonism of opioidreceptors. 7 1 Overall, clinical studies support the practice of central neuraxial coadministration oflocal anesthetics and opioids in humans for prolongation and intensification of analgesia andanesthesia. 6 9The discovery of peripheral opioid receptors offers yet another circumstance in which thecoadministration of local anesthetics and opioids may be useful. 7 2 The most promising clinicalresults have been from intra-articular administration of local anesthetic and opioid forpostoperative analgesia, 7 3 whereas combining local anesthetics and opioids for nerve blocks
appears to be ineffective. 7 4 There are several reasons for a predicted lack of effect ofcoadministration of local anesthetic and opioid for peripheral nerve blocks. Anatomically,peripheral opioid receptors are found primarily at the end terminals of afferent fibers. 7 5 However,peripheral nerves are commonly blocked by deposition of anesthetic proximal to the end terminalsof nerve fibers. In addition, common sites for peripheral nerve blocks are encased in multiplelayers of connective tissue that the anesthetics must traverse before gaining access to peripheralopioid receptors. Finally, previous studies have demonstrated the importance of concomitant localtissue inflammation for analgesic effectiveness of peripheral opioid receptors. 7 2 The mechanism forthe underlying dependence on local inflammation is speculative and may involve upregulation oractivation of peripheral opioid receptors or “loosening” of intercellular junctions to allow passageof opioids to receptors. Lack of inflammation at the site of a peripheral nerve block may alsoreduce the effects of coadministration of local anesthetic and opioid. All of these factors combineto decrease the theoretical effectiveness of combinations of local anesthetics and opioids forperipheral nerve blocks. In summary, coadministration of opioids and local anesthetic in thecentral neuraxis appears to be an effective, nontoxic 3 3 means to improve activity of localanesthetic, whereas there is little theoretical reason to expect the mixture to enhance peripheralnerve block.α-2 Adrenergic Agonistsα-2 adrenergic agonists can be a useful adjuvant to local anesthetics. α-2 agonists, such asclonidine, produce analgesia via supraspinal and spinal adrenergic receptors. 7 6 Clonidine also hasdirect inhibitory effects on peripheral nerve conduction (A and C nerve fibers). 7 7 Thus, addition ofclonidine may have multiple routes of action depending on type of application. Preliminaryevidence suggests that coadministration of an α-2 agonist and local anesthetic results in centralneuraxial and peripheral nerve analgesic synergy, 7 8 whereas systemic (supraspinal) effects areadditive. 7 9 Overall, clinical trials indicate that clonidine enhances intrathecal and epiduralanesthesia, peripheral nerve blocks, 8 0 and intravenous regional anesthesia 8 1 without evidence forneurotoxicity. 3 3PHARMACOKINETICS OF LOCAL ANESTHETICSClearance of local anesthetic from neural tissue and from the body governs both duration of effectand potential toxicity. Clinical effects of neural block from local anesthetics are primarilydependent on local factors as discussed in the Pharmacology section. However, systemic toxicity isprimarily dependent on blood levels of local anesthetics. Resultant blood levels afteradministration of local anesthetics for neural blockade depend on absorption, distribution, andelimination of local anesthetics.Systemic AbsorptionIn general, local anesthetics with decreased systemic absorption will have a greater margin ofsafety in clinical use. The rate and extent of absorption will depend on numerous factors, of whichthe most important are the site of injection, the dose of local anesthetic, the physicochemicalproperties of the local anesthetic, and the addition of epinephrine.The relative amounts of fat and vasculature surrounding the site of local anesthetic injection willinteract with the physicochemical properties of the local anesthetic to affect rate of systemicuptake. In general, areas with greater vascularity will have more rapid and complete uptake ascompared to those with more fat, regardless of type of local anesthetic. Thus, rates of absorptionfrom injection of local anesthetic into various sites generally decrease in the following order:intercostal > caudal > epidural > brachial plexus > sciatic/femoral (Table 17-5). 8 2 , 8 3 TABLE 17-5 Typical C m a x after Regional Anesthetics with Commonly Used Local Anesthetics
plexus Epidural 150 1.07 40 Intercostal 140 1.10 21 C m a x , peak plasma levels; T m a x , time until C m a x . Data from Liu SS. Local Anesthetics and Analgesia. In Ashburn MA, Rice LJ (eds): The Management of Pain. New York: Churchill Livingstone Inc., 1997:141–170, Berrisford RG. Plasma concentrations of bupivacaine and its enantiomers during continuous extrapleural intercostal nerve block. British Journal of Anaesthesia 70:201, 1993. Kopacz DJ. A comparison of epidural levobupivacaine 0.5% with or without epinephrine forlumbar spine surgery. Anesth Analg 2001 Sep:93:755, and Crews JC. Levobupivacaine for axillary brachial plexus block: a pharmacokinetic and clinical comparison in patients with normal renal function or renal disease. Anesth Analg 2002;95:219.The greater the total dose of local anesthetic injected, the greater the systemic absorption andpeak blood levels (C m a x ). This relationship is nearly linear (Fig. 17-8) and is relatively unaffectedby anesthetic concentration 8 4 and speed of injection. 8 2 , 8 3 FIGURE 17-8. Increasing doses of ropivacaine used for wound infiltration result in linearly increasing maximal plasma concentrations (C m a x ). (Data from from Mulroy MF, Burgess FW, Emanuelsson B-M: Ropivacaine 0.25% and 0.5%, but not 0.125%, provide effective wound infiltration analgesia after outpatient hernia repair, but with sustained plasma drug levels. Reg Anesth Pain Med 24:136, 1999.)Physicochemical properties of local anesthetics will affect systemic absorption. In general, themore potent agents with greater lipid solubility and protein binding will result in lower systemicabsorption and C m a x (Fig. 17-9). 8 3 Increased binding to neural and nonneural tissue probablyexplains this observation.
