Editors: Barash, Paul G.; Cullen, Bruce F.; Stoelting, Robert K.

Title: Clinical Anesthesia, 5th Edition

Copyright ©2006 Lippincott Williams & Wilkins

> Table of Contents > Section III - Basic Principles of Pharmacology in Anesthesia Practice > Chapter 17 -

Local Anesthetics

Chapter 17

Local Anesthetics

Spencer S. Liu

Raymond S. Joseph Jr.

KEY POINTS

Local anesthetics block the generation, propagation, and oscillations of

electrical impulses in electrically excitable tissue.

Molecular and genetic studies indicate that local anesthetics primarily work by

binding to a modulated receptor located on the interior of the sodium channel.

In addition to sodium channel block, mechanisms of action of both peripheral

and central neural block may involve decremental conduction, partial block of

information carrying electrical oscillations, and interactions with other

neurotransmitters such as GABA.

In general, the more potent and longer acting agents are more lipid soluble,

have increased protein binding, less systemic absorption, but more potential for

systemic toxicity.

All currently available local anesthetics are racemic mixtures with the exception

of lidocaine (achiral), levobupivacaine (l = S), and ropivacaine (S). It appears

that S isomers have nearly equal efficacy but less potential for systemic

toxicity.

Efficacy for clinical use of local anesthetics may be increased by addition of

epinephrine, opioids, and alpha-2 adrenergic agonists. The value of

alkalinization of local anesthetics appears to be debatable as a clinically useful

tool to improve anesthesia.

Systemic toxicity from the clinical use of local anesthetics for regional

anesthesia appears to be an uncommon occurrence. Surveys from France and

the United States approximate the seizure rate to be 1/10,000 for epidural

injection and 7/10,000 for peripheral nerve block.

Nonetheless, systemic toxicity from local anesthetics should be promptly

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 and

includes direct injection into tissues, topical application, and intravenous administration to

produce clinical effects at varied locations including the central neuraxis, peripheral nerves,

mucosa, skin, heart, and airway. Detailed knowledge of pertinent anatomy and pharmacology will

aid in optimal therapeutic use of local anesthetics. Care should be taken to avoid potential central

nervous system (CNS) and cardiovascular toxicity from local anesthetics.

MECHANISMS OF ACTION OF LOCAL ANESTHETICS

Anatomy of Nerves Local anesthetics are often used to block nerves either peripherally or centrally. Peripheral nerves

are 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 of

connective tissue. Finally, the entire

peripheral 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 to

the penetration of local anesthetics.1 In addition to the enveloping connective tissue, all

mammalian nerves with a diameter greater than 1 µm are myelinated. Myelinated nerve fibers are

segmentally enclosed by Schwann cells forming a bilayer lipid membrane that is wrapped several

hundred times around each axon.2 Thus, myelin accounts for over half the thickness of nerve

fibers >1 µm (Fig. 17-2). Separating the myelinated regions are the nodes of Ranvier where

structural elements for neuronal excitation are concentrated (Fig. 17-3).3 The nodes are covered

by interdigitations from nonmyelinating Schwann cells4 and by negatively charged glycoproteins.

Although axonal membranes are not freely in contact with their environment at the nodes, these

areas do allow passage of drugs and ions.5 Furthermore, the negatively charged proteins may bind

basic local anesthetics and thus act as a depot. Unmyelinated nerve fibers (diameter <1 µm) are

encased 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 of

Ranvier). The existence of multiple protective layers around both myelinated and unmyelinated

nerve fibers presents a substantial barrier to the entry of clinically used local anesthetics. For

example, animal models suggest that only 1.6% of an injected dose of local anesthetic penetrates

into the nerve following performance of peripheral nerve blocks.6

treated. Patients with cardiovascular collapse from bupivacaine, ropivacaine,

and levo-bupivacaine may be especially difficult to resuscitate.

P.454

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 a

discrete cell layer, whereas the endoneurium is a matrix of connective tissue. Both afferent

and efferent axons are shown. Sympathetic axons (not shown) are also present in mixed

peripheral nerves. (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.)

FIGURE 17-2. Schwann cells form myelin around one myelinated axon or encompass several

Nerve fibers are commonly classified by size, conduction velocity, and function (Table 17-1). In

general, increasing myelination and nerve diameter lead to increased conduction velocity. The

presence of myelin accelerates conduction velocity because of increased electrical insulation of

nerve fibers and saltatory conduction. Increased nerve diameter accelerates conduction velocity

both by increased myelination and by improved electrical cable conduction properties of the nerve.

Myelinated and unmyelinated nerves carry out both afferent and efferent functions.

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.)

TABLE 17-1 Classification of Nerve Fibers

▪CLASSIFICATION ▪DIAMETER

(µ)

▪MYELIN ▪CONDUCTION

(m/sec)

▪LOCATION ▪FUNCTION

A-alpha

A-beta

6–22 + 30–120 Afferents/efferents

for muscles and

joints

Motor and

propriocepti

A-gamma 3–6 + 15–35 Efferent to muscle

spindle

Muscle tone

A-delta 1–4 + 5–25 Afferent sensory Pain

Electrophysiology of Neural Conduction Ionic disequilibria across semipermeable membranes form the basis for neuronal resting potentials

and for the potential energy needed to initiate and maintain electrical impulses. The resting

potential of neural membranes averages -60 to -70 mV, with the cell interior being negative to the

cell exterior. This resting potential is predominantly maintained by a potassium gradient with a 10

times greater concentration of potassium within the cell. This gradient is maintained by an active

protein 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 the

only factor in resting potential, as a resting potential of approximately -90 mV is predicted by the

Nernst equation if only potassium is considered. In addition to

potassium 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 sodium

channels.7 These channels are protein structures spanning the bilayer lipid membrane composed of

structural elements, an aqueous pore, and voltage-sensing elements that control passage of ions

through the pore (Fig. 17-4).8 Sodium channels exist in several conformations depending on

membrane potential and time. At resting membrane potential, sodium channels predominantly

exist in a resting (closed) conformation.7,9 During membrane depolarization, channels open within

a few hundred microseconds and allow passage of 107 ions/sec-1. Sodium channels are relatively

selective, 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 will

spontaneously close into an inactivated state in a time-dependent fashion to allow repolarization

and then revert to a resting conformation.10 Thus, a three-state kinetic scheme (Fig. 17-5)

conceptualizes the changes in sodium channel conformation that account for changes in sodium

conductance during depolarization and repolarization.

nerve Touch

Temperature

B <3 + 3–15 Preganglionic

sympathetic

Autonomic

function

C 0.3–1.3 - 0.7–1.3 Postganglionic

sympathetic

Afferent sensory

nerve

Autonomic

function

Pain

Temperature

P.455

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 neutral

base (N) and protonated, charged form (NH+) in equilibrium. The neutral base (N) is more

lipid soluble, preferentially partitions into the lipophilic membrane interior, and easily passes

through the membrane. The charged form (NH+) is more water soluble and binds to the

sodium channel at the negatively charged membrane surface. Both forms can affect function

of the sodium channel. The N form can cause membrane expansion and closure of the sodium

channel. The NH+ form will directly inhibit the sodium channel by binding with a local

anesthetic receptor. The natural “local anesthetic” tetrodotoxin (TTX) binds at the external

surface 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 and

Management of Pain, p 35. Philadelphia, Lippincott–Raven, 1998.)

FIGURE 17-5. Illustration of dominant form of sodium channel during generation of an

action potential. R = resting form, O = open form, I = inactive form. Figure A demonstrates

An action potential will be generated by depolarization when the impulse-firing threshold of the

axon is reached. That is the point at which no further depolarization is required for local processes

to generate a complete action potential. This threshold is not an absolute voltage, but rather

depends on the dynamics of the sodium and potassium channels. For example, a brief maximally

depolarizing stimulus will not generate an

action potential because there is insufficient time for sodium channels to open. Nor will a

depolarizing stimulus that increases too slowly create an action potential. As the stimulus slowly

increases, initially activated sodium channels will spontaneously inactivate, so there will never be

enough open channels at one time to generate an action potential. Furthermore, voltage-sensitive

potassium channels would begin to increase potassium conductance that would further inhibit

generation of an action potential. Thus, successful generation of an action potential requires a

depolarizing stimulus of correct intensity and duration.

Once an action potential is generated, propagation of the potential along the nerve fiber is

required for information to be transmitted. Both impulse generation and propagation are “all or

nothing” phenomena. In the case of impulse propagation, either the locally generated action

potential reaches the threshold potential of adjacent segments and causes propagation along the

nerve, or the local depolarization ends. Nonmyelinated fibers require achievement of threshold

potential at the immediately adjacent membrane, whereas myelinated fibers require generation of

threshold potential at a subsequent node of Ranvier.

Repolarization after action potential generation and propagation rapidly follows owing to

increasing equilibria of internal and external sodium ions, a time-controlled decrease in sodium

conductance, and a voltage-controlled increase in potassium conductance.11 In addition, active

internal concentration of potassium occurs via the membrane-bound enzyme Na+/K+/ATPase that

extrudes three sodium ions for every two potassium ions absorbed. Although many mammalian

nonmyelinated nerve fibers develop a period of hyperpolarization after the action potential,

myelinated nerve fibers return directly to resting membrane potential.11

Molecular 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 neutral

and charged local anesthetics suggest that local anesthetics may act on the sodium channel either

by modification of the lipid membrane surrounding it or by direct interaction with its protein

structure.

Previous studies have demonstrated that anesthetics can reduce sodium conductance through

sodium channels by interacting with the surrounding lipid membrane.12 Alterations in neuronal

membranes by local anesthetics can occur by altering the fluidity of the membrane that causes

membrane expansion and subsequent closure of the sodium channel. Furthermore, alterations in

membrane 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 local

anesthetics, but do not explain the different activity of clinically used, tertiary amine local

anesthetics (e.g., lidocaine).

Instead, the mechanisms of action of these local anesthetics are best explained by direct

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 (INa+) and outward potassium current (IK+) together yield the net ionic current across the

membrane (Ii). (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.)

