LOCAL ANESTHETICS

Thomas M Vaughan FANZCA

CARDIOPULMONARY RESUSCITATION AND ADVANCED CARDIAC LIFE SUPPORT

James Burt FRACS

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 Conquistadors brought the leaves to Europe and by the mid-1800s cocaine was widely praised for its capacity to increase stamina and to alleviate hunger 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 anesthetic (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 for regional 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 transferring the mans addiction from morphine to cocaine. The drug could create crippling dependence and psychosis, and there were multiple reports of systemic 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 epinephrine. 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, longacting local anesthetics, but their potential for toxicity limited their usefulness. They found their niche in the practice of spinal anesthesia, where only small 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 pseudocholinesterase. This enzyme catalyzed the formation 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 amino ester 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

SRPS Volume 9, Number 4

potency and its ability to provide significantly longer anesthesia than was possible with either lidocaine or mepivacaine. In 1971, etidocaine was synthesized. This was also a long-acting agent like bupivacaine and produced a more profound motor block. The most recent addition to the local anesthetic armory is ropivacaine. It has been prepared 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 cardiotoxic than bupivacaine.4

of conduction is directly proportional to the crosssectional area of the axonie, the thicker the axon, the larger the Schwann cell, the greater the internodal distance, and the faster the impulse conduction. 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).

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 layers 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 2. Impulse transmission along unmyelinated (top) and myelinated (bottom) nerves.

In clinical practice local anesthetics must diffuse across a number of structures before reaching 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 barrier to local anesthetics. One or more perineural bundles are covered by an outermost, easily permeable connective tissue layer (epineurium). This layer also contains the nutritional blood vessels 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.

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

SRPS Volume 9, Number 4

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 perineurium exists 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 a graded depolarization of that terminal. This spreads to the axon proper, where an all-or-none depolarization action potential is produced if transmembrane potential reaches the required threshold voltage. If threshold is reached, then the action potential is propagated to the proximal terminal, where a graded 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 distribution of sodium and potassium ions between the inside and outside of the cell, and the high membrane permeability to potassium ions but not to sodium ions. Bernstein applied the Nernst equation to explain the transmembrane potential of excitable 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,

An expanded equation, the Goldman-HodgkinKatz equation, was formulated to describe the transmembrane potential of membranes permeable to several ionic species (eg, nerve axon). This equation illustrates that the actual value of transmembrane 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 concentration gradient for sodium ion. The axon in its resting 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 cellular energy. If this pump is not operative, the membrane potential would slowly disappear. In summary, the primary factors responsible for the transmembrane potential are: 1. A membrane that is somewhat selectively permeable 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 sodium ions passively enter it. Depolarization and Repolarization The electrical messages of excitable cells are changes of the electrical potential difference across the cell surface membrane. Neurophysiologists 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 stimulus for an action potential is a membrane depolarization larger than the threshold level. The response is not graded. In contrast, slow potentials do not propagate at a constant amplitude over large distances, but are effective in the immediate environment. They can

where E = membrane potential R = gas constant (8.315 joules/K) T = temperature (Kelvin) F = Faradays constant (9.65 x 104 coulombs) ln = natural logarithm [K+] = potassium ion concentration inside (i) and outside (o) the cell

SRPS Volume 9, Number 4

be depolarizing or hyperpolarizing and originate in chemical synapsespresynaptically in response to action potentials invading the presynaptic terminal and postsynaptically in response to the neurotransmitter at the postsynaptic membrane. They also originate in sensory and other receptors in response to the appropriate stimuli. Slow potentials result from structural rearrangement of membrane proteins, culminating in change in the ionic permeability of the cell membrane. Action potentials are normally initiated by depolarizing slow potentials. At threshold, a process called activation leads to the opening of the sodium permeability pathway and an inward sodium current is generated down both a chemical and an electrical gradient. Simultaneously, a slower process termed inactivation is initiated, and this leads to closing of the sodium permeability pathway, with the net result being a transient inward current. Once activated, the sodium permeability pathway cannot be reactivated until the membrane has returned to its resting value for a brief period. The sodium conductance changes are accompanied by outward flow of potassium ions related to the voltage-dependent activation of a K+ permeability pathway. The potassium ion process is slower than the sodium ion process and has no inactivation process. Depolarization is caused by the opening of the sodium channel. Repolarization is related to an outward K+ current; once the resting membrane potential is reached, the K+ flux ceases. The sodium ionpotassium ion ATPase is activated by elevation of intracellular sodium ion. It will remove sodium ion and restore extracellular potassium ion, which