FIGURE 17-9. Fraction of dose absorbed into the systemic circulation over time from epidural injection of lidocaine or bupivacaine. Bupivacaine is a more lipid soluble, more potent agent with less systemic absorption over time. (Adapted with permission from Tucker GT, Mather LE: Properties, absorption, and disposition of local anesthetic agents. In Cousins MJ, Bridenbaugh PO [eds]: Neural Blockade in Clinical Anesthesia and Management of Pain, p 55. Philadelphia, Lippincott–Raven, 1998.)The effects of epinephrine have been previously discussed. In brief, epinephrine can counteractthe inherent vasodilating characteristics of most local anesthetics. The reduction in C m a x withepinephrine is most effective for the less lipid-soluble, P.461less potent, shorter acting agents (see Table 17-4), as increased tissue binding rather than localblood flow may be a greater determinant of absorption for the long-acting agents.DistributionAfter systemic absorption, local anesthetics are rapidly distributed to the body. Regionaldistribution of local anesthetic will depend on organ blood flow, the partition coefficient of localanesthetic between compartments, and plasma protein binding. The end organs of main concernfor toxicity are within the cardiovascular and the central nervous systems. Both are consideredmembers of the “vessel-rich group” and will have local anesthetic rapidly distributed to them.Despite the high blood perfusion, regional blood and tissue levels of local anesthetics within theseorgans will not initially correlate with systemic blood levels because of hysteresis. 8 5 As regional,rather than systemic, pharmacokinetics govern subsequent pharmacodynamic effects, systemicblood levels may not correlate with effects of local anesthetics on end organs. 8 6 Regionalpharmacokinetics of local anesthetics for the heart and brain have not been fully delineated; thusthe volume of distribution at steady state (VDss) is often used to describe local anestheticdistribution (Table 17-6). However, VDss describes the extent of total body distribution and maybe inaccurate for specific organ systems. TABLE 17-6 Pharmacokinetic Parameters of Clinically Used Local Anesthetics ▪LOCAL ANESTHETIC ▪VDss (L/kg) ▪CL (L/kg/hr) ▪T1/2 (hr)
Bupivacaine 1.02 0.41 3.5 Levo-bupivacaine 0.78 0.32 2.6 Chloroprocaine 0.50 2.96 0.11 Etidocaine 1.9 1.05 2.6 Lidocaine 1.3 0.85 1.6 Mepivacaine 1.2 0.67 1.9 Prilocaine 2.73 2.03 1.6 Procaine 0.93 5.62 0.14 Ropivacaine 0.84 0.63 1.9 Data from Denson DD: Physiology and pharmacology of local anesthetics. In Sinatra RS, Hord AH, Ginsberg B, et al (eds): Acute Pain. Mechanisms and Management, p 124. St. Louis, Mosby Year Book, 1992 and Burm AG, van der Meer AD, van Kleef JW, et al: Pharmacokinetics of the enantiomers of bupivacaine following intravenous administration of the racemate. Br J Clin Pharmacol 38:125–129, 1994. P.462EliminationClearance (CL) of aminoester local anesthetics is primarily dependent on plasma clearance bycholinesterases, 8 7 whereas aminoamide local anesthetic clearance is dependent on clearance bythe liver. 8 8 Thus, hepatic extraction, hepatic perfusion, hepatic metabolism, and protein binding(Table 17-2) will primarily determine the rate of clearance of aminoamide local anesthetics. Ingeneral, local anesthetics with higher rates of clearance will have a greater margin of safety. 8 3Clinical PharmacokineticsThe primary benefit of knowledge of the systemic pharmacokinetics of local anesthetics is theability to predict C m a x after the agents are administered, thereby avoiding the administration oftoxic doses (Tables 17-5, 17-7, and 17-8). However, pharmacokinetics are difficult to predict inany given circumstance as both physical and pathophysiologic characteristics will affect theindividual pharmacokinetics. There is some evidence for increased systemic levels of localanesthetics in the very young and in the elderly owing to decreased clearance and increasedabsorption, 8 3 whereas correlation of resultant systemic blood levels between dose of localanesthetic and patient weight is often inconsistent (Figure 17-10). 8 9 Effects of gender on clinicalpharmacokinetics of local anesthetics have not been well defined, 9 0 although pregnancy maydecrease clearance. 8 3 Pathophysiologic states such as cardiac and hepatic disease will alterexpected pharmacokinetic parameters (Table 17-9), and lower doses of local anesthetics should be
used for these patients. As expected, renal disease has little effect on pharmacokinetic parametersof local anesthetics (Table 17-9). Finally, the skill of the anesthesiologist should be considered, asa large dose of local anesthetic placed in the correct location may have much less potential forsystemic toxicity than a small dose incorrectly injected intravascularly. All of these factors shouldbe considered when utilizing local anesthetics and minimizing systemic toxicity, the commonlyaccepted maximal dosages (Table 17-8) notwithstanding. TABLE 17-7 Relative Potency for Systemic Central Nervous System Toxicity by Local Anesthetics and Ratio of Dosage Needed for Cardiovascular System: Central Nervous System (CVS:CNS) Toxicity ▪AGENT ▪RELATIVE POTENCY FOR CNS ▪CVS:CNS TOXICITY Bupivacaine 4.0 2.0 Levo-bupivacaine 2.9 2.0 Chloroprocaine 0.3 3.7 Etidocaine 2.0 4.4 Lidocaine 1.0 7.1 Mepivacaine 1.4 7.1 Prilocaine 1.2 3.1 Procaine 0.3 3.7 Ropivacaine 2.9 2.0 Tetracaine 2.0 Data from Liu SS. Local Anesthetics and Analgesia. In Ashburn MA, Rice LJ, (eds): The Management of Pain. New York: Churchill Livingstone Inc., 1997:141–170. Groban L. Central nervous system and cardiac effects from long-acting amide local anesthetic toxicity in the intact animal model. Reg Anesth Pain Med 2003 Jan–Feb; 28(1):3–11. TABLE 17-8 Clinical Profile of Local Anesthetics ▪LOCAL ▪CONCENTRATION ▪CLINICAL ▪ONSET ▪DURATION ▪RECOMMENDED ANESTHETIC (%) USE (h) MAXIMUM