P.456

interaction with the sodium channel (modulated receptor theory).13 The commonly used tertiary

amine local anesthetics exist in free equilibrium as both a lipid-soluble neutral form and a hydrophilic, charged form depending on pKa and environmental pH. Although the neutral form may

exert anesthetic actions as described earlier, the cationic species is clearly the more potent form

(see Fig. 17-4).13 These tertiary amine local anesthetics also demonstrate greater sodium channel

blockade when the neural membrane is repetitively depolarized (1 to 100 Hz),14,15 whereas neutral

local anesthetics exhibit little change in activity with increased frequency of stimulation (use-

dependent block). Increasing frequency of stimulation increases the probability that sodium

channels 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 (repetitive

stimulation) and tonic (unstimulated) block are well explained by the existence of a single local

anesthetic receptor within the sodium channel that possesses different affinities during different

channel conformations (resting, open, inactive). Specifically, higher affinities occur during the

open and inactive phases. In support of this theory, when the affinity of inactive channels for local

anesthetics is decreased through genetic manipulation, use-dependent block is reduced.16,17

Molecular manipulation of the sodium channel has revealed specifics of the local anesthetic

receptor.8 Binding sites to local anesthetics are located on the intracellular side of the sodium

channel, may have different binding areas during the open and inactivated conformations of the

sodium channel, and possess stereoselectivity with preference for the R isomers.9,17,18

Mechanism 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 potential

formation and propagation. Although it remains unknown in humans by what percent the neural

action potential must be decreased before functional block occurs, animal studies suggest that the

action potential must be decreased by at least 50% before measurable loss of function is

observed.6 Previous studies have examined the differences in susceptibility of nerve fiber to local

anesthetic 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 local

anesthetic to a peripheral nerve.19 Classically, the sensation of temperature is lost, followed by

sharp pain, then light touch. Thus, an initial assumption was that small, unmyelinated (C) fibers

conducting temperature sensation were inherently more susceptible to local anesthetic blockade

than large, myelinated (A) fibers conducting touch. However, experimental studies reveal a more

complex picture. In vivo studies of sciatic nerve block in rats with lidocaine indicate that larger A

fibers are more susceptible to tonic and phasic block than smaller C fibers.15 Differential block of

large and small nerve fibers is also affected by choice of local anesthetic. Those with an amide group, high pKa, and lower lipid solubility are more potent blockers of C fibers. Thus, experimental

studies 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.14,20

During clinical applications, the exposure length of the nerve fiber may explain differential

block,21,22 as small nerve fibers require a shorter length of fiber exposed to local anesthetic for

block to occur than do large fibers. It is theorized that this observation is because of decremental

conduction block of a “critical length” of nerve.22 Decremental conduction describes the decreased

ability 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,23 larger

nerve fibers will demonstrate increasing resistance to local anesthetic block. Evidence for this

mechanism is conflicting. Sciatic nerve blocks in rats demonstrate greater length of spread along

the nerve and greater intraneural content of radiolabeled lidocaine with injections of high volume

and low concentrations of lidocaine. However, the use of small volumes and greater concentrations

of lidocaine produced more effective sensory and motor block despite lesser spread and

intraneural penetration of lidocaine.24 Further clinical studies on decremental conduction and role

of “critical

length” will be needed, especially as nerve blocks in humans typically involve much greater

P.457

lengths of affected nerve than animal models. For example, sciatic nerve blocks in humans

probably result in 5 to 10 cm of affected nerve length.6

A final mechanism whereby local anesthetics may block peripheral nerve function is via

degradation of transmitted electrical patterns. It is theorized that a large part of the sensory

information transmitted via peripheral nerves is carried via coding of electrical signals in after-

potentials and after-oscillations.25 Evidence for this theory is found in studies demonstrating loss

of sensory nerve function after incomplete local anesthetic blockade. For example, sensation of

temperature of the skin can be lost despite unimpeded conduction of small fibers.26 Furthermore,

a surgical depth of epidural and peripheral nerve block anesthesia can be obtained with only minor

changes in somatosensory evoked potentials from the anesthetized area.27,28 Previous studies

have demonstrated that application of sub-blocking concentrations of local anesthetic will

suppress normally occurring after-potentials and after-oscillations without significantly affecting

action potential conduction.29 Thus, disruption of coding of electrical information by local

anesthetics may be another mechanism for block of peripheral nerves.

Mechanism of Blockade of Central Neuraxis Central neuraxial block via spinal or epidural administration of local anesthetics involves the same

mechanisms at the level of spinal nerve roots, either intra- or extradural, as discussed earlier. In

addition, central neuraxial administration of local anesthetics allows multiple potential actions of

local 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 dorsal

horn neurons and inhibit generation and propagation of nociceptive electrical activity.30 Other

spinal cord neuronal ion channels, such as calcium channels, are also important for afferent and

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.)

efferent electrical activity. Administration of calcium channel blockers to spinal cord N (neuronal)

calcium channels results in hyperpolarization of cell membranes, resistance to electrical

stimulation from nociceptive afferents, and intense analgesia.31 Local anesthetics appear to have

similar actions on calcium channels, which may contribute to analgesic actions of central

neuraxially administered local anesthetics.32

In addition to ion channels, multiple neurotransmitters are involved in nociceptive transmission in

the dorsal horn of the spinal cord.33 For example, tachykinins (substance P) are important

neurotransmitters modulating nociception from C fibers.34 Administration of local anesthetics in

concentrations that occur after spinal and epidural anesthesia inhibits postsynaptic depolarizations

driven by substance P and may decrease nociception via this inhibitory mechanism.35 Other

neurotransmitters that are important for nociceptive processing in the spinal cord, such as

acetylcholine, γ-aminobutyric acid (GABA), and N-methyl-D-aspartate (NMDA), can all be affected

by local anesthetics either pre- or postsynaptically.8,35 These studies suggest that antinociceptive

effects of central neuraxial local anesthetic block may be mediated via complex interactions at

neural synapses in addition to ion channel blockade.

PHARMACOLOGY AND PHARMACODYNAMICS

Chemical Properties and Relationship to Activity and Potency The clinically used local anesthetics consist of a lipid-soluble, substituted benzene ring linked to an amine group (tertiary or quaternary depending on pKa and pH) via an alkyl chain containing

either an amide or ester linkage (Fig. 17-7). The type of linkage separates the local anesthetics

into either aminoamides, metabolized in the liver, or aminoesters, metabolized by plasma

cholinesterases. Several chemical properties of local anesthetics will affect their efficacy and

potency.

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 and pKa, or dissociation constant, of a local anesthetic determines how much of the compound exists in

each form (Table 17-2). As previously discussed, the primary site of action of local anesthetics

appears to exist on the intracellular side of the sodium channel, and the charged form appears to

be the predominantly active form.13 Penetration of the lipid-soluble form through the lipid neural

membrane appears to be the primary form of access of local anesthetic molecules, although some

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.)

access by the charged form can be gained via the aqueous sodium channel pore (see Fig. 17-4).39 Thus, decreasing pKa for a given environmental pH will increase the percentage of lipid-soluble

forms in existence, hastening penetration of neural membranes and onset of action.

Lipid solubility is another important determinant of activity. Although increasing lipid

solubility may hasten penetration of neural membranes, increasing solubility may also result

in increased sequestration of local anesthetic in myelin and other lipid-soluble compartments.

Thus, increasing lipid solubility usually slows the rate of onset of action.40 Similarly, duration of

TABLE 17-2 Physicochemical Properties of Clinically Used Local Anesthetics

▪LOCAL

ANESTHETIC

▪pKa ▪% IONIZED

(at pH 7.4)

▪PARTITION

COEFFICIENT (LIPID

SOLUBILITY)

▪% PROTEIN

BINDING

▪AMIDES

Bupivacainea 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.

aLevo-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

action is increased as absorption of local anesthetic molecules into myelin and surrounding neural

compartments creates a depot for slow release of local anesthetics.40 Finally, increased lipid

solubility increases potency of the local anesthetic.12,13 This observation may be explained by a

correlation between lipid solubility and both sodium channel receptor affinity and ability to alter

sodium channel conformation by direct effects on lipid cell membranes.

Degree of protein binding also affects activity of local anesthetics, as only the unbound form is

free for pharmacologic activity. In general, the more lipid soluble and longer acting agents have

increased protein binding.41 Although the sodium channel is a protein structure, it does not appear

that degree of local anesthetic protein binding correlates with binding to the local anesthetic

receptor. Studies suggest that dissociation of local anesthetic molecules from the sodium channel

occurs in a matter of seconds regardless of degree of protein binding of the local anesthetic.42

Thus, prolongation in duration of action associated with an increased degree of protein binding

must 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 the

exception of lidocaine (achiral), ropivacaine (S), and levo-bupivacaine ( l = S).43,44 Stereoisomers

of local anesthetics appear to have potentially different effects on anesthetic potency,

pharmacokinetics, and systemic toxicity.19,43,44 For example, R isomers appear to have greater in

vitro potency for block of both neural and cardiac sodium channels and may thus have greater

therapeutic efficacy and potential systemic toxicity.18,43,44,45

Relative in vitro potencies of the clinically used local anesthetics have been identified and vary

depending on individual nerve fibers and frequency of stimulation, and overall increasing lipid

solubility of local anesthetic correlates with increasing anesthetic potency (see Table 17-2).46

However, clinical use of local anesthetics is complex and in vivo potencies often do not correlate

with in vitro determinants.47 Local factors affecting diffusion and spread of anesthetic will have

great impact on clinical effects and will vary with different applications (e.g., peripheral nerve

block vs. spinal injection). Furthermore, clinical use may not require absolute suppression of the

compound action potential, but rather a disruption of information coding in the pattern of

discharges. Few rigorous studies have been performed to evaluate relative clinical potencies of

local 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-

PROCAINE

▪LIDOCAINE ▪MEPIVACAINE ▪PRILOCAINE ▪ROP

Peripheral

nerve

3.6 N/A 1 2.6 0.8

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

Tachyphylaxis to Local Anesthetics Tachyphylaxis to local anesthetics is a clinical phenomenon whereby repeated injection of the

same dose of local anesthetic leads to decreasing efficacy. Tachyphylaxis has been described after

central neuraxial blocks, peripheral nerve blocks, and for different local anesthetics.48,49 An

interesting 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 not

develop. Conversely, longer periods of patient discomfort before redosing hasten development of

tachyphylaxis.48 Both pharmacokinetic and dynamic mechanisms may be involved. A study

examining repeated sciatic nerve blocks and infiltration analgesia in rats noted tachyphylaxis

accompanied by increased clearance of radiolabeled lidocaine out of nerves and skin.50 Not all

studies support a pharmacokinetic mechanism for tachyphylaxis. For example, with the

development of clinical tachyphylaxis, there is no difference in local anesthetic spread within or

clearance from the epidural space.51

The observation that pain is important for the development of tachyphylaxis has led to speculation

that there is a pharmacodynamic mechanism for tachyphylaxis via spinal cord sensitization.52 Rats

receiving repeated sciatic nerve blocks failed to develop tachyphylaxis in the absence of noxious

stimulation. Exposure of the rats to increasingly noxious degrees of thermal stimulation

increasingly hastened development of tachyphylaxis, whereas pretreatment with an NMDA

antagonist (MK-801) that prevents spinal cord sensitization also prevented development of

tachyphylaxis. Second-messenger effects of nitric oxide for NMDA pathways may be especially

important, as administration of nitric oxide synthetase inhibitors prevented development of

tachyphylaxis in a

dose-dependent manner in the same model.53 The clinical relevance of these findings needs to be

explored, but the development of a mechanism for tachyphylaxis may lead to clinical means for its

prevention.

