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LOCAL ANESTHETICS

HISTORY

Cocaine is a naturally occurring alkaloid in the

leaves of the coca plant, Erythroxylon coca. The

coca bush grows primarily in the Andes Mountains

at elevations of 3000 to 9000 feet. The Incas

attached enormous importance to the plant and

used it for religious, mystical, social, stimulant, and

numerous medicinal purposes. The Spanish Con-

quistadors brought the leaves to Europe and by

the mid-1800s cocaine was widely praised for its

capacity to increase stamina and to alleviate hun-

ger and thirst.1,2

In 1859 Niemann characterized the active coca

alkaloid and named it cocaine. Despite numerous

suggestions of cocaines potential as a local anes-

thetic (von Anrep), it was not until 1884 that Carl

Kller demonstrated the critical link between the

observed anesthetic effects of cocaine and its

application to clinical ophthalmic practice. This new

form of anesthesia rapidly spread to other surgical

disciplines.

By the latter part of the 19th century, cocaine

was used routinely on both sides of the Atlantic to

provide anesthesia in dentistry (Hall) and forregional nerve blocks (Halsted) and spinal blocks

(Bier).

Soon the dangers of cocaine became evident.

Sigmund Freud, in an attempt to cure a colleagues

opium addiction, was successful only in transfer-

ring the mans addiction from morphine to cocaine.

The drug could create crippling dependence and

psychosis, and there were multiple reports of sys-

temic cocaine intoxication, including several deaths.

In 1924 the American Medical Association issued

safety guidelines for cocaine administration and

condemned as toxic the use of cocaine mud, a

paste made from cocaine crystals dissolved in epi-

nephrine.The toxicity of cocaine led to an intensive search

for less toxic substitutes. Procaine was synthesized

by Einhorn in 1904 and its usefulness in surgery

was reported by German surgeon Heinrich Braun

in 1905. However, procaines short duration of

activity lessened its clinical utility, and the search for

longer-acting agents led to the introduction of

dibucaine in 1925, followed by tetracaine in 1932.

Dibucaine and tetracaine proved to be potent, long-

acting local anesthetics, but their potential for toxi-

city limited their usefulness. They found their niche

in the practice of spinal anesthesia, where onlysmall volumes are required.

These drugs were all amino esters, similar to

cocaine, and were relatively unfavorable because

of the ester bond and hydrolysis by plasma pseudo-

cholinesterase. This enzyme catalyzed the forma-

tion of para-aminobenzoic acid (PABA) which was

responsible for reported allergic reactions.

Lidocaine, synthesized in 1943 by Lofgren and

Lundquist, was the first of the amino amide agents

to be introduced. It was more stable and also

could be resterilized, as opposed to the aminoester agents. Its metabolism did not produce PABA,

thus the potential for allergic reactions was less.

Lidocaine remains the flagship of local anesthetics,

and has an excellent safety record.

Subsequent research focused on the amino

amide agents and resulted in the release of

mepivacaine in 1956 and prilocaine in 1959.

Bupivacaine was introduced into clinical practice in

1963 and gained wide acceptance because of its

LOCAL ANESTHETICS

Thomas M Vaughan FANZCA

CARDIOPULMONARY RESUSCITATIONAND ADVANCED CARDIAC LIFE SUPPORT

James Burt FRACS

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SRPS Volume 9, Number 4

2

potency and its ability to provide significantly longer

anesthesia than was possible with either lidocaine

or mepivacaine. In 1971, etidocaine was synthe-

sized. This was also a long-acting agent like

bupivacaine and produced a more profound motor

block.

The most recent addition to the local anes-

thetic armory is ropivacaine. It has been pre-

pared as a pure S-(-)-enantiomer, rather than a

racemic mixture such as mepivacaine or

bupivacaine. Interest in this drug stems from the

fact that studies have shown it to be less car-

diotoxic than bupivacaine.4

NEUROPHYSIOLOGY

A knowledge of the physiology of peripheral

nerves is basic to understanding the mechanism of

action of local anesthetics.

Impulse Transmission and Diffusion of LA

A nerve fiber is a cylinder of neuroplasm (axon)

surrounded by a cellular membrane (neurilemma).

The outer surface of certain axons is insulated

by the myelin sheath, a group of concentric lay-

ers of lipoprotein. Myelin is produced by

Schwann cells. Gaps along the axons between

adjacent Schwann cells are known as nodes of

Ranvier, and it is at these breaks in the myelin

sheath that the bare nerve membrane is exposed

to extracellular fluid, producing a rapid impulse

conduction (Fig 1).

Fig 1. Structure of a myelinated nerve.

In myelinated peripheral nerves the nerve

impulse jumps from one node of Ranvier to another,

a process known as saltatory conduction. The rate

of conduction is directly proportional to the cross-

sectional area of the axonie, the thicker the axon,

the larger the Schwann cell, the greater the inter-

nodal distance, and the faster the impulse conduc-

tion. Conduction rates in myelinated nerves are

faster than in nerves without Schwann cell sheaths.

In unmyelinated nerves the wave of depolarization

has to proceed down the entire nerve membrane

(Fig 2).

Fig 2. Impulse transmission along unmyelinated (top) andmyelinated (bottom) nerves.

In clinical practice local anesthetics must dif-

fuse across a number of structures before reach-

ing the sodium channel in the axonal membrane.

Peripheral nerves contain both afferent and

efferent axons. These axons and their Schwann

cells are surrounded by a delicate layer of fine

connective tissue (endoneurium) which permits

easy diffusion of most local anesthetics. Bundles

of axons are enclosed in a squamous veil or

sheath (perineurium) which comprises several

layers of cells and acts as a semipermeable bar-

rier to local anesthetics. One or more perineu-

ral bundles are covered by an outermost, easily

permeable connective tissue layer (epineurium).

This layer also contains the nutritional blood ves-sels of larger nerves.

Factors that have an important influence on local

anesthetic diffusion to axon include:

(1) perineurium;

(2) presence or absence of myelin;

(3) size of axons;

(4) anatomical position of axons.

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The perineurium presents the largest obstacle in

the diffusion of a local anesthetics molecules. This

results in the fact that the concentration of local

anesthetic required for blocks in clinical practice is

approximately 50X that required for an unsheathed

nerve. Very little local anesthetic is required for

spinal anesthesia because only a thin perineuriumexists in the subarachnoid space.

The distribution of the nerve fibers within a nerve

affects the onset of the block. Topographically, the

fibers in a nerve trunk are arranged in concentric

layers. Fibers that innervate a limbs distal part

assume a central position, whereas those that

innervate the limbs proximal part lie in the nerves

mantle.

The neuronal communication process begins

with a stimulus (chemical, mechanical, or thermal)

acting on a distal nerve terminal and causing agraded depolarization of that terminal. This spreads

to the axon proper, where an all-or-none depolar-

ization action potential is produced if transmem-

brane potential reaches the required threshold volt-

age. If threshold is reached, then the action poten-

tial is propagated to the proximal terminal, where agraded depolarization occurs that is responsible

for initiating neurotransmitter release.