generates an outward current and hyperpolarizes the cell. Action potentials are conducted along an axon in a self-generating process. One area of an axon depolarizes the adjacent membrane to threshold. This is the case for unmyelinated fibers. In myelinated fibers, the conduction of an action potential is 7X to 100X faster. Myelinated axons are surrounded by myelin formed by Schwann cells wrapped tightly around the axon. This provides an insulating layer that is broken every 0.2 to 1.0 mm for a length of about 5 mcm in regions called nodes of Ranvier. Sodium channels are concentrated in the nodal region. An action potential jumps from one node of Ranvier to the nexta process called saltatory conduction (Table 1). Ion Channels The concept of ionic channels as discrete ionselective, molecular pores is universally accepted. Channels that can change from being primarily nonconductive to being conductive are called gated channels. The channels can be voltage-gated or ligand-gated. In voltage-gated channels conductance change is induced by electrical forces, whereas in ligand-gated channels the change is induced by a ligand binding to the receptor. Voltage-gated sodium and potassium channels are of greatest importance in terms of depolarization and repolarization of axonal membranes. The voltagegated sodium channel is generally accepted as the target of local anesthetics. Sodium channels have four repeating alpha subunits and single beta-1 and beta-2 subunits.

Table 1 Classification and Physiologic Characteristics of Nerve Fibers

(Reprinted with permission from Cousins MJ, Bridenbaugh PO (eds): Neural Blockade in Clinical Anesthesia and Management of Pain. 3rd Ed. Philadelphia, Lippincott-Raven, 1998.)

SRPS Volume 9, Number 4

The beta subunits apparently have a modulatory influence on the alpha subunits. The alpha subunits extend through the membrane and form the four sides of the Na+ selective transmembrane 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 channels (phasic block) more than resting channels (tonic block). The modulated receptor hypothesis has been advanced to explain this phenomenon. The hypothesis rests on the notion that sodium channels normally respond to membrane depolarizations by passing through defined conformational states: beginning at rest (R), activating through closed intermediate forms (C), to reach an open form (O), and then closing to an inactivated (I) state.5

Locus of Action The actual receptor for local anesthetic binding 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 channel itself. 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 membrane but strongly block sodium currents when applied to the cytoplasmic side. This binding site can be approached either by a hydrophilic pathway, 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 intermediate chain, and an amine end (Fig 3).

RttCtOtI
According to the modulated receptor hypothesis, 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 stabilizes the channels in a nonconducting state and increasingly so with each stimulating pump. Eventually some anesthetic-bound channels will return to their resting equilibrium and a steady-state level of phasic block will be reached wherein increased inhibition 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 receptor affinity for the local anesthetic remains high, but access to the receptor by the local anesthetic is limited through channel guards.

Fig 3. Chemical configuration of local anesthetics showing the two 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 characteristics, and its clinical activity.12

SRPS Volume 9, Number 4

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 allergic 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 reactions. Amino amides are broken down in the liver, are stable in solution, and only rarely cause allergic reactions.14

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 membrane and the more rapidly it produces its local anesthetic effect.

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 shortacting. 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

Fig 4. Chemical structure of some common local anesthetics.

SRPS Volume 9, Number 4

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 the free 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 Brown18 studied the phenomenon of local anesthetic 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 anesthetic 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 chloroprocaine acts more quickly than procaine because it diffuses faster through nonneural tissue. Also lidocaine, which in the laboratory is similar to prilocaine in pKa value and onset of action, is noted to have a much faster anesthetic 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 vasoconstriction, but at clinically relevant concentrations local anesthetics except cocaine tend to be vasodilatory. 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 equivalent 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 Vasoconstrictor Epinephrine is frequently added to local anesthetic 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 by adding 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 commonly used because they are readily available. Laser Doppler flowmetry studies have determined that injections of ropivacaine and epineph-

