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Transcript of Local Anesthetics
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.
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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.)
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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.
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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
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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
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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.)
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