▪ESTERSBenzocaine Up to 20 Topical Fast 0.5–1 200Chloroprocaine 1 Infiltration Fast 0.5–1 800/1,000 + epinephrine 2 Peripheral Fast 0.5–1 800/1,000 + nerve block epinephrine 2–3 Epidural Fast 0.5–1 800/1,000 + anesthesia epinephrineCocaine 4–10 Topical Fast 0.5–1 150Procaine 10 Spinal Fast 0.5–1 1,000 anesthesiaTetracaine 2 Topical Fast 0.5–1 20 0.5 Spinal Fast 2–6 20 anesthesiaAdapted with permission from Covino BG, Wildsmith JAW: Clinical pharmacology of local anestheticagents.In Cousins MJ, Bridenbaugh PO (eds): Neural blockade in clinical anesthesia and management ofpain, pp 97–128. Philadephia, Lippincott–Raven, 1998. TABLE 17-9 Effects of Cardiac, Hepatic, and Renal Disease on Lidocaine Pharmacokinetics ▪VD ss (L/Kg) ▪CL (mL/kg/min) ▪T1/2(hr)Normal 1.32 10.0 1.8Cardiac failure 0.88 6.3 1.9Hepatic disease 2.31 6.0 4.9
Renal disease 1.2 13.7 1.3 VDss, volume of distribution at steady state; CL, total body clearance; T1/2, terminal elimination half-life. Data from Thomson PD. Lidocaine pharmacokinetics in advanced heart failure, liver disease, and renal failure in humans. Ann Intern Med 1973;78:499. FIGURE 17-10. Lack of correlation between patient weight and peak plasma concentration after epidural administration of 150 mg of bupivacaine. (Data from Sharrock NE, Mather LE, Go G, et al: Arterial and pulmonary concentrations of the enatiomers of bupivacaine after epidural injection in elderly patients. Anesth Analg 86:812, 1998.)CLINICAL USE OF LOCAL ANESTHETICSLocal anesthetics are used in a variety of ways in clinical anesthesia practice. Probably the mostcommon clinical use of local anesthetics for anesthesiologists is for regional anesthesia andanalgesia. Central neuraxial anesthesia and analgesia can be accomplished by epidural or spinalinjections of local anesthetics. Placement of epidural and spinal catheters can allow continuousinfusion of local anesthetics and other analgesics for extended durations. Intravenous regionalanesthesia and peripheral nerve blocks allow for anesthesia of the head and neck including theairway, upper extremities, trunk, and lower extremities. Newly developed catheters for continuousperipheral nerve blocks can also be placed to allow continuous infusions of local anesthetics andother analgesics for prolonged analgesia in a fashion similar to continuous epidural analgesia.Topical application of local anesthetics to the airway, eye, and skin provides sufficient anesthesiafor painless performance of minor anesthetic and surgical procedures such as tracheal intubation,intravenous catheter placement, or dural puncture. 9 1 Typical applications for each local anestheticare listed in Table 17-8. 9 2Other common clinical uses for local anesthetics include administration of lidocaine to blunt
responses to tracheal instrumentation and to suppress cardiac dysrhythmias. Intravenous ortopical administrations of lidocaine have been used with variable success to blunt hemodynamicresponse to tracheal intubation and extubation. 9 3 , 9 4 In addition to hemodynamic responses,instrumentation of the airway can result in coughing, bronchoconstriction, and other airwayresponses. Intravenous lidocaine can be effective for decreasing airway sensitivity toinstrumentation by depressing airway reflexes and decreasing calcium flux in airway smoothmuscle. 9 5 , 9 6 Doses of intravenous lidocaine from 2 to 2.5 mg/kg are needed to consistently blunthemodynamic and airway responses to tracheal instrumentation. 9 5 , 9 6 , 9 7 Intravenous lidocaine isalso effective for attenuating increases in intra-ocular pressure, intracranial pressure, and intra-abdominal pressure during P.463airway instrumentation. 9 8 Attenuation of all these responses may be beneficial in selected clinicalsituations (e.g., corneal laceration or increased intracranial pressure). Intravenous lidocaine haswell-recognized cardiac antidysrhythmic effects. 9 9Finally, intravenous lidocaine (1 to 5 mg/kg) is an effective analgesic and has been used to treatpostoperative 1 0 0 and chronic neuropathic pain. 1 0 1 Peripheral and central inhibition of generationand propagation of spontaneous electrical activity in injured C nerve fibers and Aδ nerve fibers arethought to be primary mechanisms as opposed to typical conduction block. 1 0 2 , 1 0 3 , 1 0 4 Positronemission tomography in patients with neuropathic pain suggests that altered activity in cerebralblood flow to the thalamus 1 0 5 may also contribute to systemic analgesic effects of localanesthetics. The ability of local anesthetics to provide systemic analgesic effects at central andperipheral sites may in part explain the ability of a single neural block to provide long-lastinganalgesia from neuropathic pain. In addition, orally administered mexiletine (a Class Iantidysrhythmic agent similar to lidocaine) has been successfully used to treat chronic painconditions. 1 0 1TOXICITY OF LOCAL ANESTHETICSSystemic Toxicity of Local AnestheticsCentral Nervous System ToxicityLocal anesthetics readily cross the blood-brain barrier, and generalized CNS toxicity may occurfrom systemic absorption or P.464direct vascular injection. Signs of generalized CNS toxicity because of local anesthetics are dosedependent (Table 17-10). Low doses produce CNS depression, and higher doses result in CNSexcitation and seizures. 1 0 6 The rate of intravenous administration of local anesthetic will alsoaffect signs of CNS toxicity, as higher rates of infusion of the same dose will lessen theappearance of CNS depression while leaving excitation intact. 1 0 7 This dichotomous reaction to localanesthetics may be a result of a greater sensitivity of cortical inhibitory neurons to the impulseblocking effects of local anesthetics. 1 0 6 , 1 0 8 , 1 0 9 TABLE 17-10 Dose-Dependent Systemic Effects of Lidocaine ▪PLASMA CONCENTRATION (mcg/mL) ▪EFFECT 1–5 Analgesia 5–10 Lightheadedness Tinnitus Numbness of tongue