Additives to Increase Local Anesthetic Activity

Epinephrine 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, and

decreased systemic absorption of local anesthetic.54 Epinephrine's vasoconstrictive effects

augment local anesthetics by antagonizing inherent vasodilating effects of local anesthetics,

decreasing systemic absorption and intraneural clearance, and perhaps by redistributing

intraneural local anesthetic.54,55

Direct analgesic effects from epinephrine may also occur via interaction with α-2 adrenergic

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.

P.459

receptors in the brain and spinal cord,56 especially because local anesthetics increase the vascular

uptake of epinephrine.57 Clinical use of epinephrine is listed in Table 17-4. The smallest dose is

suggested, as epinephrine combined with local anesthetics may have toxic effects on tissue,58 the

cardiovascular system,59 peripheral nerves, and the spinal cord.33,54

TABLE 17-4 Effects of Addition of Epinephrine to Local Anesthetics

▪INCREASE

DURATION

▪DECREASE

BLOOD LEVELS

(%)

▪DOSE/CONCENTRATION OF

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

Alkalinization of Local Anesthetic Solution Since the late 1800s, local anesthetic solutions have been alkalinized in order to hasten onset of

neural block.60 The pH of commercial preparations of local anesthetics ranges from 3.9 to 6.47 and

is especially acidic if prepackaged with epinephrine.61 As the pKa of commonly used local anesthetics ranges from 7.6 to 8.9 (see Table 17-2), less than

3% of the commercially prepared local anesthetic exists as the lipid-soluble neutral form. As

previously discussed, the neutral form is believed to be the most important for penetration into

the neural cytoplasm, whereas the charged form primarily interacts with the local anesthetic

receptor within the sodium channel. Therefore, the rationale for alkalinization was to increase the

percentage of local anesthetic existing as the lipid-soluble neutral form. However, clinically used

local anesthetics cannot be alkalinized beyond a pH of 6.05 to 8 before precipitation occurs,61 and

such pHs will only increase the neutral form to about 10%.

Clinical studies that have shown an association between alkalinization of local anesthetics and

hastening of block onset have shown a decrease of less than 5 minutes when compared to

commercial preparations.60,62 In addition, a recent animal study suggests that alkalinization of

lidocaine decreases the duration of peripheral nerve blocks if the solution does not also contain

epinephrine.63 Overall, the value of alkalinization of local anesthetics appears debatable as a

clinically useful tool to improve anesthesia.

Opioids Addition of opioids to local anesthetics has gained popularity. Opioids have multiple central

neuraxial and peripheral mechanisms of analgesic action. Supraspinal administration of opioids

results in analgesia via opiate receptors in multiple sites,64 via activation of descending spinal

pathways65 and via activation of nonopioid analgesic pathways.66 Spinal administration of opioids

provides analgesia primarily by attenuating C fiber nociception67 and is independent of supraspinal

mechanisms.68 Coadministration of opioids with central neuraxial local anesthetics results in

synergistic analgesia.69 An exception to this analgesic synergy is 2-chloroprocaine, which appears

to decrease the effectiveness of epidural opioids when used for epidural anesthesia.70 The

mechanism for this action is unclear but does not appear to involve direct antagonism of opioid

receptors.71 Overall, clinical studies support the practice of central neuraxial coadministration of

local anesthetics and opioids in humans for prolongation and intensification of analgesia and

anesthesia.69

The discovery of peripheral opioid receptors offers yet another circumstance in which the

coadministration of local anesthetics and opioids may be useful.72 The most promising clinical

results have been from intra-articular administration of local anesthetic and opioid for

postoperative analgesia,73 whereas combining local anesthetics and opioids for nerve blocks

++, 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.

P.460

appears to be ineffective.74 There are several reasons for a predicted lack of effect of

coadministration of local anesthetic and opioid for peripheral nerve blocks. Anatomically,

peripheral opioid receptors are found primarily at the end terminals of afferent fibers.75 However,

peripheral nerves are commonly blocked by deposition of anesthetic proximal to the end terminals

of nerve fibers. In addition, common sites for peripheral nerve blocks are encased in multiple

layers of connective tissue that the anesthetics must traverse before gaining access to peripheral

opioid receptors. Finally, previous studies have demonstrated the importance of concomitant local

tissue inflammation for analgesic effectiveness of peripheral opioid receptors.72 The mechanism for

the underlying dependence on local inflammation is speculative and may involve upregulation or

activation of peripheral opioid receptors or “loosening” of intercellular junctions to allow passage

of opioids to receptors. Lack of inflammation at the site of a peripheral nerve block may also

reduce the effects of coadministration of local anesthetic and opioid. All of these factors combine

to decrease the theoretical effectiveness of combinations of local anesthetics and opioids for

peripheral nerve blocks. In summary, coadministration of opioids and local anesthetic in the

central neuraxis appears to be an effective, nontoxic33 means to improve activity of local

anesthetic, whereas there is little theoretical reason to expect the mixture to enhance peripheral

nerve block.

α-2 Adrenergic Agonists α-2 adrenergic agonists can be a useful adjuvant to local anesthetics. α-2 agonists, such as

clonidine, produce analgesia via supraspinal and spinal adrenergic receptors.76 Clonidine also has

direct inhibitory effects on peripheral nerve conduction (A and C nerve fibers).77 Thus, addition of

clonidine may have multiple routes of action depending on type of application. Preliminary

evidence suggests that coadministration of an α-2 agonist and local anesthetic results in central

neuraxial and peripheral nerve analgesic synergy,78 whereas systemic (supraspinal) effects are

additive.79 Overall, clinical trials indicate that clonidine enhances intrathecal and epidural

anesthesia, peripheral nerve blocks,80 and intravenous regional anesthesia81 without evidence for

neurotoxicity.33

PHARMACOKINETICS OF LOCAL ANESTHETICS Clearance of local anesthetic from neural tissue and from the body governs both duration of effect

and potential toxicity. Clinical effects of neural block from local anesthetics are primarily

dependent on local factors as discussed in the Pharmacology section. However, systemic toxicity is

primarily dependent on blood levels of local anesthetics. Resultant blood levels after

administration of local anesthetics for neural blockade depend on absorption, distribution, and

elimination of local anesthetics.

Systemic Absorption In general, local anesthetics with decreased systemic absorption will have a greater margin of

safety in clinical use. The rate and extent of absorption will depend on numerous factors, of which

the most important are the site of injection, the dose of local anesthetic, the physicochemical

properties of the local anesthetic, and the addition of epinephrine.

The relative amounts of fat and vasculature surrounding the site of local anesthetic injection will

interact with the physicochemical properties of the local anesthetic to affect rate of systemic

uptake. In general, areas with greater vascularity will have more rapid and complete uptake as

compared to those with more fat, regardless of type of local anesthetic. Thus, rates of absorption

from injection of local anesthetic into various sites generally decrease in the following order:

intercostal > caudal > epidural > brachial plexus > sciatic/femoral (Table 17-5).82,83

TABLE 17-5 Typical Cmax after Regional Anesthetics with Commonly Used Local

Anesthetics

▪LOCAL

ANESTHETIC

▪TECHNIQUE ▪DOSE

(mg)

▪Cmax

(mcg/mL)

▪Tmax

(min)

▪TOXIC PLASMA

CONCENTRATION

(mcg/mL)

Bupivacaine Brachial

plexus

150 1.0 20 3

Celiac plexus 100 1.50 17

Epidural 150 1.26 20

Intercostal 140 0.90 30

Lumbar

sympathetic

52.5 0.49 24

Sciatic

femoral

400 1.89 15

L-

bupivacaine

Epidural 75 0.36 50 4

Brachial

plexus

250 1.2 55

Lidocaine Brachial

plexus

400 4.00 25 5

Epidural 400 4.27 20

Intercostal 400 6.8 15

Mepivacaine Brachial

plexus

500 3.68 24 5

Epidural 500 4.95 16

Intercostal 500 8.06 9

Sciatic

femoral

500 3.59 31

Ropivacaine Brachial 190 1.3 53 4

The greater the total dose of local anesthetic injected, the greater the systemic absorption and peak blood levels (Cmax). This relationship is nearly linear (Fig. 17-8) and is relatively unaffected

by anesthetic concentration84 and speed of injection.82,83

Physicochemical properties of local anesthetics will affect systemic absorption. In general, the

more potent agents with greater lipid solubility and protein binding will result in lower systemic absorption and Cmax (Fig. 17-9).83 Increased binding to neural and nonneural tissue probably

explains this observation.

plexus

Epidural 150 1.07 40

Intercostal 140 1.10 21

Cmax, peak plasma levels; Tmax, time until Cmax.

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.

FIGURE 17-8. Increasing doses of ropivacaine used for wound infiltration result in linearly increasing maximal plasma concentrations (Cmax). (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.)

The effects of epinephrine have been previously discussed. In brief, epinephrine can counteract the inherent vasodilating characteristics of most local anesthetics. The reduction in Cmax with

epinephrine is most effective for the less lipid-soluble,

less potent, shorter acting agents (see Table 17-4), as increased tissue binding rather than local

blood flow may be a greater determinant of absorption for the long-acting agents.