SRPS Volume 9, Number 4

rine do not reduce skin blood flow as much as epinephrine alone; that is, the addition of ropivacaine diminishes the vasoconstrictive effect of epinephrine.23 Epinephrine use is not without risk. Cardiac arrhythmias are a concern in persons who have predisposing intrinsic heart disease or when epinephrine is administered concomitantly with agents that sensitize the myocardium (eg, halothane). Epinephrine may precipitate a hypertensive crisis in patients who have hypertension or hyperthyroidism. High concentrations of epinephrine may produce local tissue necrosis or trigger rebound hyperemia, resulting in bleeding or hematoma as the effect resolves. At dilutions of 1:200,000, epinephrine 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. Carbonation 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,26 but more recent double-blind studies fail to demonstrate an advantage.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 strategy 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 other than 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, compounding solutions allows single-dose techniques for epidural or caudal block in cases where a continuous 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 chloroprocainebupivacaine was significantly shorter than that obtained with bupivacaine alone, while time to onset was longer than that with chloroprocaine 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 shortacting 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 anesthetics capitalize on different routes of disposition, permitting 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 concentration 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 influences the systemic absorption; the highest plasma concentration of local anesthetic is seen after intercostal blocks. Much lower levels are seen in the plasma after sciatic and femoral nerve blocks, with epidural 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 epinephrine, 1:1,000,000. Klein21 estimates the maximum

SRPS Volume 9, Number 4

safe dosage of local anesthetic to be 35 mg/Kg, and cautions against using bupivacaine for this purpose. Case reports of severe toxicity with relatively 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

drug or from an excessive dosage. Toxicity secondary to extravascular administration is related to the pharmacokinetic properties of the drug. Most toxic reactions involve the central nervous system (CNS). Local anesthetic-induced cardiovascular depression occurs less frequently but tends to be more serious and more difficult to manage. CNS Toxicity

TOXICITY

Systemic Toxicity Local anesthetics vary considerably in their potential for causing systemic toxic reactions (Fig 5).

The response to elevated levels of local anesthetic 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 progressing to generalized tonic-clonic convulsion.40,41 With further increased levels of anesthetic in the CNS, a depression phase ensues, with drowsiness, unconsciousness, and respiratory arrest. When there is a very rapid rise in the concentration 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 binding, 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 addition 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

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

SRPS Volume 9, Number 4

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 implications of this difference are that the early warning signs of CNS toxicity from bupivacaine occur at a blood level much lower than that associated with cardiovascular collapse. Hypomagnesemia may enhance the cardiotoxicity of bupivacaine. This may explain the increased susceptibility of the pregnant patient who is relatively hypomagnesemicto the cardiotoxic effects of bupivacaine.47 In 1979 Albright48 demonstrated the correlation between cardiovascular toxicity and the longeracting, highly lipid-soluble local anesthetics, bupivacaine and etidocaine. Of 49 fatal cases, 43% involved bupivacaine. The FDA subsequently somewhat 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 administering these drugs, use of a test dose and incremental dosing. Local anesthetics affect both the conduction pathways and contractility. Lidocaine, which is used clinically as an antiarrhythmic, decreases the maximal rate of depolarizationthe Vmaxwithout altering resting membrane potential of cardiac muscle. In isolated 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 reentrant 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 application of local anesthetics within vasomotor and cardioactive regionsin the medullaleads to hypotension, bradycardia, and ventricular arrhythmias.53,54 Bupivacaine 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 premedication with a benzodiazepine.57 Once started, the arrhythmias can also be terminated by CNS administration of midazolam, a GABAergic stimulant.58 The majority of clinical reports of bupivacaine cardiac toxicity have been in pregnant patients. Morishima and colleagues46 found 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 profile.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 models65,66 and children.67 In human volunteer studies, ropivacaine was associated with higher tolerated doses. In addition, 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 probable intravascular injection of ropivacaine during interscalene brachial plexus block was associated with unconsciousness, seizure activity, and hypotension. 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 negative aspiration tests. The use of a test dose contain-

10

SRPS Volume 9, Number 4

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 concentration of bupivacaine is associated with decrease in the R wave amplitude and increase in the QRS complex. Blood pressure is insensitive to increasing blood levels of local anesthetic. The pressure seems to be well maintained by an increase in systemic vascular resistance despite a 40% decrease in cardiac output.71 The use of fractionated doses allows earlier detection 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 vertebral artery during interscalene approach to brachial plexus.72 In the conscious patient, early warning signs of intravascular injection include circumoral numbness and tinnitus. Treatment consists of stopping the injection, cardiovascular monitoring, administration of O2, and encouragement to breathe at a normal minute-volume. 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 anesthetic are outlined in Table 3. Appropriate monitoring and availability of personnel skilled in advanced cardiac life support are mandatory for all major regional techniques.