A resting excitable cell has a measurable voltage

across its membranethe resting membrane

potential. The potential is due to the unequal distri-

bution of sodium and potassium ions between theinside and outside of the cell, and the high mem-

brane permeability to potassium ions but not to

sodium ions. Bernstein applied the Nernst equa-

tion to explain the transmembrane potential of ex-

citable cells. The Nernst equation is derived from

equations that describe the chemical forces and

electrical forces present when charged molecules

are separated by a selectively permeable membrane.

For example, for potassium ions,

where E = membrane potential

R = gas constant (8.315 joules/K)

T = temperature (Kelvin)

F = Faradays constant (9.65 x 104coulombs)

ln = natural logarithm

[K+] = potassium ion concentration inside(i)

and outside(o)

the cell

An expanded equation, the Goldman-Hodgkin-

Katz equation, was formulated to describe the trans-

membrane potential of membranes permeable to

several ionic species (eg, nerve axon). This equa-

tion illustrates that the actual value of transmem-

brane potential is set by the concentration of each

ion and its respective permeability coefficient.

The resting membrane potential actually requires

an active component to maintain the concentra-

tion gradient for sodium ion. The axon in its rest-

ing state is somewhat permeable to sodium ions

and permits passive movement of sodium into the

axon. This movement is balanced by the action of

the sodium pump, requiring the input of cellularenergy. If this pump is not operative, the mem-

brane potential would slowly disappear.

In summary, the primary factors responsible for

the transmembrane potential are:

1. A membrane that is somewhat selectively per-

meable to ion species.

2. A concentration gradient across the membrane.

3. Charged ions that distribute unevenly across the

membrane.

4. An active process that removes sodium from

inside the neuron at the same rate as sodiumions passively enter it.

Depolarization and Repolarization

The electrical messages of excitable cells are

changes of the electrical potential difference

across the cell surface membrane. Neurophysi-

ologists distinguish action potentials from slow

potentials. Action potentials are used to send

messages rapidly and usually over large distances.They are transmitted as brief, depolarizing

changes of membrane potential at a constant

speed with no loss of amplitude. The only stimu-

lus for an action potential is a membrane depo-

larization larger than the threshold level. The

response is not graded.

In contrast, slow potentialsdo not propagate at

a constant amplitude over large distances, but are

effective in the immediate environment. They can

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The beta subunits apparently have a modulatory

influence on the alpha subunits. The alpha sub-

units extend through the membrane and form

the four sides of the Na+ selective transmem-

brane pore.

Mechanism of Action

Local anesthetics block impulses by inhibiting

individual sodium channels in the vicinity. The

sodium channel inhibition is accomplished by

using the aggregate inward current of a nerve

fiber. Local anesthetics inhibit stimulated chan-

nels (phasic block) more than resting channels

(tonic block). The modulated receptor hypoth-

esishas been advanced to explain this phenom-enon. The hypothesis rests on the notion that

sodium channels normally respond to membrane

depolarizations by passing through defined con-

formational states: beginning at rest (R), activat-

ing through closed intermediate forms (C), to

reach an open form (O), and then closing to an

inactivated(I) state.5

R t tC tO tI

According to the modulated receptor hypoth-

esis, local anesthetics have a higher affinity for

open and especially inactivated sodium channels

than for resting channels.6 During stimulation,

channels that are open and inactivated bind local

anesthetics more tightly. This binding then stabi-

lizes the channels in a nonconducting state and

increasingly so with each stimulating pump. Even-

tually some anesthetic-bound channels will return

to their resting equilibrium and a steady-state level

of phasic block will be reached wherein increasedinhibition during depolarization is exactly

reversed by drug dissociation in the time between

pulses.

An alternative mechanism is proposed as the

guarded receptor hypothesis, in which the recep-

tor affinity for the local anesthetic remains high, but

access to the receptor by the local anesthetic is

limited through channel guards.

Locus of Action

The actual receptor for local anesthetic bind-

ing is not definitively known, and there may be

more than one site. The most likely site, at least

for the ionizable species, is the sodium channelitself. This receptor is likely to be on the inside

of the sodium channel, as evidenced by the fact

that permanently charged quaternary ammonium

local anesthetics do not block sodium currents

when applied to the outside of the cell mem-

brane but strongly block sodium currents when

applied to the cytoplasmic side. This binding site

can be approached either by a hydrophilic path-

way, which is more likely through the pore of

the sodium channel, or through a hydrophobic

pathway via the membrane.7-11

CHEMICAL STRUCTURE

Local anesthetics have an aromatic end, an inter-

mediate chain, and an amine end (Fig 3).

Fig 3.Chemical configuration of local anesthetics showing thetwo possible types of bond between the aromatic ring and the

intermediate chain.

The aromatic end is lipophilic and the amine end

is hydrophilic. Alteration at either end will result in

a change in the lipid-water distribution coefficient

of the anesthetic agent, its protein binding charac-

teristics, and its clinical activity.12

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Amino esters have an ester link between the

aromatic portion and the intermediate chain. Amino

amides have an amide link between the aromatic

end and the intermediate chain (Fig 4).

Differences in metabolism and allergic potential

of the various agents can be traced to the nature of

the bond. Degradation of local anesthetics occurs

at the bond level.13

Ester and amide local anesthetics are different

in the way they are metabolized, their chemical

stability in solution, and their potential for aller-

gic reactions. Amino esters are degraded in

plasma via pseudocholinesterase, are relatively

unstable in solution, and are much more capable

than amino amides of causing true allergic reac-

tions. Amino amides are broken down in the

liver, are stable in solution, and only rarely causeallergic reactions.14

PHARMACOLOGIC FACTORS AFFECTING

ANESTHETIC ACTIVITY

Physicochemical Properties

Lipid Solubility

Lipid solubility relates directly to an anesthetics

potency. Because 90% of the axon is lipid, the

more lipid-soluble a local anesthetic is, the more

quickly it penetrates the nerve membrane and

the more quickly it produces a blockade on the

nerve. In other words, the more lipid-soluble a

local anesthetic agent is, the more potent it is.15-17

Highly protein-bound drugs such as bupivacaine

(95% bound) have a long duration of action,

whereas procaine (6% protein-bound) is short-

acting.

pKa

The pKa of a chemical compound is the pH at

which the ionized and nonionized forms of the

compound are in equilibrium. The pKa value is

constant for any single compound. The amount

of local anesthetic in the uncharged base form

determines the rate at which it will diffuse across

the nerve membrane and controls the rate of

onset of anesthesia. The greater the percentage

of local anesthetic in the uncharged base form,

the more rapid its diffusion across the nerve mem-

brane and the more rapidly it produces its local

anesthetic effect.

Fig 4. Chemical structure of some common local anesthetics.

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The proportion of uncharged base to charged

cation depends upon the pH of the solution and

the pKa of the compound. A decrease in pH will

shift the equilibrium toward the charged cation

form and result in relatively more cation present

than free uncharged base. On the other hand, a

rise in pH changes the equilibrium in favor of thefree base form. Examples of this are lidocaine

and etidocaine, with pKa in the range of 7.6 to

7.8. At normal tissue pH, they have relatively

rapid onsets, in that about 35% of the drug is in

the uncharged base form. By comparison,

bupivacaine and tetracaine, with pKa between 8.1

and 8.9, are 80% to 95% cation at normal tissue

pH of 7.4, and their onset of action is much

slower.15

Brown18studied the phenomenon of local anes-

thetic failure in the presence of inflammation.Inflammation leads to a more acidic state of the

tissues, which decreases membrane permeability

and causes local anesthetic agents to exist in largely

cationic forms. This limits their diffusion across

nerve cell membranes and thus their local anes-

thetic capabilities.