Distribution After systemic absorption, local anesthetics are rapidly distributed to the body. Regional

distribution of local anesthetic will depend on organ blood flow, the partition coefficient of local

anesthetic between compartments, and plasma protein binding. The end organs of main concern

for toxicity are within the cardiovascular and the central nervous systems. Both are considered

members 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 these

organs will not initially correlate with systemic blood levels because of hysteresis.85 As regional,

rather than systemic, pharmacokinetics govern subsequent pharmacodynamic effects, systemic

blood levels may not correlate with effects of local anesthetics on end organs.86 Regional

pharmacokinetics of local anesthetics for the heart and brain have not been fully delineated; thus

the volume of distribution at steady state (VDss) is often used to describe local anesthetic

distribution (Table 17-6). However, VDss describes the extent of total body distribution and may

be inaccurate for specific organ systems.

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.)

P.461

TABLE 17-6 Pharmacokinetic Parameters of Clinically Used Local Anesthetics

▪LOCAL ANESTHETIC ▪VDss (L/kg) ▪CL (L/kg/hr) ▪T1/2 (hr)

Elimination Clearance (CL) of aminoester local anesthetics is primarily dependent on plasma clearance by

cholinesterases,87 whereas aminoamide local anesthetic clearance is dependent on clearance by

the liver.88 Thus, hepatic extraction, hepatic perfusion, hepatic metabolism, and protein binding

(Table 17-2) will primarily determine the rate of clearance of aminoamide local anesthetics. In

general, local anesthetics with higher rates of clearance will have a greater margin of safety.83

Clinical Pharmacokinetics The primary benefit of knowledge of the systemic pharmacokinetics of local anesthetics is the ability to predict Cmax after the agents are administered, thereby avoiding the administration of

toxic doses (Tables 17-5, 17-7, and 17-8). However, pharmacokinetics are difficult to predict in

any given circumstance as both physical and pathophysiologic characteristics will affect the

individual pharmacokinetics. There is some evidence for increased systemic levels of local

anesthetics in the very young and in the elderly owing to decreased clearance and increased

absorption,83 whereas correlation of resultant systemic blood levels between dose of local

anesthetic and patient weight is often inconsistent (Figure 17-10).89 Effects of gender on clinical

pharmacokinetics of local anesthetics have not been well defined,90 although pregnancy may

decrease clearance.83 Pathophysiologic states such as cardiac and hepatic disease will alter

expected pharmacokinetic parameters (Table 17-9), and lower doses of local anesthetics should be

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.462

used for these patients. As expected, renal disease has little effect on pharmacokinetic parameters

of local anesthetics (Table 17-9). Finally, the skill of the anesthesiologist should be considered, as

a large dose of local anesthetic placed in the correct location may have much less potential for

systemic toxicity than a small dose incorrectly injected intravascularly. All of these factors should

be considered when utilizing local anesthetics and minimizing systemic toxicity, the commonly

accepted 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

TOXICITY

▪CVS:CNS

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

ANESTHETIC

▪CONCENTRATION

(%)

▪CLINICAL

USE

▪ONSET ▪DURATION

(h)

▪RECOMMENDED

MAXIMUM

▪ESTERS

Benzocaine Up to 20 Topical Fast 0.5–1 200

Chloroprocaine 1 Infiltration Fast 0.5–1 800/1,000 +

epinephrine

2 Peripheral

nerve block

Fast 0.5–1 800/1,000 +

epinephrine

2–3 Epidural

anesthesia

Fast 0.5–1 800/1,000 +

epinephrine

Cocaine 4–10 Topical Fast 0.5–1 150

Procaine 10 Spinal

anesthesia

Fast 0.5–1 1,000

Tetracaine 2 Topical Fast 0.5–1 20

0.5 Spinal

anesthesia

Fast 2–6 20

Adapted with permission from Covino BG, Wildsmith JAW: Clinical pharmacology of local anesthetic

agents.

In Cousins MJ, Bridenbaugh PO (eds): Neural blockade in clinical anesthesia and management of

pain, 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 1.8

Cardiac failure 0.88 6.3 1.9

Hepatic disease 2.31 6.0 4.9

CLINICAL USE OF LOCAL ANESTHETICS Local anesthetics are used in a variety of ways in clinical anesthesia practice. Probably the most

common clinical use of local anesthetics for anesthesiologists is for regional anesthesia and

analgesia. Central neuraxial anesthesia and analgesia can be accomplished by epidural or spinal

injections of local anesthetics. Placement of epidural and spinal catheters can allow continuous

infusion of local anesthetics and other analgesics for extended durations. Intravenous regional

anesthesia and peripheral nerve blocks allow for anesthesia of the head and neck including the

airway, upper extremities, trunk, and lower extremities. Newly developed catheters for continuous

peripheral nerve blocks can also be placed to allow continuous infusions of local anesthetics and

other 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 anesthesia

for painless performance of minor anesthetic and surgical procedures such as tracheal intubation,

intravenous catheter placement, or dural puncture.91 Typical applications for each local anesthetic

are listed in Table 17-8.92

Other common clinical uses for local anesthetics include administration of lidocaine to blunt

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.)

responses to tracheal instrumentation and to suppress cardiac dysrhythmias. Intravenous or

topical administrations of lidocaine have been used with variable success to blunt hemodynamic

response to tracheal intubation and extubation.93,94 In addition to hemodynamic responses,

instrumentation of the airway can result in coughing, bronchoconstriction, and other airway

responses. Intravenous lidocaine can be effective for decreasing airway sensitivity to

instrumentation by depressing airway reflexes and decreasing calcium flux in airway smooth

muscle.95,96 Doses of intravenous lidocaine from 2 to 2.5 mg/kg are needed to consistently blunt

hemodynamic and airway responses to tracheal instrumentation.95,96,97 Intravenous lidocaine is

also effective for attenuating increases in intra-ocular pressure, intracranial pressure, and intra-

abdominal pressure during

airway instrumentation.98 Attenuation of all these responses may be beneficial in selected clinical

situations (e.g., corneal laceration or increased intracranial pressure). Intravenous lidocaine has

well-recognized cardiac antidysrhythmic effects.99

Finally, intravenous lidocaine (1 to 5 mg/kg) is an effective analgesic and has been used to treat

postoperative100 and chronic neuropathic pain.101 Peripheral and central inhibition of generation

and propagation of spontaneous electrical activity in injured C nerve fibers and Aδ nerve fibers are

thought to be primary mechanisms as opposed to typical conduction block.102,103,104 Positron

emission tomography in patients with neuropathic pain suggests that altered activity in cerebral

blood flow to the thalamus105 may also contribute to systemic analgesic effects of local

anesthetics. The ability of local anesthetics to provide systemic analgesic effects at central and

peripheral sites may in part explain the ability of a single neural block to provide long-lasting

analgesia from neuropathic pain. In addition, orally administered mexiletine (a Class I

antidysrhythmic agent similar to lidocaine) has been successfully used to treat chronic pain

conditions.101

TOXICITY OF LOCAL ANESTHETICS

Systemic Toxicity of Local Anesthetics

Central Nervous System Toxicity Local anesthetics readily cross the blood-brain barrier, and generalized CNS toxicity may occur

from systemic absorption or

direct vascular injection. Signs of generalized CNS toxicity because of local anesthetics are dose

dependent (Table 17-10). Low doses produce CNS depression, and higher doses result in CNS

excitation and seizures.106 The rate of intravenous administration of local anesthetic will also

affect signs of CNS toxicity, as higher rates of infusion of the same dose will lessen the

appearance of CNS depression while leaving excitation intact.107 This dichotomous reaction to local

anesthetics may be a result of a greater sensitivity of cortical inhibitory neurons to the impulse

blocking effects of local anesthetics.106,108,109

P.463

P.464

TABLE 17-10 Dose-Dependent Systemic Effects of Lidocaine

▪PLASMA CONCENTRATION (mcg/mL) ▪EFFECT

1–5 Analgesia

5–10 Lightheadedness

Tinnitus

Numbness of tongue

Local anesthetic potency for generalized CNS toxicity approximately parallels action potential

blocking potency (Tables 17-3 and 17-7).106 In general, decreased local anesthetic protein binding

and clearance will increase potential CNS toxicity. External factors can increase potency for CNS toxicity, such as acidosis and increased PCO2, perhaps via increased cerebral perfusion or

decreased protein binding of local anesthetic.106 There are also external factors that can decrease

local anesthetic potency for generalized CNS toxicity. For example, seizure thresholds of local

anesthetics are increased by administration of barbiturates and benzodiazepines.110

Addition of vasoconstrictors such as epinephrine may reduce or promote the potential for

generalized local anesthetic CNS toxicity. Addition of epinephrine to local anesthetics will decrease

systemic absorption and peak blood levels and increase the safety margin. On the other hand, the

convulsive threshold for intravenous administration of lidocaine in the rat is decreased by about

42% when epinephrine (1:100,000), norepinephrine, or phenylephrine is added to the plain

solution.111 The mechanisms of increased toxicity with addition of epinephrine are unclear but

appear to depend on the development of hypertension from vasoconstriction. A hyperdynamic

circulatory system may enhance the toxic effects of local anesthetics by causing increased

cerebral blood flow and delivery of lidocaine to the brain112,113 or through disruption of the blood-

brain barrier.114 In addition to enhancing distribution of local anesthetic to the brain,

hyperdynamic circulatory changes can also decrease clearance of local anesthetic from the body

because of changes in distribution of blood flow away from the liver. Changes in total body

clearance from hyperdynamic circulatory changes induced by local anesthetic seizures have been

studied in dogs.115 Seizures significantly increased heart rate, blood pressure, and cardiac output

while 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 regional

anesthesia report an incidence of seizures with epidural injection approximating 1/10,000 and an

incidence of 7/10,000 with peripheral nerve blocks.108,109 There appears to be a higher incidence

of local anesthetic toxicity during peripheral nerve blocks, perhaps because of differences in

practice or less clinical awareness. Nonetheless, epidural anesthesia (primarily obstetrical)

constituted all the cases of death or brain damage resulting from unintentional intravenous

injection of local anesthetic in an analysis of closed malpractice claims in the United States from

1980 to 1999.116

Cardiovascular Toxicity of Local Anesthetics In 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 anesthetic

potency of the agent (Tables 17-3 and 17-7). Attention has focused on the apparently exceptional

cardiotoxicity of the more potent, more lipid-soluble agents (bupivacaine, levo-bupivacaine,

10–15 Seizures

Unconsciousness

15–25 Coma

Respiratory arrest

>25 Cardiovascular depression

ropivacaine). These agents appear to have a different sequence of CV toxicity than less potent

agents, with bupivacaine being the most cardiotoxic. For example, increasingly toxic doses of

lidocaine lead to hypotension, bradycardia, and hypoxia, whereas toxic doses of bupivacaine, levo-

bupivacaine, and ropivacaine often result in sudden cardiovascular collapse as a result of

ventricular dysrhythmias that are resistant to resuscitation (Fig. 17-11).106,110,117

Use of the single–optical isomer (S/L) preparations of ropivacaine and levo-bupivacaine may

improve the safety profile for long-lasting regional anesthesia. Both ropivacaine and

levo-bupivacaine appear to be approximately equipotent to racemic bupivacaine for epidural and

plexus anesthesia (see Table 17-3).118,119 Both ropivacaine and levo-bupivacaine have

approximately 30 to 40% less systemic toxicity than bupivacaine on a mg:mg basis in animal

studies46,106 (Fig. 17-12), although human studies are less dramatic (Fig. 17-13).120,121 Reduced

potential for cardiotoxicity is likely because of reduced affinity for brain and myocardial tissue

from their single isomer preparation.18,45,106 In addition to stereoselectivity, the larger butyl side

chain in bupivacaine may also have more of a cardiodepressant effect as opposed to the propyl-

side chain of ropivacaine.122

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.)