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

Local Tissue Toxicity Histologic studies demonstrate reversible myotonic effects in animals and humans when local anesthetics are injected into skeletal muscle.73 Miscellaneous Tonic Responses In doses greater than 600 mg, prilocaine has been associated with the development of methemoglobinemia because one of its metabolites, hydroxylated D-toluidine, reduces any hemoglobin.74,75 Methemoglobinemia manifests clinically 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

11

SRPS Volume 9, Number 4

Table 3 Differential 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.)

intranasal surgerythe mucosal shrinkage greatly facilitates surgical accessand that makes cocaine popular with otolaryngologists and plastic surgeons.76,77 The sympathomimetic effects of cocaine are responsible for cardiovascular stimulation, which may result in myocardial ischemia or even infarction in susceptible patients.78,79 In the CNS, cocaine blocks reuptake of dopamine, leading to increased neurotransmission at the synapse and euphoria,80 which is the basis for the highly addictive nature of this drug. ALLERGIES The amino ester drugs such as procaine, which are p-aminobenzoic acid derivatives, may produce allergic reactions. True allergy to amino amide agents is extremely rare, although these agents may contain a preservative, methylparaben, whose chemical structure is similar to that of PABA.81 SEDOANALGESIA The use of sedative drugs facilitates the performance of surgery under local anesthesia.

Pain from the procedure due to inadequate block should be managed by supplementation of the block or by conversion to general anesthesia. The most commonly used agents in the past to achieve sedoanalgesia have been a combination 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 patient be cared for by trained personnel who are experienced in airway management, with appropriate monitoring of vital functions and documentation 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 tetrodotoxin (TTX) 83 and the use of controlled-release polymer microspheres containing bupivacaine. 84,85

12

SRPS Volume 9, Number 4

CARDIOPULMONARY RESUSCITATION
Cardiac arrest is defined as the sudden and unexpected cessation of myocardial contractility for a period of 60 seconds.1 About 1000 Americans experience cardiac arrest daily.2 The most common 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 myocardial contractility. The technique of cardiopulmonary resuscitation was described by Kouwenhoven, Jude, and Knickerbocker in 1960. Even then it was recognized that the most crucial of the hemodynamic parameters was coronary perfusion pressure during 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 mechanism for restoring blood flow during cardiopulmonary resuscitation. There are two basic theories. One theory holds that the heart is compressed between the sternum and the thoracic spine, forcing blood out of the heart during closed cardiac massage.57 A second theory is that chest compressions cause a general intrathoracic pressure increasea thoracic pump and that blood flow is not in fact dependent on ventricular compression.8 During chest compression the increase in intrathoracic pressure is transmitted as increased intravascular pressures that are differentially transmitted peripherally as a result of venous valve closure.

with terminal disease. CPR should be stopped when resuscitation outside the hospital has been unsuccessful 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 cause of the arrest is asystole or EMD (electromechanical 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 fibrillation and the presence of a witness to the cardiac arrest. Survival is much more likely if the cardiac rhythm is ventricular fibrillation.15 Resuscitation efforts are usually unsuccessful in the event of a pulseless rhythm. Asystole, idioventricular rhythms with pulselessness, and electromechanical dissociation are associated with survival rates after CPR of 1.6%, 4.7%, and 6.9% respectively.15 Pulseless rhythms often are simple manifestations of catastrophic events such as cardiac rupture, rupture of abdominal aortic aneurysm, global cardiac ischemia, pulmonary embolism, and respiratory arrest. Defibrillation is the single most important treatment for patients in ventricular fibrillation. Survival rates higher than 35% have been reported when CPR is initiated at the scene of the arrest and defibrillator-equipped rescue personnel respond within 3 to 5 minutes.1618 Nevertheless, patients who suffer cardiorespiratory arrest outside the hospital have significantly lower survival rates compared with patients who arrest while hospitalized. In out-of-hospital arrests overall survival is 4% to 10%, while inhospital arrests are successfully resuscitated 20% of the time when patients are younger than 70 years old, but survival is only 3.4% for patients older than 70.19,20