Diffusability

The speed of onset of a local anesthetic is

affected by the diffusion rate of the compound

through tissues other than nerve. To illustrate,

procaine and chloroprocaine have similar pKa

and onset times in vitro, but in living tissue chlo-

roprocaine acts more quickly than procaine

because it diffuses faster through nonneural tis-

sue. Also lidocaine, which in the laboratory is

similar to prilocaine in pKa value and onset of

action, is noted to have a much faster anes-

thetic effect in the clinical situation due to its

higher diffusability.

Intrinsic Vasodilator Activity

All local anesthetics except cocaine exhibit a

vasoactive effect on vascular smooth muscle: At

very low concentrations they cause vasoconstric-

tion, but at clinically relevant concentrations local

anesthetics except cocaine tend to be vaso-

dilatory. Vasodilation will promote removal of

local anesthetic molecules from the site of action

and thereby decrease intensity of block and

duration of action. The addition of epinephrine

will counter these effects and prolong duration

of action.

Other Factors

Dosage

The mass of local anesthetic (ie, the number

of milligrams administered) influences the onset,

depth of block, and duration of action, such that

20 mL of 1% lidocaine has an effect equivalent

to 10 mL of 2% lidocaine. In the epidural space,

however, an increased volume with an equiva-

lent mass of drug is associated with increased

dermatomal spread.

Site of Injection

Spinal anesthesia is associated with a rapid onset

of action and a relatively short duration of action.

On the other hand, regional techniques such as a

brachial plexus block have a slow onset and, because

of the large volumes used, a long duration of

action.19-21

Addition of VasoconstrictorEpinephrine is frequently added to local anes-

thetic solutions to decrease the rate of absorption.

This has the effect of decreasing the rate at which

local anesthetic molecules leave the site of action

to be absorbed into the systemic circulation, with

the result that the local anesthetic activity is more

profound, with a longer duration of action, and the

potential for systemic toxicity is less. In addition,

surgical conditions are improved by the promotion

of hemostasis.

Effective vasoconstriction can be achieved byadding as little as 1:800,000 epinephrine to the

local anesthetic solution.22 However, this mixture

is unstable after a few hours, must be mixed by

hand, and requires a longer postinjection interval

for maximum effect. Commercial solutions of

1:100,000 and 1:200,000 epinephrine are com-

monly used because they are readily available.

Laser Doppler flowmetry studies have deter-

mined that injections of ropivacaine and epineph-

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rine do not reduce skin blood flow as much as

epinephrine alone; that is, the addition of ropivacaine

diminishes the vasoconstrictive effect of epineph-

rine.23

Epinephrine use is not without risk. Cardiac

arrhythmias are a concern in persons who have

predisposing intrinsic heart disease or when epi-nephrine is administered concomitantly with agents

that sensitize the myocardium (eg, halothane). Epi-

nephrine may precipitate a hypertensive crisis in

patients who have hypertension or hyperthyroid-

ism. High concentrations of epinephrine may pro-

duce local tissue necrosis or trigger rebound hype-

remia, resulting in bleeding or hematoma as the

effect resolves. At dilutions of 1:200,000, epineph-

rine is detrimental to the survival of delayed skin

flaps.24,25

Other Additives

Carbonation of local anesthetic solutions has

been tried to speed the onset of nerve block. Car-

bonation lowers the intracellular pH, thereby

increasing the proportion of cationic form of the

local anesthetic and trapping it in the axoplasm.

The early studies were promising,26but more recent

double-blind studies fail to demonstrate an advan-

tage.27,28

On the other side of the cell membrane, sodium

bicarbonate has been added to local anesthetics to

increase the extracellular pH, which then increases

the amount of drug in the uncharged base form. In

theory, the uncharged base diffuses faster across

the nerve membrane and as such decreases the

latency of action of the local anesthetic. This strat-

egy has been shown to be clinically effective with

lidocaine and bupivacaine for epidural block, with

lidocaine for brachial plexus block, and with

mepivacaine for sciatic and femoral nerve block.29,30

Other studies dispute these findings and note no

advantage to alkalinized local anesthetics31-34

otherthan reactivation of epinephrines vasoconstrictor

activity.33

Mixtures of Local Anesthetics

(Compounding)

In theory, compounding local anesthetic agents

takes advantage of certain qualities of each. For

example, chloroprocaine, lidocaine, or mepivacaine,

all of which have rapid onset of action, could be

combined with tetracaine or bupivacaine, whose

effects are of long duration.35 Moreover, com-

pounding solutions allows single-dose techniques

for epidural or caudal block in cases where a con-

tinuous technique would be mandatory if a single

agent were to be used.Interestingly, subsequent studies have not

always borne this out. Cohen and colleagues,36

for example, report that the duration of epidural

anesthesia produced by a mixture of chloro-

procainebupivacaine was significantly shorter

than that obtained with bupivacaine alone, while

time to onset was longer than that with chloro-

procaine alone.

The toxicity of a mixture is no greater than

that of its individual components.37,38 The safety

of a mixture is particularly apparent when short-acting agentspresent in the serum earlyare

combined with long-acting agents whose effect

on excitable membranes never exceeds the toxic

threshold.

Mixtures of ester- and amide-type local anesthet-

ics capitalize on different routes of disposition, per-

mitting administration of larger total volumes per

dose. To date there are no studies of any possible

toxicity of these combinations.

SYSTEMIC ABSORPTION

The rate of systemic absorption is controlled by

the extent of local binding. The peak concentra-

tion is lower and reached after a longer period of

time for the lipophilic drugs compared to the more

hydrophilic drugs.39 The site of injection also influ-

ences the systemic absorption; the highest plasma

concentration of local anesthetic is seen after inter-

costal blocks. Much lower levels are seen in the

plasma after sciatic and femoral nerve blocks, withepidural techniques occupying an intermediate

position.

The envelope for maximum safe dosage of a

local anesthetic has been pushed with the advent

of the tumescent technique of liposuction. The

key elements of the tumescent technique are slow

injection over 45 minutes and the use of very dilute

solutions of lidocaine, 0.05% to 0.1%, and epineph-

rine, 1:1,000,000. Klein21estimates the maximum

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safe dosage of local anesthetic to be 35 mg/Kg,

and cautions against using bupivacaine for this pur-

pose. Case reports of severe toxicity with rela-

tively small doses of bupivacaine, less than 0.5 mg/

Kg, are causes for concern. In one of these cases

the toxic effects of bupivacaine were thought to

have been potentiated by isovolemic acidemia.20

TOXICITY

Systemic Toxicity

Local anesthetics vary considerably in their

potential for causing systemic toxic reactions (Fig 5).