P.465

FIGURE 17-12. Serum concentrations in sheep at each toxic manifestation for bupivacaine,

levo-bupivacaine, and ropivacaine in sheep. Both levo-bupivacaine and ropivacaine required

significantly greater serum concentrations than bupivacaine. (Data from Santos AC, DeArmas

PI: Systemic toxicity of levobupivacaine, bupivacaine, and ropivacaine during continuous

intravenous infusion to nonpregnant and pregnant ewes. Anesthesiology 95:1256, 2001.)

FIGURE 17-13. Mild prolongation in QRS interval and reduction in cardiac output are

observed after intravenous infusions of bupivacaine (103 mg), levobupivacaine (37 mg), and

ropivacaine (115 mg) in healthy volunteers. Data from: Knudsen K, Beckman Suurkula M, et

al. Central nervous and cardiovascular effects of i.v. infusions of ropivacaine, bupivacaine

and placebo in volunteers. Br Anaesth 1997:78:507. Stewart J, Kellett N, Castro D. The

central nervous system and cardiovascular effects of levobupivacaine and ropivacaine in

healthy volunteers. Anesth Analg 2003:97:412.

Cardiovascular Toxicity Mediated at the CNS. It has been demonstrated that the central and

peripheral nervous systems may be involved in the increased cardiotoxicity with bupivacaine. The

nucleus tractus solitarii in the medulla is an important region for autonomic control of the

cardiovascular system. Neural activity in the nucleus tractus solitarii of rats is markedly

diminished by intravenous doses of bupivacaine immediately prior to development of hypotension.

Furthermore, direct intracerebral injection of bupivacaine can elicit sudden dysrhythmias and

cardiovascular collapse.123

Peripheral effects of bupivacaine on the autonomic and vasomotor systems may also augment its

CV toxicity. Bupivacaine possesses a potent peripheral inhibitory effect on sympathetic reflexes123

that has been observed even at blood concentrations similar to those measured after

uncomplicated regional anesthesia.124 Finally, bupivacaine also has potent direct vasodilating

properties, which may exacerbate cardiovascular collapse.125

Cardiovascular Toxicity Mediated at the Heart. The more potent local anesthetics appear to

possess greater potential for direct cardiac electrophysiologic toxicity.45,106 Although all local

anesthetics block the cardiac conduction system via a dose-dependent block of sodium channels,

two features of bupivacaine's sodium channel blocking abilities may enhance its cardiotoxicity.

First, bupivacaine exhibits a much stronger binding affinity to resting and inactivated sodium

channels than lidocaine.126 Second, local anesthetics bind to sodium channels during systole and

dissociate during diastole (Fig. 17-14). Bupivacaine dissociates from sodium channels during

cardiac diastole much more slowly than lidocaine. Indeed, bupivacaine dissociates so slowly that

the duration of diastole at physiologic heart rates (60 to 180 bpm) does not allow enough time for

complete recovery of sodium channels and bupivacaine conduction block accumulates. In contrast,

lidocaine fully dissociates from sodium channels during diastole and little accumulation of

conduction block occurs (Fig. 17-15).126,127 Thus, enhanced electrophysiologic effects of more

potent local anesthetics on the cardiac conduction system may explain their increased potential to

produce 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

Increased potency for direct myocardial depression from the more potent local anesthetics is

another contributing factor to increased cardiotoxicity (Fig. 17-16).106,122 Again, multiple

mechanisms may account for the increased potency for myocardial depression from more potent

local anesthetics. Bupivacaine, the most completely studied potent local anesthetic, possesses a

high affinity for sodium channels in the cardiac myocyte.18,45,106 Furthermore, bupivacaine inhibits

myocyte release and utilization of calcium128 and reduces mitochondrial energy metabolism,

especially during hypoxia.129 Thus, multiple direct effects of bupivacaine on activity of the cardiac

myocyte may explain the cardiotoxicity of bupivacaine and other potent local anesthetics.

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 (Vmax). Bupivacaine progressively decreases Vmax at heart rates above

10 bpm because of accumulation of sodium channel block, whereas lidocaine does not decrease Vmax 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.466

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 by

systemic absorption of excessive doses placed in the correct area. Unintentional intravascular and

intra-arterial injections can be minimized by frequent syringe aspiration for blood, use of a small

test 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 of

local anesthetic.110 Detailed knowledge of local anesthetic pharmacokinetics will also aid in

reducing the administration of excessive doses of local anesthetics. Ideally, heart rate, blood

pressure, and the electrocardiogram should be monitored during administration of large doses

local anesthetics. Pretreatment with a benzodiazepine may also lower the probablility of seizure by

raising the seizure threshhold.

Treatment of systemic toxicity is primarily supportive. Injection of local anesthetic should be

stopped. Oxygenation and ventilation should be maintained, as systemic toxicity of local

anesthetics is enhanced by hypoxemia, hypercarbia, and acidosis.110 If needed, the patient's

trachea 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 body

metabolism and cause hypoxemia, hypercarbia, and acidosis. Pharmacologic treatment to

terminate 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 (1

mg/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

activity in the CNS, and increased cerebral metabolic demands will continue unabated.

Cardiovascular depression from less potent local anesthetics (e.g., lidocaine) is usually mild and

caused by mild myocardial depression and vasodilation. Hypotension and bradycardia can usually

be treated with ephedrine (10 to 30 mg) and atropine (0.4 mg). As previously discussed, potent

local anesthetics (e.g., bupivacaine) can produce profound CV depression and malignant

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.)

P.467

dysrhythmias that should be promptly treated. Oxygenation and ventilation must be immediately

instituted, with cardiopulmonary resuscitation if needed. Ventricular dysrhythmias may be difficult

to 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 not

recommended, as its cardiodepressant effect is exaggerated.110 A novel and promising treatment

for cardiac toxicity is the administration of intravenous lipid to theoretically remove bupivacaine

from sites of action. Administration of a 20% lipid solution at a dose of 4 mL/kg followed by a 0.5

mL/kg/min infusion for 10 minutes allowed for the resuscitation of 100% of dogs with induced

bupivacaine cardiotoxicity at a dose of 10mg/kg.130 None of the dogs given an equivalent volume

of crystalloid were rescuscitated in this study. These findings raise the question of whether

propofol in a 10% lipid solution would be a preferred treatment for cardiac toxicity. Propofol has

been reported to terminate bupivacaine-induced seizures and cardiac depression in patients.130

However, the dose of lipid in a standard induction dose of propofol (2 mg/kg) would be only 3% of

the dose used in the aforementioned animal experiment. As effects of lipid on cardiac toxicity are

dose related, further information is needed prior to reaching conclusions on clinical use of propofol

for local anesthetic–induced cardiac toxicity.

Neural Toxicity of Local Anesthetics In addition to systemic toxicity, local anesthetics can cause injury to the central and peripheral

nervous system from direct exposure. Mechanisms for local anesthetic neurotoxicity remain

speculative, but previous studies have demonstrated local anesthetic–induced injury to Schwann

cells, inhibition of fast axonal transport, disruption of the blood-nerve barrier, decreased neural

blood flow with associated ischemia, and disruption of cell membrane integrity via a detergent

property of local anesthetics.131,132 Although all clinically used local anesthetics can cause

concentration-dependent nerve fiber damage in peripheral nerves when used in high enough

concentrations, previous studies have demonstrated that local anesthetics in clinically used

concentrations are generally safe for peripheral nerves.133 The spinal cord and the nerve roots, on

the other hand, are more prone to injury.

Spinal cord toxicity of local anesthetics has been assessed by administration of local anesthetics

to 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 not

disrupt spinal cord histology or cause nerurological deficits.134 Desheathed peripheral nerve

models, designed to mimic unprotected nerve roots in the cauda equina, have been used to further

assess electrophysiologic neurotoxicity of local anesthetics.135,136,137 Lidocaine 5% and tetracaine

0.5% caused irreversible conduction block in these models, whereas lidocaine 1.5%, bupivacaine

0.75%, and tetracaine 0.06% did not. Electrophysiologic toxicity of lidocaine in isolated nerve

preparations 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 and

tetracaine may be especially neurotoxic in a concentration-dependent fashion and that

neurotoxicity could theoretically occur with clinically used solutions. Local anesthetic effects on

spinal cord blood flow, another possible etiology of neurotoxicity from direct drug exposure,

appear benign. Spinal administration of bupivacaine, lidocaine, mepivacaine, and tetracaine cause

vasodilation and increase spinal cord blood flow, whereas ropivacaine causes vasoconstriction and

reduction in spinal cord blood flow in a concentration-dependent fashion.138

Neurohistopathologic data in humans after intrathecal exposure to local anesthetics is not

available. Electrophysiologic parameters such as somatosensory evoked potentials, monosynaptic

H-reflex,139 and cutaneous current perception thresholds140 have been used to evaluate recovery

after spinal anesthesia. These measurements have shown complete return to baseline activity

after 5% lidocaine spinal anesthesia in very small study populations. Prospective surveys of over

80,000 spinal anesthetics report an incidence of 0 to 0.02% long-term neurologic injury in

patients undergoing spinal anesthesia.109 Thus, spinally administered local anesthetics have not

notably manifested clinical neurotoxicity.