10–15 Seizures Unconsciousness 15–25 Coma Respiratory arrest >25 Cardiovascular depressionLocal anesthetic potency for generalized CNS toxicity approximately parallels action potentialblocking potency (Tables 17-3 and 17-7). 1 0 6 In general, decreased local anesthetic protein bindingand clearance will increase potential CNS toxicity. External factors can increase potency for CNStoxicity, such as acidosis and increased PCO 2 , perhaps via increased cerebral perfusion ordecreased protein binding of local anesthetic. 1 0 6 There are also external factors that can decreaselocal anesthetic potency for generalized CNS toxicity. For example, seizure thresholds of localanesthetics are increased by administration of barbiturates and benzodiazepines. 1 1 0Addition of vasoconstrictors such as epinephrine may reduce or promote the potential forgeneralized local anesthetic CNS toxicity. Addition of epinephrine to local anesthetics will decreasesystemic absorption and peak blood levels and increase the safety margin. On the other hand, theconvulsive threshold for intravenous administration of lidocaine in the rat is decreased by about42% when epinephrine (1:100,000), norepinephrine, or phenylephrine is added to the plainsolution. 1 1 1 The mechanisms of increased toxicity with addition of epinephrine are unclear butappear to depend on the development of hypertension from vasoconstriction. A hyperdynamiccirculatory system may enhance the toxic effects of local anesthetics by causing increasedcerebral blood flow and delivery of lidocaine to the brain 1 1 2 , 1 1 3 or through disruption of the blood-brain barrier. 1 1 4 In addition to enhancing distribution of local anesthetic to the brain,hyperdynamic circulatory changes can also decrease clearance of local anesthetic from the bodybecause of changes in distribution of blood flow away from the liver. Changes in total bodyclearance from hyperdynamic circulatory changes induced by local anesthetic seizures have beenstudied in dogs. 1 1 5 Seizures significantly increased heart rate, blood pressure, and cardiac outputwhile significantly decreasing total body clearance (29 to 68%) of lidocaine, mepivacaine,bupivacaine, and etidocaine. Clinical reports suggest toxicity from local anesthetics used for regional anesthesia is uncommon. Surveys from France and the United States of over 280,000 cases of regionalanesthesia report an incidence of seizures with epidural injection approximating 1/10,000 and anincidence of 7/10,000 with peripheral nerve blocks. 1 0 8 , 1 0 9 There appears to be a higher incidenceof local anesthetic toxicity during peripheral nerve blocks, perhaps because of differences inpractice or less clinical awareness. Nonetheless, epidural anesthesia (primarily obstetrical)constituted all the cases of death or brain damage resulting from unintentional intravenousinjection of local anesthetic in an analysis of closed malpractice claims in the United States from1980 to 1999. 1 1 6Cardiovascular Toxicity of Local AnestheticsIn general, much greater doses of local anesthetics are required to produce cardiovascular (CV)toxicity than CNS toxicity. Similar to CNS toxicity, potency for CV toxicity reflects the anestheticpotency of the agent (Tables 17-3 and 17-7). Attention has focused on the apparently exceptionalcardiotoxicity of the more potent, more lipid-soluble agents (bupivacaine, levo-bupivacaine,
ropivacaine). These agents appear to have a different sequence of CV toxicity than less potentagents, with bupivacaine being the most cardiotoxic. For example, increasingly toxic doses oflidocaine lead to hypotension, bradycardia, and hypoxia, whereas toxic doses of bupivacaine, levo-bupivacaine, and ropivacaine often result in sudden cardiovascular collapse as a result ofventricular dysrhythmias that are resistant to resuscitation (Fig. 17-11). 1 0 6 , 1 1 0 , 1 1 7 FIGURE 17-11. Success of resuscitation of dogs after cardiovascular collapse from intravenous infusions of lidocaine, bupivacaine, levo-bupivacaine, and ropivacaine. Success rates were greater for lidocaine (100%), than ropivacaine (90%), than levo-bupivacaine (70%), and than bupivacaine (50%). Required doses to induce cardiovascular collapse were greater for lidocaine (127 mg/kg), than ropivacaine (42 mg/kg), than levo-bupivacaine (27 mg/kg), and than bupivacaine (22 mg/kg). (Data from Groban L, Deal DD, Vernon JC, et al: Cardiac resuscitation after incremental overdosage with lidocaine, bupivacaine, levobupivacaine, and ropivacaine in anesthetized dogs. Anesth Analg 92:37, 2001.)Use of the single–optical isomer (S/L) preparations of ropivacaine and levo-bupivacaine mayimprove the safety profile for long-lasting regional anesthesia. Both ropivacaine and P.465levo-bupivacaine appear to be approximately equipotent to racemic bupivacaine for epidural andplexus anesthesia (see Table 17-3). 1 1 8 , 1 1 9 Both ropivacaine and levo-bupivacaine haveapproximately 30 to 40% less systemic toxicity than bupivacaine on a mg:mg basis in animalstudies 4 6 , 1 0 6 (Fig. 17-12), although human studies are less dramatic (Fig. 17-13). 1 2 0 , 1 2 1 Reducedpotential for cardiotoxicity is likely because of reduced affinity for brain and myocardial tissuefrom their single isomer preparation. 1 8 , 4 5 , 1 0 6 In addition to stereoselectivity, the larger butyl sidechain in bupivacaine may also have more of a cardiodepressant effect as opposed to the propyl-side chain of ropivacaine. 1 2 2
FIGURE 17-12. Serum concentrations in sheep at each toxic manifestation for bupivacaine,levo-bupivacaine, and ropivacaine in sheep. Both levo-bupivacaine and ropivacaine requiredsignificantly greater serum concentrations than bupivacaine. (Data from Santos AC, DeArmasPI: Systemic toxicity of levobupivacaine, bupivacaine, and ropivacaine during continuousintravenous infusion to nonpregnant and pregnant ewes. Anesthesiology 95:1256, 2001.)FIGURE 17-13. Mild prolongation in QRS interval and reduction in cardiac output areobserved after intravenous infusions of bupivacaine (103 mg), levobupivacaine (37 mg), andropivacaine (115 mg) in healthy volunteers. Data from: Knudsen K, Beckman Suurkula M, etal. Central nervous and cardiovascular effects of i.v. infusions of ropivacaine, bupivacaineand placebo in volunteers. Br Anaesth 1997:78:507. Stewart J, Kellett N, Castro D. Thecentral nervous system and cardiovascular effects of levobupivacaine and ropivacaine inhealthy volunteers. Anesth Analg 2003:97:412.