CPR Techniques Upon diagnosis of cardiac arrest, basic cardiopulmonary resuscitation should begin immediately. The well-known treatment algorithm is A (airway), B (breathing), C (circulation), and D (definitive therapy). Stauffer21 offers a comprehensive review of airway management in basic and advanced life

Indications and Contraindications to CPR Cardiopulmonary resuscitation should be instituted when cardiorespiratory arrest occurs, but it should not be used to prolong the lives of patients

13

SRPS Volume 9, Number 4

support and stepwise instructions on the many ways to deliver oxygen to the patient. The American Heart Association publishes a list of guidelines for cardiopulmonary resuscitation, compression, ventilations, etc. AHA guidelines generally recommend a rate of 80 to 100 compressions per minute. Stauffer21, Tresch20 and Melker22 believe that the best method to deliver oxygen is via an endotracheal tube during CPR. Melker22 recommends a single slow breath rather than two incremental breaths and pausing for 1 to 1.5 seconds for ventilation after every fifth chest compression. Recently there has been considerable interest in active compression-decompression CPR, which studies associate with increased 24-hour survival rates.2328 However, the benefit of active compression-decompression CPR in extending long-term survival is still in question.5,6,2328 In patients with high-risk cardiac arrhythmias (tachyarrhythmias), simple coughing can prolong consciousness for sustained periods and can even lead to resolution of the arrhythmia and restoration of normal cardiac rhythm.29 The interposed abdominal compression technique as an adjunct to cardiopulmonary resuscitation has generated considerable interest since our last review. Multiple studies show that even during optimally performed standard CPR, total blood flow is only 20% to 35% of normal and coronary perfusion pressure is often less than 15 mmHg, far below the level necessary for a return of spontaneous circulation. Interposed abdominal compressions are used in an attempt to increase peripherovascular resistance and thereby increase systemic perfusion of vital organs. Initially static abdominal binding was used to inhibit diastolic runoff from the thoracic aorta to nonvital vascular beds. Fatal hepatic trauma resulted and it was abandoned. A more attractive way of achieving the hemodynamic benefit of abdominal pressure while placing the viscera at minimal risk for trauma is via abdominal compression during the diastolic phase of CPRie, between chest compressions. This is known as interposed abdominal compression-cardiopulmonary resuscitation (IAC-CPR).3035 In these authors hands, IACCPR has had a positive effect on short-term survival after cardiac arrest, although the impact of IACCPR on long-term survival is still not clear.

Halperin35 adds a pneumatic vest for chest compression to increase aortic pressure and coronary perfusion pressure. Preliminary studies show that return of spontaneous circulation is more likely with vest CPR than with continued manual CPR. When administered late in the resuscitation effort, the technique is associated with increased shortterm survival, but like the other methods its value in long-term survival after cardiac arrest is not clear.35 The best method for monitoring the effectiveness of chest compression in stimulating coronary perfusion during cardiopulmonary resuscitation is measurement of the end-tidal carbon dioxide concentration. Clinical data strongly support the use of end tidal CO2 levels to detect changes in pulmonary blood flow during cardiopulmonary resuscitation.36 End tidal CO2 is the product of generated CO2, alveolar ventilation, and pulmonary blood flow. If ventilation rate and inspired CO2 are constant and CO2 production is assumed to be constant, an increase or decrease in the end tidal CO2 should reflect an increase or decrease in pulmonary blood flowie, cardiac output.36