Fig. 5.Local anesthetic agents arranged in order of increasing

toxicity. (Reprinted with permission from Cousins MJ, Mather LE:

Clinical pharmacology of local anesthetics. Anaesth Intens Care

8:257, 1980.)

In clinical practice, the systemic toxic responses

to local anesthetic drugs result from unintentional

intravascular injection of an appropriate dose of

drug or from an excessive dosage. Toxicity sec-

ondary to extravascular administration is related to

the pharmacokinetic properties of the drug.

Most toxic reactions involve the central nervous

system (CNS). Local anesthetic-induced cardiovas-

cular depression occurs less frequently but tends

to be more serious and more difficult to manage.

CNS Toxicity

The response to elevated levels of local anes-

thetic in the CNS is biphasic. Initially there is an

excitatory phase thought to be due to the block of

inhibitory pathways in the amygdala. This inhibition

allows facilitatory neurons to function unopposed,

and manifests initially as muscle twitching in the face

and distal extremities, followed by tremors and pro-

gressing to generalized tonic-clonic convulsion.40,41

With further increased levels of anesthetic in theCNS, a depression phase ensues, with drowsiness,

unconsciousness, and respiratory arrest.

When there is a very rapid rise in the concentra-

tion of local anesthetic, as may occur with direct

injection into the carotid or vertebral artery, the

excitatory phase may not be seen, especially when

CNS-depressant drugs such as sedatives have been

administered.

The presence of hypercapnea, which increases

the cerebral blood flow and decreases protein bind-

ing, will increase the amount of free drug presented

to the brain. Acidosis will increase the cationic

form of local anesthetic and theoretically lessen

diffusion across the cell membrane. However, the

overall effect is the potentiation of toxicity, and

one of the key elements of treatment is to control

ventilation and effect a respiratory alkalosis.42,43

Bernards and colleagues44 found that the addi-

tion of epinephrine lowers the dose of bupivacaine

that causes seizures in pigs.

Cardiovascular Toxicity

The cardiovascular system is thought to be more

resistant than the central nervous system to the

effect of local anesthetic drugs.45 CNS toxic

responses usually occur at lower blood levels than

cardiovascular system toxic responses. The ratio

of dosage or blood levels required to produce

irreversible cardiovascular collapse to dosage or

blood levels required to elicit convulsionsie, CNS

toxicityhas been termed the CC/CNS ratio. This

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ratio is lower for bupivacaine and etidocaine than

for the less lipid-soluble lidocaine in adult sheep.

The CC/CNS ratio for lidocaine is 7.0, whereas for

bupivacaine it is 2.7 in pregnant sheep.46 The impli-

cations of this difference are that the early warning

signs of CNS toxicity from bupivacaine occur at a

blood level much lower than that associated withcardiovascular collapse.

Hypomagnesemia may enhance the cardio-

toxicity of bupivacaine. This may explain the

increased susceptibility of the pregnant patient

who is relatively hypomagnesemicto the car-

diotoxic effects of bupivacaine.47

In 1979 Albright48demonstrated the correlation

between cardiovascular toxicity and the longer-

acting, highly lipid-soluble local anesthetics,

bupivacaine and etidocaine. Of 49 fatal cases, 43%

involved bupivacaine. The FDA subsequentlysomewhat illogicallyrecommended against the use

of 0.75% bupivacaine in obstetrical practice. Since

that time, however, there has been a decrease in

the incidence of severe cardiac toxicity, primarily

as a result of changes in the method of administer-

ing these drugs, use of a test dose and incremental

dosing.

Local anesthetics affect both the conduction path-

ways and contractility. Lidocaine, which is used clini-

cally as an antiarrhythmic, decreases the maximal

rate of depolarizationthe Vmax

without altering rest-

ing membrane potential of cardiac muscle. In iso-

lated muscle preparations, recovery from this

depression of the rapid phase of depolarization is

complete even at rapid heart rates.6,49 In contrast,

bupivacaine causes depression which does not

recover completely when heart rate is greater than

100,50,51 suggesting unidirectional block and a re-

entrant type of arrhythmia caused by this drug.52

The high concentrations of local anesthetic in

the CNS may also contribute to local anesthetic

toxicity in the cardiovascular system. Direct appli-

cation of local anesthetics within vasomotor andcardioactive regionsin the medullaleads to

hypotension, bradycardia, and ventricular arrhyth-

mias.53,54Bupivacaine shares the same site of action

as other agents of its class (ie, the medulla), but

bupivacaine is 3 to 4X more potent in producing

arrhythmias.55

The CNS-mediated cardiotoxicity that occurs after

direct CNS administration of bupivacaine is also seen

after intravenous administration of the drug.56 The

onset of arrhythmias can be delayed by premedica-

tion with a benzodiazepine.57 Once started, the

arrhythmias can also be terminated by CNS adminis-

tration of midazolam, a GABAergic stimulant.58

The majority of clinical reports of bupivacaine

cardiac toxicity have been in pregnant patients.

Morishima and colleagues46found that the dose of

bupivacaine producing cardiovascular collapse was

significantly lower in pregnant ewes compared with

nonpregnant ewes. This increased susceptibility to

cardiovascular toxicity in pregnancy is not seen

with the other agents.

The recent release of ropivacaine into clinical

practice offers a drug with a similar physiologic

profile to bupivacaine but with a lower toxicity pro-

file.59-61 Ropivacaine shares with bupivacaine the

advantages of being long acting and selectively

affecting sensory nerves over motor nerves,62

which makes it a useful agent for epidural analgesia

in the laboring parturient.63

The formulation of ropivacaine as a pure S-(-)-

enantiomer has exploited the stereospecific nature

of binding at the sodium channel. In its depressant

effect on Vmax

in guinea pig papillary muscle,

ropivacaine is intermediate between bupivacaine

(highest) and lignocaine (lowest).64 Recovery from

block is slower with bupivacaine than with

ropivacaine. This observation has been confirmed

in other animal models65,66and children.67

In human volunteer studies, ropivacaine was

associated with higher tolerated doses. In addi-

tion, the CNS symptoms and cardiovascular

changessuch as depression of conduction and

ventricular functionseen with very high doses of

anesthetic were less pronounced with ropivacaine

than with bupivacaine.61,68 A case report of prob-

able intravascular injection of ropivacaine during

interscalene brachial plexus block was associated

with unconsciousness, seizure activity, and hypoten-

sion. No arrhythmias were noted and the patient

made an uneventful recovery.69

Treatment of Systemic Toxicity

Careful technique with attention to appropriate

dosage guidelines will go a long way to prevent

local anesthetic toxicity. Nevertheless, unrecognized

intravascular injections can still occur despite nega-

tive aspiration tests. The use of a test dose contain-

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ing epinephrine is helpful in detecting intravascular

injection, although its use in certain situations such

as the laboring patient has been questioned.70

ECG monitoring is a reliable indicator of

bupivacaine toxicity. Elevation in the blood con-

centration of bupivacaine is associated with decrease

in the R wave amplitude and increase in the QRScomplex. Blood pressure is insensitive to increas-

ing blood levels of local anesthetic. The pressure

seems to be well maintained by an increase in sys-

temic vascular resistance despite a 40% decrease

in cardiac output.71

The use of fractionated doses allows earlier de-

tection of local anesthetic toxicity, though it must

be remembered that only a very small amount of

the drug will cause convulsions if injected directly

into the cerebral circulationeg, injection into ver-

tebral artery during interscalene approach to bra-chial plexus.72 In the conscious patient, early warn-

ing signs of intravascular injection include circu-

moral numbness and tinnitus.