Cardiovascular Toxicity Mediated at the CNS. It has been demonstrated that the central andperipheral nervous systems may be involved in the increased cardiotoxicity with bupivacaine. Thenucleus tractus solitarii in the medulla is an important region for autonomic control of thecardiovascular system. Neural activity in the nucleus tractus solitarii of rats is markedlydiminished by intravenous doses of bupivacaine immediately prior to development of hypotension.Furthermore, direct intracerebral injection of bupivacaine can elicit sudden dysrhythmias andcardiovascular collapse. 1 2 3Peripheral effects of bupivacaine on the autonomic and vasomotor systems may also augment itsCV toxicity. Bupivacaine possesses a potent peripheral inhibitory effect on sympathetic reflexes 1 2 3that has been observed even at blood concentrations similar to those measured afteruncomplicated regional anesthesia. 1 2 4 Finally, bupivacaine also has potent direct vasodilatingproperties, which may exacerbate cardiovascular collapse. 1 2 5Cardiovascular Toxicity Mediated at the Heart. The more potent local anesthetics appear topossess greater potential for direct cardiac electrophysiologic toxicity. 4 5 , 1 0 6 Although all localanesthetics block the cardiac conduction system via a dose-dependent block of sodium channels,two features of bupivacaines sodium channel blocking abilities may enhance its cardiotoxicity.First, bupivacaine exhibits a much stronger binding affinity to resting and inactivated sodiumchannels than lidocaine. 1 2 6 Second, local anesthetics bind to sodium channels during systole anddissociate during diastole (Fig. 17-14). Bupivacaine dissociates from sodium channels duringcardiac diastole much more slowly than lidocaine. Indeed, bupivacaine dissociates so slowly thatthe duration of diastole at physiologic heart rates (60 to 180 bpm) does not allow enough time forcomplete recovery of sodium channels and bupivacaine conduction block accumulates. In contrast,lidocaine fully dissociates from sodium channels during diastole and little accumulation ofconduction block occurs (Fig. 17-15). 1 2 6 , 1 2 7 Thus, enhanced electrophysiologic effects of morepotent local anesthetics on the cardiac conduction system may explain their increased potential toproduce sudden cardiovascular collapse via cardiac dysrhythmias. FIGURE 17-14. Diagram illustrating relationship between cardiac action potential (top), sodium channel state (middle), and block of sodium channels by bupivacaine (bottom). R = resting, O = open, and I = inactive forms of the sodium channel. Sodium channels are predominantly in the resting form during diastole, open transiently during the action potential upstroke, and are in the inactive form during the action potential plateau. Block of sodium channels by bupivacaine accumulates during the action potential (systole) with recovery occurring during diastole. Recovery of sodium channels is from dissociation of bupivacaine and is time dependent. Recovery during each diastolic interval is incomplete and
results in accumulation of sodium channel block with successive heartbeats. (Adapted with permission from Clarkson CW, Hondegham LM: Mechanisms for bupivacaine depression of cardiac conduction: Fast block of sodium channels during the action potential with slow recovery from block during diastole. Anesthesiology 62:396, 1985.) FIGURE 17-15. Heart rate dependent effects of lidocaine and bupivacaine on velocity of the cardiac action potential (V m a x ). Bupivacaine progressively decreases V m a x at heart rates above 10 bpm because of accumulation of sodium channel block, whereas lidocaine does not decrease V m a x until heart rate exceeds 150 bpm. (Adapted with permission from Clarkson CW, Hondegham LM: Mechanisms for bupivacaine depression of cardiac conduction: Fast block of sodium channels during the action potential with slow recovery from block during diastole. Anesthesiology 62:396, 1985.) P.466Increased potency for direct myocardial depression from the more potent local anesthetics isanother contributing factor to increased cardiotoxicity (Fig. 17-16). 1 0 6 , 1 2 2 Again, multiplemechanisms may account for the increased potency for myocardial depression from more potentlocal anesthetics. Bupivacaine, the most completely studied potent local anesthetic, possesses ahigh affinity for sodium channels in the cardiac myocyte. 1 8 , 4 5 , 1 0 6 Furthermore, bupivacaine inhibitsmyocyte release and utilization of calcium 1 2 8 and reduces mitochondrial energy metabolism,especially during hypoxia. 1 2 9 Thus, multiple direct effects of bupivacaine on activity of the cardiacmyocyte may explain the cardiotoxicity of bupivacaine and other potent local anesthetics.