Transient Neurologic Symptoms after Spinal Anesthesia Prospective, 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.139 These symptoms have been reported with other local

anesthetics as well (Table 17-11). Increased risk of TNS is associated with lidocaine, the lithotomy

position, and ambulatory anesthesia, but not with baricity of solution or dose of local

anesthetic.139 The potential neurological etiology of this syndrome coupled with known

concentration-dependent toxicity of lidocaine led to concerns over a neurotoxic etiology for TNS

from spinal lidocaine.

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 Ringer's 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.)

TABLE 17-11 Incidences of Transient Neurological Symptoms (TNS) Vary with Type of

Spinal Local Anesthetic and Surgery

▪LOCAL

ANESTHETIC

▪CONCENTRATION

(%)

▪TYPE OF

SURGERY

▪APPROXIMATE

INCIDENCE OF TNS

As previously discussed, laboratory work in both intrathecal and desheathed peripheral nerve

models has proved that

the concentration of lidocaine is a critical factor in neurotoxicity. As concentrations of lidocaine

below 40 mM (~1.0%) are not neurotoxic to desheathed peripheral nerve, such dilute

concentrations of spinal lidocaine should not cause TNS if the syndrome is a result of subclinical

concentration-dependent neurotoxicity. The dilution of lidocaine to as low as 0.5%, however, does

not decrease the incidence of TNS.141 The high incidence of TNS observed with lidocaine

concentrations <1% despite further dilution in cerebrospinal fluid lessens the plausibility of a

concentration-dependent neurotoxic etiology. Furthermore, a volunteer study comparing

individuals with and without TNS symptoms after lidocaine spinal anesthesia showed no difference

detected by electromyography, nerve conduction studies, or somatosensory evoked potentials.

(%)

Lidocaine 2–5 Lithotomy

position

30–36

2–5 Knee

arthroscopy

18–22

0.5 Knee

arthroscopy

17

2–5 Mixed supine

position

4–8

Mepivacaine 1.5–4 Mixed 23

Procaine 10 Knee

arthroscopy

6

Bupivacaine 0.5–0.75 Mixed 1

Levo-

bupivacaine

0.5 Mixed 1

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.

P.468

Overall, there is little evidence to support a neurotoxic etiology for TNS.139 Other potential

etiologies for TNS include patient positioning, sciatic nerve stretch, muscle spasm, and myofascial

strain.139

Interest in finding a short-acting spinal anesthetic with a lesser incidence of TNS has served as an

impetus for investigations into the use of 2-chloroprocaine as a spinal anesthetic. Preliminary

studies show that preservative-free 2-chloroprocaine provides an anesthetic profile similar to

lidocaine without report of TNS, which would make 2-chloroprocaine potentially useful for

outpatient procedures (Table 17-12). Enthusiasm for spinal 2-chloroprocaine should be tempered

by 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 spinal

cord to the same degree as 2.5% lidocaine. This finding calls into question the long held belief

that the antioxidant sodium bisulfite is to blame for 2-chloroprocaine's clinical neurotoxicity.142

The clinical applicability of this finding is uncertain, as the dose of chloroprocaine is far greater

than the dose used for spinals in humans (0.6 mg/kg).

Myotoxicity of Local Anesthetics Toxicity to skeletal muscle is an uncommon side effect of local anesthetic injection. Experimental

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

(mins)

53±30 75±14 92±13 84±35

Thigh tourniquet

tolerance (mins)

37±11 42±11 62±10 38±24

Complete regression

(mins)

98±20 116±15 132±23 126±16

Time to ambulation

(mins)

100±20 119±15 133±20 134±14

Time to bladder void

(mins)

100±21 132±19 141±21 134±14

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.

data suggests, however, that local anesthetics have the potential for myotoxicity in clinically

applicable concentrations (Fig. 17-18). Histopathologic evidence shows that the injection of these

agents causes diffuse myonecrosis, which is both reversible and clinically imperceptible. The

reversible nature of this injury is possibly because of the relative resilience of myoblasts, which

regenerate damaged tissue. Theoretical mechanisms of injury are numerous but dysregulation of

intracellular calcium concentrations is the most likely culprit. One study shows that ropivacaine is

less myotoxic than bupivacaine primarily because of the latter causing

apoptosis (programmed cell death).143 Further investigation is needed to determine the clinical

relevance of local or systemic myotoxicity following single injection or continuous infusion of local

anesthetics.

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.144,145 Type I reactions are worrisome, as anaphylaxis may occur,

and are more common with ester than amide local anesthetics. True Type I allergy to aminoamide

agents is extremely rare.145 Increased allergenic potential with esters may be a result of

hydrolytic metabolism to para-aminobenzoic acid, which is a documented allergen. Added

preservatives such as methylparaben and metabisulfite can also provoke an allergic response. Skin

testing with intradermal injections of preservative-free local anesthetics has been advocated as a

means 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.145

References

P.469

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.)

1. Ritchie JM, Ritchie B, Greengard P: The effect of the nerve sheath on the action of local

anesthetics. J Pharmacol Exp Ther 150:160, 1965

2. Coggeshall RE: A fine structured analysis of the myelin sheath in rat spinal roots. Anat Rec

194:201, 1979

3. Waxman SG, Ritchie JM: Molecular dissection of the myelinated axon. Ann Neurol 33:121,

1993

4. Landon N, Williams PL: Ultrastructure of the node of Ranvier. Nature 199:575, 1963

5. London DN, Langely OK: The local chemical environment of nodes of Ranvier: A study of

cation binding. J Anat 108:419, 1971

6. Popitz-Berger FA, Leeson S, Strichartz GR, et al: Relation between functional

deficit and intraneural local anesthetic during peripheral nerve block. Anesthesiology

83:583, 1995

7. Wann KT: Neuronal sodium and potassium channels: Structure and function. Br J Anaesth

71:2, 1993

8. Ogata N, Ohishi Y: Molecular diversity of structure and function of the voltage-gated Na+

channels. Jpn J Pharmacol 88:365, 2002

9. French RJ, Zamponi GW, Sierralta IE: Molecular and kinetic determinants of local

anaesthetic action on sodium channels. Toxicol Lett 100:247, 1998

10. Caterall WA: The molecular basis of neuronal excitability. Science 223:653, 1984

11. Chiu SY, Ritchie JM, Rogart RB: A quantitative description of membrane current in rabbit

myelinated nerve. J Physiol (Lond) 292:149, 1979

12. Yun I, Cho ES, Jang HO, et al: Amphiphilic effects of local anesthetics on rotational

mobility in neuronal and model membranes. Biochim Biophys Acta 1564:123, 2002

13. Butterworth JF, Strichartz GR: Molecular mechanisms of local anesthesia: A

review. Anesthesiology 72:711, 1990

14. Huang JH, Thalhammer JG, Raymond SA, et al: Susceptibility to lidocaine of impulses in

different somatosensory afferent fibers of rat sciatic nerve. J Pharmacol Exp Ther 282:802,

1997

15. Gokin AP, Philip B, Strichartz GR: Preferential block of small myelinated sensory and

motor fibers by lidocaine: In vivo electrophysiology in the rat sciatic nerve. Anesthesiology

95:1441, 2001

16. Yarov-Yarovoy V, McPhee JC, Idsvoog D, et al: Role of amino acid residues in

transmembrane segments IS6 and IIS6 of the Na+ channel alpha subunit in voltage-

dependent gating and drug block. J Biol Chem 277:35393, 2002

17. Li HL, Galue A, Meadows L, et al: A molecular basis for the different local anesthetic

affinities of resting versus open and inactivated states of the sodium channel. Mol Pharmacol

55:134, 1999

18. Nau C, Strichartz GR: Drug chirality in anesthesia. Anesthesiology 97:497, 2002

19. Butterworth J, Ririe DG, Thompson RB, et al: Differential onset of median nerve block:

Randomized, double-blind comparison of mepivacaine and bupivacaine in healthy volunteers.

Br J Anaesth 81:515, 1998

20. Jaffe RA, Rowe MA: Differential nerve block: Direct measurements on individual

myelinated and unmyelinated dorsal root axons. Anesthesiology 84:1455, 1996

21. Raymond SA, Steffensen SC, Gugino LD, et al: The role of length of nerve exposed to local

anesthetics in impulse blocking action. Anesth Analg 68:563, 1989

22. Fink BR: Mechanisms of differential axial blockade in epidural and spinal

anesthesia. Anesthesiology 70:851, 1989

23. Ritchie JM: On the relation between fiber diameter and conduction velocity in myelinated

nerve fibers. Proc R Soc Lond 29:B217, 1982

24. Nakamura T, Popitz-Bergez F, Birknes J, et al: The critical role of concentration for

lidocaine block of peripheral nerve in vivo: studies of function and drug uptake in the rat.

Anesthesiology 99:1189, 2003

25. Waikar SS, Thalhammer JG, Raymond SA, et al: Mechanoreceptive afferents exhibit

functionally-specific activity dependent changes in conduction velocity. Brain Res 721:91,

1996

26. Mackenzie RA, Burke D, Skuse NF: Fibre function and perception during cutaneous nerve

block. J Neurol Neurosurg Psychiatry 38:865, 1975

27. Narita Y, Nagai M, Kuzuhara S: Trigeminal somatosensory evoked potentials before,

during and after an inferior alveolar nerve block in normal subjects. Psych Clin Neurosci

51:241, 1997

28. Zaric D, Hallgren S, Leissner L, et al: Evaluation of epidural sensory block by thermal

stimulation, laser stimulation, and recording of somatosensory evoked potentials. Reg Anesth

21:124, 1996

29. Raymond SA: Subblocking concentrations of local anesthetics: Effects on impulse

generation and conduction in single myelinated sciatic nerve axons in frog. Anesth Analg

75:906, 1992

30. Olschewski A, Wolff M, Brau ME, et al: Enhancement of delayed-rectifier potassium

conductance by low concentrations of local anaesthetics in spinal sensory neurones. Br J

Pharmacol 136:540, 2002

31. Bowersox SS, Luther R: Pharmacotherapeutic potential of omega-conotoxin MVIIA (SNX-

111), an N-type neuronal calcium channel blocker found in the venom of Conus magus.