Treatment consists of stopping the injection, car-

diovascular monitoring, administration of O2,and

encouragement to breathe at a normal minute-vol-

ume. If convulsions occur, the aim is to treat any

respiratory or cardiovascular depression before

hypoxia or hypercarbia supervene. The treatment

is outlined in Table 2.

The differential diagnosis of clinical reactions that

may be observed after administration of local anes-

thetic are outlined in Table 3.

Appropriate monitoring and availability of per-

sonnel skilled in advanced cardiac life support are

mandatory for all major regional techniques.

Local Tissue Toxicity

Histologic studies demonstrate reversible myo-

tonic effects in animals and humans when localanesthetics are injected into skeletal muscle.73

Miscellaneous Tonic Responses

In doses greater than 600 mg, prilocaine has

been associated with the development of meth-

emoglobinemia because one of its metabolites,

hydroxylated D-toluidine, reduces any hemoglo-

bin.74,75 Methemoglobinemia manifests clinically

as cyanosis, and can be treated with methylene

blue, 1 mg/Kg. Most patients tolerate treatment

well. Other than this, prilocaine has an excellent

safety profile, is the least toxic of the amino amide

local anesthetics, and is particularly suited to IVRA

because of its rapid clearance.

Table 2

Treatment of Acute Local Anesthetic Toxicity

(Reprinted with permission from Cousins MJ, Bridenbaugh PO

(eds): Neural Blockade in Clinical Anesthesia and Manage-

ment of Pain. 2nd Ed. Philadelphia, JB Lippincott, 1988, p 118.)

COCAINE

Cocaines sympathomimetic actions make it

unique among local anesthetics. Cocaine blocks

the reuptake of norepinephrine and epinephrine

into sympathetic nerve endings. It may also act

postsynaptically to produce a change in effector

cells, making them capable of generating an

increased maximal response. These actions are

responsible for the vasoconstriction that is exploited

in the use of cocaine as a topical anesthetic for

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intranasal surgerythe mucosal shrinkage greatly

facilitates surgical accessand that makes cocaine

popular with otolaryngologists and plastic sur-geons.76,77

The sympathomimetic effects of cocaine are

responsible for cardiovascular stimulation, which may

result in myocardial ischemia or even infarction insusceptible patients.78,79 In the CNS, cocaine blocksreuptake of dopamine, leading to increased neu-

rotransmission at the synapse and euphoria,80whichis the basis for the highly addictive nature of this drug.

ALLERGIES

The amino ester drugs such as procaine, whichare p-aminobenzoic acid derivatives, may produce

allergic reactions. True allergy to amino amide

agents is extremely rare, although these agentsmay contain a preservative, methylparaben, whose

chemical structure is similar to that of PABA.81

SEDOANALGESIA

The use of sedative drugs facilitates the per-

formance of surgery under local anesthesia.

Table 3Differential Diagnosis of Local Anesthetic Reactions

(Reprinted with permission from Cousins MJ, Bridenbaugh PO (eds): Neural Blockade in Clinical Anesthesia and Management of Pain.

2nd Ed. Philadelphia, JB Lippincott, 1988, p 118.)

Pain from the procedure due to inadequate

block should be managed by supplementation

of the block or by conversion to general anes-

thesia.

The most commonly used agents in the past

to achieve sedoanalgesia have been a combina-

tion of fentanyl and midazolam. Propofol is also

capable of producing easily controllable levels

of sedation during a variety of procedures. All

these agents are cardiorespiratory depressants,

and safe sedation practices require that the pa-

tient be cared for by trained personnel who are

experienced in airway management, with appro-

priate monitoring of vital functions and docu-

mentation of care provided.82

FUTURE DIRECTIONS

The ability to provide long-lasting analgesia

from a single injection would be very useful.

Research has focused on two areas: the use

of naturally occurring agents such as tetrodot-

oxin (TTX)83 and the use of controlled-release

polymer microspheres containing bupiva-

caine.84,85

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CARDIOPULMONARY

RESUSCITATION

Cardiac arrest is defined as the sudden and un-

expected cessation of myocardial contractility for a

period of 60 seconds.1

About 1000 Americansexperience cardiac arrest daily.2 The most com-

mon cause of cardiac arrest is heart related in adults

and of respiratory origin in children. Regardless of

the cause of arrest, asphyxia is the proximate cause

of sudden death. The key to resuscitation is to

reverse asphyxia by transporting oxygen to tissues,

reoxygenating the myocardium, and restoring myo-

cardial contractility.

The technique of cardiopulmonary resuscitation

was described by Kouwenhoven, Jude, and

Knickerbocker in 1960. Even then it was recog-

nized that the most crucial of the hemodynamic

parameters was coronary perfusion pressure dur-

ing cardiopulmonary resuscitation.3 There is little

question that early intervention is vital for survival

in cardiorespiratory arrest. When basic life support

is instituted within 1 minute, there is a 99% chance

of surviving 24 hours. When life support has not

begun for 10 minutes after arresting, the likelihood

of survival plummets to approximately 1 in 10,000.4

There is some controversy regarding the mecha-

nism for restoring blood flow during cardiopulmo-

nary resuscitation. There are two basic theories.One theory holds that the heart is compressed

between the sternum and the thoracic spine, forc-

ing blood out of the heart during closed cardiac

massage.57 A second theory is that chest com-

pressions cause a general intrathoracic pressure

increasea thoracic pump and that blood flow

is not in fact dependent on ventricular compres-

sion.8 During chest compression the increase in

intrathoracic pressure is transmitted as increased

intravascular pressures that are differentially trans-

mitted peripherally as a result of venous valve clo-

sure.

Indications and Contraindications to CPR

Cardiopulmonary resuscitation should be insti-

tuted when cardiorespiratory arrest occurs, but it

should not be used to prolong the lives of patients

with terminal disease. CPR should be stopped whenresuscitation outside the hospital has been unsuc-

cessful and further inhospital measures have failed,unless the patient is a victim of hypothermia or

drowning.913

The type of cardiac arrest suffered by the patient

is a large determinant of outcome. When the causeof the arrest is asystole or EMD (electromechani-cal dissociation), survival rates are less than 60%.14

When the cause is ventricular fibrillation, survival is

15% to 35%.14,15

The two strongest predictors of outcome after

cardiac arrest are the occurrence of ventricular fi-brillation and the presence of a witness to the car-

diac arrest. Survival is much more likely if the car-

diac rhythm is ventricular fibrillation.15 Resuscita-tion efforts are usually unsuccessful in the event of

a pulseless rhythm. Asystole, idioventricular rhythmswith pulselessness, and electromechanical disso-

ciation are associated with survival rates after CPR

of 1.6%, 4.7%, and 6.9% respectively.15 Pulselessrhythms often are simple manifestations of cata-

strophic events such as cardiac rupture, rupture ofabdominal aortic aneurysm, global cardiac ischemia,

pulmonary embolism, and respiratory arrest.