FIGURE 17-16. Plasma concentrations required to induce myocardial depression in dogs administered bupivacaine, levo-bupivacaine, ropivacaine, and lidocaine. dP/dtmax = 35% reduction of inotropy from baseline measure. %EF = 35% reduction in ejection fraction from baseline measure. CO = 25% reduction in cardiac output from baseline measure. (Data from Groban L, Deal DD, Vernon JC, et al: Does local anesthetic stereoselectivity or structure predict myocardial depression in anesthetized canines? Reg Anesth Pain Med 27:460, 2002.)Treatment of Systemic Toxicity from Local Anesthetics The best method for avoiding systemic toxicity from local anesthetics is through prevention. Toxic systemic levels can occur by unintentional intravenous or intra-arterial injection or bysystemic absorption of excessive doses placed in the correct area. Unintentional intravascular andintra-arterial injections can be minimized by frequent syringe aspiration for blood, use of a smalltest dose of local anesthetic (~3 mL) to test for subjective systemic effects from the patient (e.g.,tinnitus, circumoral numbness), and either slow injection or fractionation of the rest of the dose oflocal anesthetic. 1 1 0 Detailed knowledge of local anesthetic pharmacokinetics will also aid inreducing the administration of excessive doses of local anesthetics. Ideally, heart rate, bloodpressure, and the electrocardiogram should be monitored during administration of large doseslocal anesthetics. Pretreatment with a benzodiazepine may also lower the probablility of seizure byraising the seizure threshhold.Treatment of systemic toxicity is primarily supportive. Injection of local anesthetic should bestopped. Oxygenation and ventilation should be maintained, as systemic toxicity of localanesthetics is enhanced by hypoxemia, hypercarbia, and acidosis. 1 1 0 If needed, the patientstrachea should be intubated and positive pressure ventilation instituted. As previously discussed,signs of CNS toxicity will typically occur prior to CV events. Seizures can increase bodymetabolism and cause hypoxemia, hypercarbia, and acidosis. Pharmacologic treatment toterminate seizures may be needed if oxygenation and ventilation cannot be maintained.Intravenous administration of thiopental (50 to 100 mg), midazolam (2 to 5 mg), and propofol (1mg/kg) can terminate seizures from systemic local anesthetic toxicity. Succinylcholine (50 mg)can terminate muscular activity from seizures and facilitate ventilation and oxygenation. However,succinylcholine will not terminate seizure P.467activity in the CNS, and increased cerebral metabolic demands will continue unabated.Cardiovascular depression from less potent local anesthetics (e.g., lidocaine) is usually mild andcaused by mild myocardial depression and vasodilation. Hypotension and bradycardia can usuallybe treated with ephedrine (10 to 30 mg) and atropine (0.4 mg). As previously discussed, potentlocal anesthetics (e.g., bupivacaine) can produce profound CV depression and malignant
dysrhythmias that should be promptly treated. Oxygenation and ventilation must be immediatelyinstituted, with cardiopulmonary resuscitation if needed. Ventricular dysrhythmias may be difficultto treat and may need large and multiple doses of electrical cardioversion, epinephrine,vasopressin, and amiodarone. The use of calcium channel blockers in this setting is notrecommended, as its cardiodepressant effect is exaggerated. 1 1 0 A novel and promising treatmentfor cardiac toxicity is the administration of intravenous lipid to theoretically remove bupivacainefrom sites of action. Administration of a 20% lipid solution at a dose of 4 mL/kg followed by a 0.5mL/kg/min infusion for 10 minutes allowed for the resuscitation of 100% of dogs with inducedbupivacaine cardiotoxicity at a dose of 10mg/kg. 1 3 0 None of the dogs given an equivalent volumeof crystalloid were rescuscitated in this study. These findings raise the question of whetherpropofol in a 10% lipid solution would be a preferred treatment for cardiac toxicity. Propofol hasbeen reported to terminate bupivacaine-induced seizures and cardiac depression in patients. 1 3 0However, the dose of lipid in a standard induction dose of propofol (2 mg/kg) would be only 3% ofthe dose used in the aforementioned animal experiment. As effects of lipid on cardiac toxicity aredose related, further information is needed prior to reaching conclusions on clinical use of propofolfor local anesthetic–induced cardiac toxicity.Neural Toxicity of Local AnestheticsIn addition to systemic toxicity, local anesthetics can cause injury to the central and peripheralnervous system from direct exposure. Mechanisms for local anesthetic neurotoxicity remainspeculative, but previous studies have demonstrated local anesthetic–induced injury to Schwanncells, inhibition of fast axonal transport, disruption of the blood-nerve barrier, decreased neuralblood flow with associated ischemia, and disruption of cell membrane integrity via a detergentproperty of local anesthetics. 1 3 1 , 1 3 2 Although all clinically used local anesthetics can causeconcentration-dependent nerve fiber damage in peripheral nerves when used in high enoughconcentrations, previous studies have demonstrated that local anesthetics in clinically usedconcentrations are generally safe for peripheral nerves. 