Toxicon 36:1651, 1998

32. Xiong Z, Bukusoglu C, Strichartz GR: Local anesthetics inhibit the G protein-mediated

modulation of K+ and Ca++ currents in anterior pituitary cells. Mol Pharmacol 55:150, 1999

33. Hodgson PS, Neal JM, Pollock JE, et al: The neurotoxicity of drugs given

intrathecally (spinal). Anesth Analg 88:797, 1999

34. Too HP, Maggio JE: Immunocytochemical localization of neuromedin K (neurokinin B) in

rat spinal ganglia and cord. Peptides 12:431, 1991

35. Nagy I, Woolf CJ: Lignocaine selectively reduces C fibre-evoked neuronal activity in rat

spinal cord in vitro by decreasing N-methyl-D-aspartate and neurokinin receptor-mediated

post-synaptic depolarizations; implications for the development of novel centrally acting

analgesics. Pain 64:59, 1996

36. Nordmark J, Rydqvist B: Local anaesthetics potentiate GABA-mediated Cl- currents by

inhibiting GABA uptake. Neuroreport 8:465, 1997

37. Pascual JM, Karlin A: Delimiting the binding site for quaternary ammonium lidocaine

derivatives in the acetylcholine receptor channel. J Gen Physiol 112:611, 1998

38. Sugimoto M, Uchida I, Mashimo T: Local anaesthetics have different mechanisms and sites

of action at the recombinant N-methyl-D-aspartate (NMDA) receptors. Br J Pharmacol

138:876, 2003

39. Frazier DY, Narahashi T, Yamada M: The site of action and active form of local anesthetic.

II. Experiments with quaternary compounds. J Pharmacol Exp Ther 171:45, 1970

40. Gissen AJ, Covino BG, Gregus J: Differential sensitivity of fast and slow fibers in

mammalian nerve. II. Margin of safety for nerve transmission. Anesth Analg 61:561, 1982

41. Taheri S, Cogswell LP 3rd, Gent A, et al: Hydrophobic and ionic factors in the binding of

local anesthetics to the major variant of human alpha1-acid glycoprotein. J Pharmacol Exp

Ther 304:71, 2003

42. Ulbricht W: Kinetics of drug action and equilibrium results at the node of Ranvier. Physiol

Rev 61:785, 1981

P.470

43. Foster RH, Markham A: Levobupivacaine: A review of its pharmacology and use as a local

anaesthetic. Drugs 59:551, 2000

44. Wang RD, Dangler LA, Greengrass RA: Update on ropivacaine. Expert Opin Pharmacother

2:2051, 2001

45. Heavner JE: Cardiac toxicity of local anesthetics in the intact isolated heart model: A

review. Reg Anesth Pain Med 27:545, 2002

46. Strichartz GR, Sanchez V, Arthur GR: Fundamental properties of local anesthetics. II. Measured octanol:buffer partition coefficients and pKa values of clinically used drugs. Anesth

Analg 71:158, 1990

47. Pateromichelakis S, Prokopiou AA: Local anaesthesia efficacy: Discrepancies between in

vitro and in vivo studies. Acta Anaesthesiol Scand 32:672, 1988

48. Bromage PR, Pettigrew RT, Crowell DE: Tachyphylaxis in epidural analgesia: I.

Augmentation and decay of local anesthetic. J Clin Pharmacol 9:30, 1969

49. Baker CE, Berry RL, Elston RC: Effects of pH of bupivacaine on duration of repeated sciatic

nerve blocks in the albino rat: Local anesthetics for neuralgia study group. Anesth Analg

72:773, 1991

50. Choi RH, Birknes JK, Popitz-Bergez FA, et al: Pharmacokinetic nature of tachyphylaxis to

lidocaine: Peripheral nerve blocks and infiltration anesthesia in rats. Life Sci 61:PL177, 1997

51. Mogensen T, Simonsen L, Scott NB: Tachyphylaxis associated with repeated epidural

injections of lidocaine is not related to changes in distribution or the rate of elimination of the

epidural space. Anesth Analg 69:71, 1989

52. Lee K-C, Wilder RT, Smith RL et al: Thermal hyperalgesia accelerates and MK-801

prevents the development of tachyphylaxis to rat sciatic nerve blockade.

Anesthesiology 81:1284, 1994

53. Wilder RT, Sholas MG, Berde CB: NG-nitro-L-arginine methyl ester (L-NAME) prevents

tachyphylaxis to local anesthetics in a dose-dependent manner. Anesth Analg 83:1251, 1996

54. Neal JM: Effects of epinephrine in local anesthetics on the central and peripheral nervous

systems: Neurotoxicity and neural blood flow. Reg Anesth Pain Med 28:124, 2003

55. Sinnott CJ, Cogswell III LP, Johnson A et al: On the mechanism by which epinephrine

potentiates lidocaine's peripheral nerve block. Anesthesiology 98:181, 2003

56. Curatolo M, Petersen-Felix S, Arendt-Nielsen L et al: Epidural epinephrine and clonidine:

Segmental analgesia and effects on different pain modalities. Anesthesiology 87:785, 1997

57. Ueda W, Hirakawa M, Mori K: Acceleration of epinephrine absorption by lidocaine.

Anesthesiology 63:717, 1985

58. Magee C, Rodeheaver GT, Edgerton MT, et al: Studies of the mechanisms by which

epinephrine damages tissue defenses. J Surg Res 23:126, 1977

59. Hall JA, Ferro A: Myocardial ischaemia and ventricular arrhythmias precipitated by

physiological concentrations of adrenaline in patients with coronary artery disease. Br Heart J

67:419, 1992

60. Lambert DH: Clinical value of adding sodium bicarbonate to local anesthetics. Reg Anesth

Pain Med 27:328, 2002

61. Ikuta PT, Raza SM, Durrani Z: pH adjustment schedule for the amide local anesthetics.

Reg Anesth 14:229, 1989

62. Neal JM, Hebl JR, Gerancher JC, et al: Brachial plexus anesthesia: essentials of our

current understanding. Reg Anesth Pain Med 27:402, 2002

63. Sinnott CJ, Garfield JM, Thalhammer JG: Addition of sodium bicarbonate to lidocaine

decreases the duration of peripheral nerve block in the rat. Anesthesiology 93:1045, 2000

64. Fields HL: Pain modulation: Expectation, opioid analgesia and virtual pain. Prog Brain Res

122:245, 2000

65. Matos FF, Rollema H, Brown JL, et al: Do opioids evoke the release of serotonin in the

spinal cord? An in vivo microdialysis study of the regulation of extracellular serotonin in the

rat. Pain 48:439, 1992

66. Barke KE, Hough LB: Simultaneous measurement of opiate-induced histamine release in

the periaqueductal gray and opiate antinociception: An in vivo microdialysis study. J

Pharmacol Exp Ther 266:934, 1993

67. Wang C, Chakrabarti MK, Galletly DC, et al: Relative effects of intrathecal administration

of fentanyl and midazolam on A delta and C fibre reflexes. Neuropharmacology 31:439, 1992

68. Niv D, Nemirovsky A, Rudick V: Antinociception induced by simultaneous intrathecal and

intraperitoneal administration of low doses of morphine. Anesth Analg 80:886, 1995

69. Walker SM, Goudas LC, Cousins MJ, et al: Combination spinal analgesic

chemotherapy: a systematic review. Anesth Analg 95:674, 2002

70. Karambelkar DJ, Ramanathan S: 2-Chloroprocaine antagonism of epidural morphine

analgesia. Acta Anaesth Scand 41:774, 1997

71. Coda B, Bausch S, Haas M, et al: The hypothesis that antagonism of fentanyl analgesia by

2-chloroprocaine is mediated by direct action on opioid receptors. Reg Anesth 22:43, 1997

72. Janson W, Stein C: Peripheral opioid analgesia. Curr Pharm Biotechnol 4:270, 2003

73. Kalso E, Smith L, McQuay HJ, et al: No pain, no gain: Clinical excellence and scientific

rigour—lessons learned from IA morphine. Pain 98:269, 2002

74. Picard PR, Tramer MR, McQuay HJ, et al: Analgesic efficacy of peripheral opioids (all

except intra-articular): A qualitative systematic review of randomised controlled trials. Pain

72:309, 1997

75. Fields HL, Emson PC, Leigh BK: Multiple opiate receptor sites on primary afferent fibres.

Nature 284:351, 1980

76. Eisenach JC, De Kock M, Klimscha W: Alpha(2)-adrenergic agonists for regional

anesthesia: A clinical review of clonidine (1984–1995). Anesthesiology 85:655, 1996

77. Butterworth JF, Strichartz GR: The α2-adrenergic agonists clonidine and guanfacine

produce tonic and phasic block of conduction in rat sciatic nerve fibers. Anesth Analg 76:295,

1993

78. Gaumann DM, Brunet PC, Jirounek P: Clonidine enhances the effects of lidocaine on C

fiber action potential. Anesth Analg 74:719, 1992

79. Pertovaara A, Hamalainen MM: Spinal potentiation and supraspinal additivity in the antinociceptive interaction between systemically administered α2-adrenoreceptor agonist and

cocaine in the rat. Anesth Analg 79:261, 1994

80. Bernard JM, Macaire P: Dose–range effects of clonidine added to lidocaine for brachial

plexus block. Anesthesiology 87:277, 1997

81. Reuben SS, Steinberg RB, Klatt JL, et al: Intravenous regional anesthesia using lidocaine

and clonidine. Anesthesiology 91:654, 1999

82. Tucker GT, Moore DC, Bridenbaugh PO: Systemic absorption of mepivacaine in commonly

used regional block procedures. Anesthesiology 37:277, 1972

83. 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, 3d ed, p 55. Philadelphia, Lippincott–Raven, 1998

84. Morrison LM, Emanuelsson BM, McClure JH: Efficacy and kinetics of extradural

ropivacaine: Comparison with bupivacaine. Br J Anaesth 72:164, 1994

85. Huang YF, Upton RN, Runciman WB: I.V. bolus administration of subconvulsive doses of

lignocaine to conscious sheep: Myocardial pharmacokinetics. Br J Anaesth 70:326, 1993