Defibrillation is the single most important treat-ment for patients in ventricular fibrillation. Survival

rates higher than 35% have been reported whenCPR is initiated at the scene of the arrest and defibril-

lator-equipped rescue personnel respond within 3to 5 minutes.1618 Nevertheless, patients who suf-

fer cardiorespiratory arrest outside the hospital have

significantly lower survival rates compared with pa-tients who arrest while hospitalized. In out-of-hos-

pital arrests overall survival is 4% to 10%, while in-hospital arrests are successfully resuscitated 20%

of the time when patients are younger than 70

years old, but survival is only 3.4% for patientsolder than 70.19,20

CPR Techniques

Upon diagnosis of cardiac arrest, basiccardiop-

ulmonary resuscitation should begin immediately.The well-known treatment algorithm is A (airway),

B (breathing), C (circulation), and D (definitivetherapy). Stauffer21offers a comprehensive review

of airway management in basic and advanced life

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gers while the child is supine. The other technique

opposes the thumbs against the sternum, with the

hands wrapped around the childs chest. Circum-

ferential compression improves arterial and coro-

nary perfusion pressures. This is the technique

preferred by most authors.37,42,43

Zaritsky44offers a comprehensive review of the

pharmacology of pediatric resuscitation. The au-

thor recommends low-dose epinephrine (0.01 mg/

kg), and reserves calcium, atropine, sodium bicar-

bonate, and bretyllium for specific indications. The

drugs can be administered by peripheral IV infu-

sion, central IV infusion, endotracheally, or

intraosseally. A central line during CPR can be

dangerous because the torso of the small child is

constantly moving, and most clinicians recommend

intraosseous drug administration instead. In pedi-

atric CPR a childs bones should be considered anoncompressible venous plexus. Drug delivery

times by the intraosseous route are equal or faster

than by peripheral IV injection.37,44,45

According to Tibballs,45all drugs and resuscita-

tive fluids can be infused into the tibial bone mar-

row using an intraosseous needle. The current

doses of intraosseous drugs are the same as those

used for intravenous resuscitation, (Table 1) al-

though animal studies suggest that larger doses

are needed to achieve comparable hemodynamic

effects.45,46

Table 1

Intravenous Doses of Frequently UsedPediatric Resuscitative Drugs

(Data from Tibballs J: Endotracheal and intraosseous drug

administration for pediatric CPR. Aust Fam Phys 21:1477, 1992.)

Pharmacology

Epinephrine is the drug of choice in cardiopul-

monary resuscitation.4751 Epinephrine exhibits both

alpha and beta agonist activity. Its alpha 1 and

alpha 2 adrenergic effects improve myocardial and

cerebral blood flow by preventing arterial collapse

and increasing peripherovascular constriction and

peripherovascular resistance.5255 Currently the

recommended dose range in CPR is 0.0075 to

0.015 mg/kg every 5 minutes. Gonzales and

Ornato14and Cipolotti50recommend larger doses

of up to 1 mg given initially, followed by 35 mgevery 5 minutes until circulation is restored or CPR

is discontinued. Alternatively, epinephrine may be

given by continuous infusion of 0.20.6 mg/min

until there is response or cessation.

Dopamine is infused to maintain perfusion pres-

sures after epinephrine administration. The recom-

mended dose is 210 mg/kg/min, titrated to the

desired effect. Norepinephrine raises systolic and

diastolic pressure, increases peripherovascular re-

sistance, and may increase flow to the coronary

arteries by increasing peripherovascular resistance.The recommended dose of norepinephrine is 2

12 mg/min.

Phenylephrine raises systolic and diastolic blood

pressure and is a strong alpha agonist. The recom-

mended dosage of phenylephrine in CPR is 1040

mg/min.

Antiarrhythmic drugs such as lidocaine, procain-

amide, and bretyllium may be given as needed in

CPR, but always after electrical countershock.

Lidocaine is the drug of choice for initial control of

ventricular fibrillation or tachycardia after defibrilla-

tion. The initial dose of 1 mg/kg is given intrave-

nously or endotracheally, followed by titratable in-

fusion until it is no longer necessary.

Procainamide is a second choice to lidocaine

and is sometimes used for controlling ventricular

tachycardia in the absence of circulatory compro-

mise. Procainamide is administered slowly because

it may cause hypotension and resultant decreased

tissue perfusion. After the loading dose is adminis-

tered, 14 mg/min may be required, up to a maxi-

mum dose of 20 mg/min.

Bretyllium is another option in the managementof ventricular fibrillation or tachycardia after electri-

cal defibrillation. A bolus dose is given intrave-

nously over 15 minutes and may be repeated

every 15 minutes, thus doubling the initial dose.

Adenosine is now the drug of choice in paroxys-

mal supraventricular tachycardia. The initial dose is

6 mg given by IV push, followed with saline flush.

If the supraventricular tachycardia does not resolve

within 2 minutes, a second 12-mg dose may be

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given by IV push. A third and final 12-mg IV dose

may be required. Verapamil remains an extremely

efficacious drug but has well-known side effects,

including hypertension. In the event of adenosine

being unavailable, however, verapamil should be

the next line of treatment.

Atropine is the drug of choice in asystole andbradycardia. Bolus doses of 0.51 mg are given IV

or endotracheally every 25 minutes until a 2-mg

dose is attained in adults.

Isoproterenol is a second choice for temporary

control of bradycardia until a pacemaker can be

installed. Isoproterenol causes vasodilatation and

thus can induce hypotension, increasing the car-

diac workload and myocardial ischemia. Recom-

mended dose is 0.510 mg/min by IV infusion.

Buffers in general and sodium bicarbonate in

particular are condemned in CPR. Initially sodiumbicarbonate was intended to correct metabolic or

respiratory acidosis. Acidosis decreases myocar-

dial contractility, inhibits the hearts response to

catecholamines, increases cardiac workload, and

leads to myocardial ischemia. It is now known that

sodium bicarbonate corrects extracellular metabolic

acidosis at the expense of a transient increase in

intracellular acidosis and lower myocardial contrac-

tility. Its breakdown product is CO2, which raises

the arterial pCO2and adds to the burden of a re-

cently resuscitated heart.5157

After fibrillatory arrest of even brief duration, the

arterial pH may be normal but the intramyocardial

pH is decreased. Bicarbonate fails to reverse

intramyocardial acidosis, which is best corrected

by adequate ventilation. In CPR this means hyper-

ventilation, and therefore 100% oxygen should be

administered in a deliberate effort to compensate

for the metabolic acidosis until respiratory and cir-

culatory function are restored.

Calcium chloride is no longer recommended in

CPR except in extremely unusual cases. CaCl seems

to be minimally effective and may lead to cellulardeath by calcium accumulation.51

Outcome Studies

In a study of the overall success of advanced

cardiac life support (ACLS) and cardiopulmonary

resuscitation, Pepe et al58evaluated the effective-

ness of endotracheal intubation, pharmacologic in-

terventions, and ACLS training, among other fac-

tors, in raising survival rates after cardiac arrest.