1 3 3 The spinal cord and the nerve roots, onthe other hand, are more prone to injury.Spinal cord toxicity of local anesthetics has been assessed by administration of local anestheticsto rabbits via intrathecal catheters. These studies suggest that bupivacaine (2%), lidocaine (8%),and tetracaine (1%) cause histopathologic changes and neurologic deficits. On the other hand,clinically relevant concentrations of these agents, chloroprocaine and ropivacaine (2%), did notdisrupt spinal cord histology or cause nerurological deficits. 1 3 4 Desheathed peripheral nervemodels, designed to mimic unprotected nerve roots in the cauda equina, have been used to furtherassess electrophysiologic neurotoxicity of local anesthetics. 1 3 5 , 1 3 6 , 1 3 7 Lidocaine 5% and tetracaine0.5% caused irreversible conduction block in these models, whereas lidocaine 1.5%, bupivacaine0.75%, and tetracaine 0.06% did not. Electrophysiologic toxicity of lidocaine in isolated nervepreparations represented by incomplete recovery of neuromuscular function occurs at 40 mM(~1%) (Fig. 17-17), with irreversible ablation of the compound action potential seen at 80 mM(~2%). Although such studies do not reflect in vivo conditions, they suggest that lidocaine andtetracaine may be especially neurotoxic in a concentration-dependent fashion and thatneurotoxicity could theoretically occur with clinically used solutions. Local anesthetic effects onspinal cord blood flow, another possible etiology of neurotoxicity from direct drug exposure,appear benign. Spinal administration of bupivacaine, lidocaine, mepivacaine, and tetracaine causevasodilation and increase spinal cord blood flow, whereas ropivacaine causes vasoconstriction andreduction in spinal cord blood flow in a concentration-dependent fashion. 1 3 8
FIGURE 17-17. The nonreversible effect of 40 mM lidocaine on the compound action potential (CAP) of frog sciatic nerve. Lidocaine was applied to a stable nerve preparation for 15 minutes and then washed with frog Ringers solution for 2 hours. Tracings represent CAPs in response to stimulus (1-Hz stimulus = heavy line; 40-Hz stimulus = thin line). 40 mM lidocaine completely ablated the CAP when applied to the nerve. The 1-Hz CAP response began to return after 10 to 15 minutes of washing and reached a new level in 45 minutes, where it was stable for the subsequent 2 hours of observation. The recovered 1-Hz CAP is only 65% of the original. (Adapted with permission from Bainton C: Concentration dependence of lidocaine-induced irreversible conduction loss frog nerve. Anesthesiology 81:657, 1994.)Neurohistopathologic data in humans after intrathecal exposure to local anesthetics is notavailable. Electrophysiologic parameters such as somatosensory evoked potentials, monosynapticH-reflex, 1 3 9 and cutaneous current perception thresholds 1 4 0 have been used to evaluate recoveryafter spinal anesthesia. These measurements have shown complete return to baseline activityafter 5% lidocaine spinal anesthesia in very small study populations. Prospective surveys of over80,000 spinal anesthetics report an incidence of 0 to 0.02% long-term neurologic injury inpatients undergoing spinal anesthesia. 1 0 9 Thus, spinally administered local anesthetics have notnotably manifested clinical neurotoxicity.Transient Neurologic Symptoms after Spinal AnesthesiaProspective, randomized studies reveal a 4 to 40% incidence of transient neurologic symptoms(TNS), including pain or sensory abnormalities in the lower back, buttocks, or lower extremities,after lidocaine spinal anesthesia. 1 3 9 These symptoms have been reported with other localanesthetics as well (Table 17-11). Increased risk of TNS is associated with lidocaine, the lithotomyposition, and ambulatory anesthesia, but not with baricity of solution or dose of localanesthetic. 1 3 9 The potential neurological etiology of this syndrome coupled with knownconcentration-dependent toxicity of lidocaine led to concerns over a neurotoxic etiology for TNSfrom spinal lidocaine. TABLE 17-11 Incidences of Transient Neurological Symptoms (TNS) Vary with Type of Spinal Local Anesthetic and Surgery ▪LOCAL ▪CONCENTRATION ▪TYPE OF ▪APPROXIMATE ANESTHETIC (%) SURGERY INCIDENCE OF TNS
(%) Lidocaine 2–5 Lithotomy 30–36 position 2–5 Knee 18–22 arthroscopy 0.5 Knee 17 arthroscopy 2–5 Mixed supine 4–8 position Mepivacaine 1.5–4 Mixed 23 Procaine 10 Knee 6 arthroscopy Bupivacaine 0.5–0.75 Mixed 1 Levo- 0.5 Mixed 1 bupivacaine Prilocaine 2–5 Mixed 1 Ropivacaine 0.5–0.75 Mixed 1 Data from: Pollock JE. Transient neurologic symptoms: etiology, risk factors, and management. Reg Anesth Pain Med 2002;27:581 and Breebaart MB. Urinary bladder scanning after day-case arthroscopy under spinal anaesthesia: comparison between lidocaine, ripovacaine, and levobupivacaine. Br J Anaesth 2003;90:309.As previously discussed, laboratory work in both intrathecal and desheathed peripheral nervemodels has proved that P.468the concentration of lidocaine is a critical factor in neurotoxicity. As concentrations of lidocainebelow 40 mM (~1.0%) are not neurotoxic to desheathed peripheral nerve, such diluteconcentrations of spinal lidocaine should not cause TNS if the syndrome is a result of subclinicalconcentration-dependent neurotoxicity. The dilution of lidocaine to as low as 0.5%, however, doesnot decrease the incidence of TNS. 1 4 1 The high incidence of TNS observed with lidocaineconcentrations <1% despite further dilution in cerebrospinal fluid lessens the plausibility of aconcentration-dependent neurotoxic etiology. Furthermore, a volunteer study comparingindividuals with and without TNS symptoms after lidocaine spinal anesthesia showed no differencedetected by electromyography, nerve conduction studies, or somatosensory evoked potentials.