86. Huang YF, Upton RN, Runciman WB: I.V. bolus administration of subconvulsive doses of

lidocaine to conscious sheep: Relationships between myocardial pharmacokinetics and

pharmacodynamics. Br J Anaesth 70:556, 1993

87. Kuhnert BR, Kuhnert PM, Philipson EH: The half-life of 2-chloroprocaine. Anesth Analg

65:273, 1986

88. Rutten AJ, Mather LE, Nancarrow C: Cardiovascular effects and regional clearances of

intravenous ropivacaine in sheep. Anesth Analg 70:577, 1990

89. Braid DP, Scott DB: Dosage of lignocaine in epidural block in relation to toxicity. Br J

Anaesth 38:596, 1966

90. Adinoff B, Devous MD Sr, Best SE, et al: Gender differences in limbic responsiveness, by

SPECT, following pharmacologic challenge in healthy subjects. Neuroimage 18:697, 2003

91. Chen BK, Cunningham BB: Topical anesthetics in children: Agents and techniques that

equally comfort patients, parents, and clinicians. Curr Opin Pediatr 13:324, 2001

92. Covino BG, Wildsmith JAW: Clinical pharmacology of local anesthetic agents. In Cousins

MJ, Bridenbaugh PO (eds): Neural Blockade in Clinical Anesthesia and Management of Pain,

3rd ed, p 97. Philadelphia, Lippincott–Raven, 1998

93. Paulissian R, Salem MR, Joseph NJ, et al: Hemodynamic responses to endotracheal

extubation after coronary artery bypass grafting. Anesth Analg 73:10, 1991

94. Kindler CH, Schumacher PG, Schneider MC, et al: Effects of intravenous lidocaine and/or

esmolol on hemodynamic responses to laryngoscopy and intubation: A double-blind, controlled

clinical trial. J Clin Anesth 8:491, 1996

95. Gonzalez RM, Bjerke RJ, Drobycki T, et al: Prevention of endotracheal tube-induced

coughing during emergence from general anesthesia. Anesth Analg 79:792, 1994

96. Yukioka H, Hayashi M, Terai T, et al: Intravenous lidocaine as a suppressant of coughing

during tracheal intubation in elderly patients. Anesth Analg 77:309, 1993

97. Helfman SM, Gold MI, DeLisser EA, et al: Which drug prevents tachycardia and

hypertension associated with tracheal intubation: Lidocaine, fentanyl, or esmolol? Anesth

Analg 72:482, 1991

98. Nakayama M, Fujita S, Kanaya N, et al: Effect of intravenous lidocaine on intraabdominal

pressure response to airway stimulation. Anesth Analg 78:1149, 1994

99. Chamberlain DA: Antiarrhythmic drugs in resuscitation. Heart 80:408, 1998

100. Koppert W, Weigand M, Neumann F, et al: Perioperative intravenous lidocaine has

preventive effects on postoperative pain and morphine consumption after major abdominal

surgery. Anesth Analg 98:1050, 2004

101. Kingery WS: A critical review of controlled clinical trials for peripheral neuropathic pain

and complex regional pain syndromes. Pain 73:123, 1997

102. Devor M, Wall PD, Catalan N: Systemic lidocaine silences neuroma and DRG discharge

without blocking nerve conduction. Pain 48:261, 1992

103. Tanelian DL, MacIver MB: Analgesic concentrations of lidocaine suppress tonic A-delta

and C fiber discharges produced by acute injury. Anesthesiology 74:934, 1991

104. Persaud N, Strichartz GR: Micromolar lidocaine selectively blocks propagating ectopic

impulses at a distance from their site of origin. Pain 99:333, 2002

105. Cahana A, Carota A, Montadon ML, et al: The long-term effect of repeated intravenous

lidocaine on central pain and possible correlation in positron emission tomography

measurements. Anesth Analg 98:1581, 2004

106. Groban L: Central nervous system and cardiac effects from long-acting amide

local anesthetic toxicity in the intact animal model. Reg Anesth Pain Med 28:3, 2003

107. Shibata M, Shingu K, Murakawa M: Tetraphasic actions of local anesthetics on central

nervous system electrical activity in cats. Reg Anesth 19:255, 1994

108. Brown DL, Ransom DM, Hall JA, et al: Regional anesthesia and local anesthetic-induced

systemic toxicity: Seizure frequency and accompanying cardiovascular changes. Anesth Analg

81:321, 1995

109. Auroy Y, Benhamou D, Bargues L, et al: Major complications of regional anesthesia in

France: The SOS Regional Anesthesia Hotline Service. Anesthesiology 97:1274, 2002

110. Weinberg GL: Current concepts in resuscitation of patients with local anesthetic

cardiac toxicity. Reg Anesth Pain Med 27:568, 2002

111. Yokoyama M, Hirakawa M, Goto H: Effect of vasoconstrictive agents added to lidocaine

on intravenous lidocaine-induced convulsions in rats. Anesthesiology 82:574, 1995

112. Yamauchi Y, Kotani J, Ueda Y: The effects of exogenous epinephrine on a convulsive dose

of lidocaine: Relationship with cerebral circulation. J Neurosurg Anesth 10:178, 1998

113. Sokrab TEO, Johansson BB: Regional cerebral bloodflow in acute hypertension induced by

adrenaline, noradrenaline, and phenylephrine in the conscious rat. Acta Physiol Scand

137:101, 1989

114. Mayhan WG, Faraci FM, Siems JL: Role of molecular charge in disruption of the blood–

P.471

brain barrier during acute hypertension. Circ Res 64:658, 1989

115. Arthur GR, Feldman HS, Covino BG: Alterations in the pharmacokinetic properties of

amide local anaesthetics following local anaesthetic induced convulsions. Acta Anaesthesiol

Scand 32:522, 1988

116. Lee LA, Posner KL, Domino KB, et al: Injuries associated with regional anesthesia in the

1980s and 1990s: A closed claim analysis. Anesthesiology 101:143, 2004

117. Klein SM, Pierce T, Rubin Y, et al: Successful resuscitation after ropivacaine induced

ventricular fibrillation. Anesth Analg 97:901, 2003

118. McClellan KJ, Faulds D: Ropivacaine: An update of its use in regional anaesthesia. Drugs

60:1065, 2000

119. McLeod GA, Burke D: Levobupivacaine. Anaesthesia 56:331, 2001

120. Knudsen K, Beckman Suurkula M, Blomberg S, et al: Central nervous and cardiovascular

effects of i.v. infusions of ropivacaine, bupivacaine and placebo in volunteers. Br J Anaesth

78:507, 1997

121. Stewart J, Kellett N, Castro D: The central nervous system and cardiovascular effects of

levobupivacaine and ropivacaine in healthy volunteers. Anesth Analg 97:412, 2003

122. 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

123. Pickering AE, Waki H, Headley PM, et al: Investigation of systemic bupivacaine toxicity

using the in situ perfused working heart-brainstem preparation of the rat. Anesthesiology

97:1550, 2002

124. Chang KSK, Yang M, Andresen MC: Clinically relevant concentrations of bupivacaine

inhibit rat aortic baroreceptors. Anesth Analg 78:501, 1994

125. Hogan QH, Stadnicka A, Bosnjak ZJ, et al: Effects of lidocaine and bupivacaine on

isolated rabbit mesenteric capacitance veins. Reg Anesth Pain Med 23:409, 1998

126. Guo XT, Castle NA, Chernoff DM, et al: Comparative inhibition of voltage-gated cation

channels by local anesthetics. Ann N Y Acad Sci 625:181, 1991

127. 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

128. Mio Y, Fukuda N, Kusakari Y, et al: Bupivacaine attenuates contractility by decreasing

sensitivity of myofilaments to Ca2+ in rat ventricular muscle. Anesthesiology 97:1168, 2002

129. Nouette-Gaulain K, Forestier F, Malgat M, et al: Effects of bupivacaine on mitochondrial

energy metabolism in heart of rats following exposure to chronic hypoxia. Anesthesiology

97:1507, 2002

130. Weinberg G, Ripper R, Feinstein DL, et al: Lipid emulsion infusion rescues dogs from

bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med 28:198, 2003

131. Kitagawa N, Oda M, Totoki T: Possible mechanism of irreversible nerve injury caused by

local anesthetics and membrane disruption. Anesthesiology 100:962, 2004

132. Kalichman MW: Physiologic mechanisms by which local anesthetics may cause injury to

nerve and spinal cord. Reg Anesth 18:448, 1993

133. Selander D: Neurotoxicity of local anesthetics: Animal data. Reg Anesth 18:461, 1993

134. Yamashita A, Matsumoto M, Matsumoto S, et al: A comparison of the neurotoxic effects

on the spinal cord of tetracaine, lidocaine, bupivacaine, and ropivacaine administered

intrathecally in rabbits. Anesth Analg 97:512, 2003

135. Bainton C, Strichartz G: Concentration dependence of lidocaine-induced irreversible

conduction loss in frog nerve. Anesthesiology 81:657, 1994

136. Kanai T, Katsuki H, Takasake M: Graded, irreversible changes in crayfish giant axon as

manifestations of lidocaine neurotoxicity in vitro. Anesth Analg 86:569, 1998

137. Lambert L, Lambert D, Strichartz G: Irreversible conduction block in isolated nerve by

high concentrations of local anesthetics. Anesthesiology 80:1082, 1994

138. Iida H, Watanabe Y, Dohi S, et al: Direct effects of ropivacaine and bupivacaine on spinal

pial vessels in canine. Anesthesiology 87:75, 1997

139. Pollock JE: Transient neurologic symptoms: Etiology, risk factors, and management. Reg

Anesth Pain Med 27:581, 2002

140. Liu S, Kopacz D, Carpenter R: Quantitative assessment of differential sensory nerve

block after lidocaine spinal anesthesia. Anesthesiology 82:60, 1995

141. Pollock JE, Liu SS, Neal JM, et al: Dilution of lidocaine does not decrease the incidence of

transient neurologic symptoms. Anesthesiology 90:445, 1999

142. Taniguchi M, Bollen AW, Drasner K: Sodium bisulfite: Scapegoat for chloroprocaine

neurotoxicity? Anesthesiology 100:85, 2004

143. Zink W, Graf B: Local anesthetic myotoxicity. Reg Anesth Pain Med 29:333, 2004

144. Chen AH: Toxicity and allergy to local anesthesia. J California Dent Assoc 26:683, 1998

145. Finder RL, Moore PA: Adverse drug reactions to local anesthesia. Dent Clin North Am

46:747, 2002