Only early defibrillation by electroshock was found

to be of value in increasing long-term survival.

Despite the innovations mentioned earlier, namely

IAC-CPR, compression-decompression CPR, vestcompression, and ACLS, their benefit in terms of

extended lifespan is not supported by scientifically

rigorous evidence. While most authors believe

that ACLS probably does improve the outcome in

cardiac arrest, strong clinical data are lacking.58

Nonetheless, improved training of emergency per-

sonnel and continued interest in the patho-

mechanics of cardiac arrest will undoubtedly lead

to increased survival in years to come.

CPR in Your Office

It may be necessary to perform cardiopulmo-

nary resuscitation in either of these clinical settings:

1) after cardiac arrest of a patient or visitor to your

office on whom you have not operated (the coin-

cidental cardiac arrest); and 2) after cardiac arrest

of a patient on whom you are operating or on

whom you have recently operated. These circum-

stances may arise in your consulting office, clinic,

day-surgery facility, or hospital, and an anesthesi-

ologist may or may not be present. The obvious

issues arising when considering the above scenarios

are:

1) All physicians should have a crisis protocol

integrated into their office management scheme.

This is true even if no surgical procedures are per-

formed in your office. The public expects the phy-

sician (whatever his/her specialty interest) to be

adequately trained to respond to these basic life-

threatening situations in expert and timely fashion.The plan should include training of all the staff to a

proficient level in basic life-support and a well-re-

hearsed protocol for summoning immediate help

in the event of a cardiac arrest.

2) In offices where surgical procedures are per-

formed, it is essential to have ready access to the

appropriate resuscitation-care equipment. This

equipment includes airway-maintenance devices

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and instruments, oxygen, emergency resuscitation

drugs, and defibrillator. Automatic external

defibrillators (AED) have been among the most

exciting advances in CPR. Their key advantage is

the time saved to the initial countershock; at least 1

minute may be gained before defibrillation by skilled

paramedic teams. Whatever the knowledge andefficiency of the personnel present at the time of

the arrest, an automatic external defibrillator is an

extremely useful tool to have in your office.

3) In offices where surgical procedures are regu-

larly performed, an arrangement should be in

place for the transfer of a critically ill patient to

an appropriate nearby facility. In other words,

you must establish a relationship with your local

emergency room, ambulance service, and hospi-

tal ER before starting to do surgeries in your

office.

The algorithms appended to this booklet rep-

resent current guidelines for cardiopulmonary

resuscitation in various cardiac conditions.59,60

We suggest that you copy these pages and dis-

play them prominently in your work environ-

ment.

LOCAL ANESTHETICS

1. Fleming JA, Byck R, Barash PG: Pharmacology andtherapeutic applications of cocaine. Anesthesiology

73:518, 1990.

2. Gay GR et al: Cocaine: History, epidemiology, human

pharmacology and treatment. A perspective on a new

debut for an old girl. Clin Toxicol 8:149, 1975.

3. VanDyke C, Beck R: Cocaine. Sci Am 246:128, 1982.

4. Cousins MJ, Bridenbaugh PO (eds): Neural Blockade inClinical Anesthesia and Management of Pain. 2nd ed.Philadelphia, JB Lippincott, 1988.

5. Butterworth JF IV and Strichartz GR: Molecular mecha-nisms of local anesthesia: a review. Anesthesiology

72:711, 1990.

6. Reiz S, Nath S: Cardiotoxicity of local anesthetic agents.Br J Anaesth 58:736, 1986.

7. Hille B: Local anesthetics: hydrophilic and hydrophobicpathways for the drug receptor reaction. J Gen Physiol

69:497, 1977.

8. Seelig A: The use of monolayers for simple and quantita-tive analysis of lipid-drug interactions exemplified with

dibucaine and substance P. Cell Biol Intl Rep 14:369, 1990.

9. Smith ICP, Auger M, Jarrell HC: Molecular details ofanesthetic-lipid interaction. Ann NY Acad Sci 625:668,

1991.

10. Khodorov BI: Role of inactivation in local anesthetic

action. Ann NY Acad Sci 625:224, 1991.

11. Leonard RJ et al: Reverse pharmacology of the nicotinicacetylcholine receptor. Ann NY Acad Sci 625:588, 1991.

12. Covino BG: Local anesthesia (Part 1). N Engl J Med286:975, 1972.

13. Cousins MJ, Mather LE: Clinical pharmacology of local

anesthetics. Anaesth Intensive Care 8:257, 1980.

14. Covino BG: Pharmacology of local anesthetic agents.

Ration Drug Ther 21:1, 1987.

15. Covino BG: Physiology and pharmacology of localanesthetic agents. Anesth Prog 4:98, 1981.

16. Truant AP, Takman B: Differential physical-chemical and

neuropharmacologic properties of local anesthetic agents.Anesth Analg 38:478, 1969.

17. Tucker GT: Binding of anilide-type local anesthetic in

human plasma: I. Relationships between binding, physico-chemical properties, and anesthetic activity. Anesthesi-

ology 33:287, 1970.

18. Brown RD: The failure of local anesthesia in acuteinflammationSome recent concepts. Br Dent J 151:47,

1981.

19. Yan AC, Newman RD: Bupivacaine-induced seizures and

ventricular fibrillation in a 13-year-old girl undergoing

wound debridement. Pediatr Emerg Care 14(5):354, 1998.20. Weinberg GL, Laurito CE, Geldner P, et al: Malignant

ventricular dysrhythmias in a patient with isovaleric aci-demia receiving general and local anesthesia for suction

lipectomy. J Clin Anesthesiol 9:668, 1997.

21. Klein JA: Anesthesia: modified liposuction technique.Dermatol Clin 8(3):421, 1990.

22. Siegel RJ, Vistnes LM, Iverson RE: Effective hemostasiswith less epinephrine. An experimental and clinical study.

Plast Reconstr Surg 51:129, 1973.

23. Cederholm I, Evers H, Lofstrom JB: Skin blood flow afterintradermal injection of ropivacaine in various concentra-

tions with and without epinephrine evaluated by laserDoppler flowmetry. Reg Anesth 17:322, 1992.

24. Reinisch J, Myers B: The effect of local anesthesia withepinephrine on skin flap survival. Plast Reconstr Surg54:324, 1974.

25. Wu G, Calamel PM, Shedd DP: The hazards of injecting

local anesthetic solutions with epinephrine in f laps. PlastReconstr Surg 62:396, 1978.

26. Bromage PR: Improved conduction blockade in surgeryand obstetrics: carbonated local anesthetics. Can Med

Assoc J 97(23):1377, Dec 2, 1967.

27. Morison DH: A double-blind comparison of carbonatedlidocaine and lidocaine hydrochloride in epidural anaes-

thesia. Can Anaesth Soc J 28(4):387, 1981.

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28. Hickey R, Knape KG, Blanchard J, et al: Lidocainehydrocarbonate is not superior to lidocaine hydrochlo-ride in interscalene brachial plexus block. Reg Anesth15(4):194, 1990.