Overall, there is little evidence to support a neurotoxic etiology for TNS. 1 3 9 Other potentialetiologies for TNS include patient positioning, sciatic nerve stretch, muscle spasm, and myofascialstrain. 1 3 9Interest in finding a short-acting spinal anesthetic with a lesser incidence of TNS has served as animpetus for investigations into the use of 2-chloroprocaine as a spinal anesthetic. Preliminarystudies show that preservative-free 2-chloroprocaine provides an anesthetic profile similar tolidocaine without report of TNS, which would make 2-chloroprocaine potentially useful foroutpatient procedures (Table 17-12). Enthusiasm for spinal 2-chloroprocaine should be temperedby the potential for neurotoxicity. In a laboratory study, 2-chloroprocaine (14 mg/kg)administered to rats via intrathecal catheter was noted to be histologically neurotoxic to the spinalcord to the same degree as 2.5% lidocaine. This finding calls into question the long held beliefthat the antioxidant sodium bisulfite is to blame for 2-chloroprocaines clinical neurotoxicity. 1 4 2The clinical applicability of this finding is uncertain, as the dose of chloroprocaine is far greaterthan the dose used for spinals in humans (0.6 mg/kg). TABLE 17-12 Dose Range of Spinal 2-Chloroprocaine and Comparison to Lidocaine ▪2-CHLOROPROCAINE ▪30 MG ▪45 MG ▪60 MG ▪LIDOCAINE 40 MG Sensory Block Height Peak T7 T5 T2 T8 Time to L1 regression 53±30 75±14 92±13 84±35 (mins) Thigh tourniquet 37±11 42±11 62±10 38±24 tolerance (mins) Complete regression 98±20 116±15 132±23 126±16 (mins) Time to ambulation 100±20 119±15 133±20 134±14 (mins) Time to bladder void 100±21 132±19 141±21 134±14 (mins) Data from Kouri ME, Kopacz DJ: Spinal 2-chloroprocaine: A comparison with lidocaine in volunteers. Anesth Analg 98(1):75–80, Jan 2004, and Smith KN, Kopacz DJ, McDonald SB: Spinal 2-chloroprocaine: A dose-ranging study and the effect of added epinephrine. Anesth Analg 98(1): 81–88, Jan 2004.Myotoxicity of Local AnestheticsToxicity to skeletal muscle is an uncommon side effect of local anesthetic injection. Experimental
data suggests, however, that local anesthetics have the potential for myotoxicity in clinicallyapplicable concentrations (Fig. 17-18). Histopathologic evidence shows that the injection of theseagents causes diffuse myonecrosis, which is both reversible and clinically imperceptible. Thereversible nature of this injury is possibly because of the relative resilience of myoblasts, whichregenerate damaged tissue. Theoretical mechanisms of injury are numerous but dysregulation ofintracellular calcium concentrations is the most likely culprit. One study shows that ropivacaine isless myotoxic than bupivacaine primarily because of the latter causing P.469apoptosis (programmed cell death). 143 Further investigation is needed to determine the clinicalrelevance of local or systemic myotoxicity following single injection or continuous infusion of localanesthetics. FIGURE 17-18. Skeletal muscle cross section with characteristic histologic changes after continuous exposure to bupivacaine for 6 hours. A whole spectrum of necrobiotic changes can be encountered, ranging from slightly damaged vacuolated fibers and fibers with condensed myofibrils to entirely disintegrated and necrotic cells. The majority of the myocytes are morphologically affected. Additionally, a marked interstitial and myoseptal edema appears within the sections. However, scattered fibers remain intact. (Reprinted with permission from Zink W, Graf B: Local anesthetic myotoxicity. Reg Anesth Pain Med 29(4):333–40, Jul–Aug 2004.)Allergic Reactions to Local Anesthetics (see also Chapter 49)True allergic reactions to local anesthetics are rare and usually involve Type I (IgE) or Type IV(cellular immunity) reactions. 1 4 4 , 1 4 5 Type I reactions are worrisome, as anaphylaxis may occur,and are more common with ester than amide local anesthetics. True Type I allergy to aminoamideagents is extremely rare. 1 4 5 Increased allergenic potential with esters may be a result ofhydrolytic metabolism to para-aminobenzoic acid, which is a documented allergen. Addedpreservatives such as methylparaben and metabisulfite can also provoke an allergic response. Skintesting with intradermal injections of preservative-free local anesthetics has been advocated as ameans to determine tolerance to local anesthetic. These tests should be undertaken with caution,as potentially severe and even fatal reactions can occur in truly allergic patients. 1 4 5References
1. Ritchie JM, Ritchie B, Greengard P: The effect of the nerve sheath on the action of localanesthetics. J Pharmacol Exp Ther 150:160, 19652. Coggeshall RE: A fine structured analysis of the myelin sheath in rat spinal roots. Anat Rec194:201, 19793. Waxman SG, Ritchie JM: Molecular dissection of the myelinated axon. Ann Neurol 33:121,19934. Landon N, Williams PL: Ultrastructure of the node of Ranvier. Nature 199:575, 19635. London DN, Langely OK: The local chemical environment of nodes of Ranvier: A study ofcation binding. J Anat 108:419, 19716. Popitz-Berger FA, Leeson S, Strichartz GR, et al: Relation between functionaldeficit and intraneural local anesthetic during peripheral nerve block. Anesthesiology83:583, 19957. Wann KT: Neuronal sodium and potassium channels: Structure and function. Br J Anaesth71:2, 19938. Ogata N, Ohishi Y: Molecular diversity of structure and function of the voltage-gated Na+channels. Jpn J Pharmacol 88:365, 20029. French RJ, Zamponi GW, Sierralta IE: Molecular and kinetic determinants of localanaesthetic action on sodium channels. Toxicol Lett 100:247, 199810. Caterall WA: The molecular basis of neuronal excitability. Science 223:653, 198411. Chiu SY, Ritchie JM, Rogart RB: A quantitative description of membrane current in rabbitmyelinated nerve. J Physiol (Lond) 292:149, 197912. Yun I, Cho ES, Jang HO, et al: Amphiphilic effects of local anesthetics on rotationalmobility in neuronal and model membranes. Biochim Biophys Acta 1564:123, 200213. Butterworth JF, Strichartz GR: Molecular mechanisms of local anesthesia: Areview. Anesthesiology 72:711, 199014. Huang JH, Thalhammer JG, Raymond SA, et al: Susceptibility to lidocaine of impulses indifferent somatosensory afferent fibers of rat sciatic nerve. J Pharmacol Exp Ther 282:802,199715. Gokin AP, Philip B, Strichartz GR: Preferential block of small myelinated sensory andmotor fibers by lidocaine: In vivo electrophysiology in the rat sciatic nerve. Anesthesiology95:1441, 2001