29. Tezlaff JE, Yoon HJ, Brems J, Javorsky T: Alkalinization ofmepivacaine improves the quality of motor block asso-ciated with interscalene brachial plexus anesthesia for

shoulder surgery. Reg Anesth 20(2):128, 1995.30. Capogna G, Celleno D, Laudano D, Giunta F: Alkaliniza-tion of local anesthetics. Which block, which localanesthetic? Reg Anesth 20(5):369, 1995.

31. Bedder MD, Kozody R, Craig DB: Comparison ofbupivacaine and alkalinized bupivacaine in brachial plexusanesthesia. Anesth Analg 67(1):48, 1988.

32. Benlabed M, Jullien P, Guelmi K, et al: Alkalinization of0.5% lidocaine for intravenous regional anesthesia. Reg

Anesth 15(2):59, 1990.33. Candido KD, Winnie AP, Covino BG, et al: Addition of

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34. Chow MY, Sia AT, Koay CK, Chan YW: Alkalinization of

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36. Cohen SE, Thurlow A: Comparison of a chloroprocainebupivacaine mixture with chloroprocaine and bupivacaineused individually for obstetric epidural analgesia. Anes-thesiology 51(4):288, 1979.

37. De Jong RH, Bonin JD: Mixtures of local anesthetics areno more toxic than the parent drugs. Anesthesiology54:177, 1981.

38. Kennedy KS, Cave RH: Anaphylactic reaction to lidocaine.Arch Otolaryngol Head Neck Surg 112:671, 1986.

39. Tucker GT, Mather LE: Properties, absorption, and dispo-sition of anesthetic agents. In: Cousins MJ, BridenbaughPO (eds), Neural Blockade in Clinical Anesthesia andManagement of Pain,3rd Ed. Philadelphia, Lippincott-Raven, 1998. Part 1, Ch 3, p 55-96.

40. Momota Y, Artru AA, Powers KM, et al: Posttreatmentwith propofol terminates lidocaine-induced epileptiformelectroencephalogram activity in rabbits: effects oncerebrospinal fluid dynamics.Anesth Analg 87:900, 1998.

41. Mehra P, Caiazzo A, Maloney P: Lidocaine toxicity.Anesth Prog 45:38, 1998.

42. Englesson S: The influence of acid-base changes on centralnervous system toxicity of local anaesthetic agents. I. Anexperimental study in cats. Acta Anaesthesiol Scand18(2):79, 1974.

43. Englesson S, Grevsten S: The influence of acid-base changeson central nervous system toxicity of local anaestheticagents. II. Acta Anaesthesiol Scand 18(2):88, 1974.

44. Bernards CM, Carpenter RL, Kenter ME, et al: Effect ofepinephrine on central nervous system and cardiovascu-lar system toxicity of bupivacaine in pigs. Anesthesiology71(5):711, 1989.

45. [No authors listed]: Cardiotoxicity of local anaestheticdrugs. Lancet 2(8517):1192, Nov 22, 1986.

46. Morishima HO, Pedersen H, Finster M, et al: Bupivacainetoxicity in pregnant and nonpregnant ewes. Anesthesiol-ogy 63:134, 1985.

47. Solomon D, Bunegin L, Albin M: The effect of magnesiumsulfate administration on cerebral and cardiac toxicity ofbupivacaine in dogs. Anesthesiology 72:341, 1990.

48. Albright GA: Cardiac arrest following regional anesthesiawith etidocaine or bupivacaine. Anesthesiology 51:285,1979.

49. Tanz RD, Heskett T, Loehning RW, Fairfax CA: Comparative

cardiotoxicity of bupivacaine and lidocaine in the isolated,perfused mammalian heart. Anesth Analg 63:549, 1984.

50. Moller RA, Covino BG: Cardiac electrophysiologic ef-fects of articaine compared with bupivacaine andlidocaine. Anesth Analg 76:1266, 1993.

51. Clarkson C, Hondeghem L: Mechanism for bupivacainedepression of cardiac conduction: fast block of sodiumchannels during the action potential with slow recoveryfrom block during diastole.Anesthesiology 62:396, 1985.

52. Atlee JL III, Bosnjak ZJ: Mechanisms for cardiac dysrhythmiasduring anesthesia. Anesthesiology 72:347, 1990.

53. Thomas RD, Behbehani MM, Coyle DE, et al: Cardiovas-cular toxicity of local anesthetics: an alternative hypoth-esis. Anesth Analg 65:444, 1986.

54. Feldman HS, Arthur GR, Pitkanen M, et al: Treatment of

acute systemic toxicity after the rapid intravenous injec-tion of ropivacaine and bupivacaine in the conscious dog.

Anesth Analg 73:373, 1991.55. Chen AH: Toxicity and allergy to local anesthesia. CDAJ

26(9):683, 1998.56. Bernards CM, Artru AA: Effect of intracerebroventricular

picrotoxin and muscimol on intravenous bupivacainetoxicity. Evidence supporting central nervous systeminvolvement in bupivacaine cardiovascular toxicity.

Anesthesiology 78:902, 1993.57. Bernards CM, Carpenter RL, Rupp SM, et al: Effect of

midazolam and diazepam premedication on central ner-vous system and cardiovascular toxicity of bupivacainein pigs. Anesthesiology 70(2):318, 1989.

58. Bernards CM, Artru AA: Hexamethonium and midazolamterminate dysrhythmias and hypertension caused byintracerebroventricular bupivacaine in rabbits. Anesthe-siology 74:89, 1991.

59. Scott DB, Lee A, Fagan D, et al: Acute toxicity ofropivacaine compared with that of bupivacaine. Anesth

Analg 69:563, 1989.

60. McClure JH: Ropivacaine. Br J Anaesth 76:300, 1996.61. Knudsen K, Beckman Suurkula M, Blomberg S, et al:

Central nervous and cardiovascular effects of i.v. infu-sions of ropivacaine, bupivacaine and placebo in volun-teers. Br J Anaesth 78:507, 1997.

62. Klein SM, Greengrass RA, Steele SM, et al: A comparisonof 0.5% bupivacaine, 0.5% ropivacaine, and 0.75%ropivacaine for interscalene brachial plexus block.Anesth

Analg 87(6):1316, 1998.63. Sia AT, et al: Epidural 0.2% ropivacaine for labour

analgesia: parturient-controlled or continuous infusion?Anaesth Intensive Care 27(2):154, 1999.

64. Arlock P: Actions of three local anaesthetics: lidocaine,bupivacaine and ropivacaine on guinea pig papillarymuscle sodium channels (Vmax). Pharmacol Toxicol63(2):96, 1988.

65. Kohane DS, Sankar WN, Shubina M, et al: Sciatic nerveblockade in infant, adolescent, and adult rats: a compari-son of ropivacaine with bupivacaine. Anesthesiology

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Fig 1A-1. Primary and Secondary Mechanisms of Cardiopulmonary Arrest.

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Fig 1B-1. Treatment of Ventricular Fibrillation.

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Fig 1B-2. Additional Antifibrillatory Measures.

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Fig 1C-1. Treatment of Sustained Ventricular Tachycardia.

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Fig 1D-1. Treatment of Bradycardia/EMD/Asystole.

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Fig 1E-1. Treatment of Supraventricular Tachyarrhythmias.

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Fig 1F-1. Use of the AED in Cardiac Arrest.

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