CPR in Children Leuthner, Jansen, and Hageman37 provide an overview of CPR in newborns. They point out that cardiopulmonary resuscitation is difficult in children and adults.37,38 Although children do require more chest compressions per minute than adult patients, new guidelines recommend 90 compressions per minute instead of 120 for the neonate, with a 3:1 ratio of compressions to ventilations. Indications for chest compressions remain the same, that is, to begin when heart rate is less than 60 per minute. Positive pressure ventilation and 100% oxygen should always be given to children. The preferred method for ventilation is endotracheal tube. When endotracheal intubation is not possible, then mouthto-nose breathing is considered more effective than mouth-over-mouth-and nose and-mouth-over mouth.3941 Positive pressure ventilation and 100% oxygen should always be administered before trying any drug therapy.37 There are two recommended techniques for chest compression in small children. One simply consists of depressing the sternum with two fin-

14

SRPS Volume 9, Number 4

gers while the child is supine. The other technique opposes the thumbs against the sternum, with the hands wrapped around the childs chest. Circumferential compression improves arterial and coronary perfusion pressures. This is the technique preferred by most authors.37,42,43 Zaritsky44 offers a comprehensive review of the pharmacology of pediatric resuscitation. The author recommends low-dose epinephrine (0.01 mg/ kg), and reserves calcium, atropine, sodium bicarbonate, and bretyllium for specific indications. The drugs can be administered by peripheral IV infusion, 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 pediatric CPR a childs bones should be considered a noncompressible venous plexus. Drug delivery times by the intraosseous route are equal or faster than by peripheral IV injection.37,44,45 According to Tibballs,45 all drugs and resuscitative fluids can be infused into the tibial bone marrow using an intraosseous needle. The current doses of intraosseous drugs are the same as those used for intravenous resuscitation, (Table 1) although animal studies suggest that larger doses are needed to achieve comparable hemodynamic effects.45,46

Table 1 Intravenous Doses of Frequently Used Pediatric 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 cardiopulmonary 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 Ornato14 and Cipolotti50 recommend larger doses of up to 1 mg given initially, followed by 35 mg every 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 pressures after epinephrine administration. The recommended dose is 210 mg/kg/min, titrated to the desired effect. Norepinephrine raises systolic and diastolic pressure, increases peripherovascular resistance, 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 recommended dosage of phenylephrine in CPR is 1040 mg/min. Antiarrhythmic drugs such as lidocaine, procainamide, 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 defibrillation. The initial dose of 1 mg/kg is given intravenously or endotracheally, followed by titratable infusion 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 compromise. Procainamide is administered slowly because it may cause hypotension and resultant decreased tissue perfusion. After the loading dose is administered, 14 mg/min may be required, up to a maximum dose of 20 mg/min. Bretyllium is another option in the management of ventricular fibrillation or tachycardia after electrical defibrillation. A bolus dose is given intravenously over 15 minutes and may be repeated every 15 minutes, thus doubling the initial dose. Adenosine is now the drug of choice in paroxysmal 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

15

SRPS Volume 9, Number 4

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 and bradycardia. 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 cardiac workload and myocardial ischemia. Recommended dose is 0.510 mg/min by IV infusion. Buffers in general and sodium bicarbonate in particular are condemned in CPR. Initially sodium bicarbonate was intended to correct metabolic or respiratory acidosis. Acidosis decreases myocardial 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 contractility. Its breakdown product is CO2, which raises the arterial pCO2 and adds to the burden of a recently 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 hyperventilation, and therefore 100% oxygen should be administered in a deliberate effort to compensate for the metabolic acidosis until respiratory and circulatory 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 cellular death by calcium accumulation.51

ness of endotracheal intubation, pharmacologic interventions, and ACLS training, among other factors, 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, vest compression, 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 personnel and continued interest in the pathomechanics of cardiac arrest will undoubtedly lead to increased survival in years to come.

CPR in Your Office It may be necessary to perform cardiopulmonary 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 coincidental cardiac arrest); and 2) after cardiac arrest of a patient on whom you are operating or on whom you have recently operated. These circumstances may arise in your consulting office, clinic, day-surgery facility, or hospital, and an anesthesiologist 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 performed in your office. The public expects the physician (whatever his/her specialty interest) to be adequately trained to respond to these basic lifethreatening 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-rehearsed protocol for summoning immediate help in the event of a cardiac arrest. 2) In offices where surgical procedures are performed, it is essential to have ready access to the appropriate resuscitation-care equipment. This equipment includes airway-maintenance devices

Outcome Studies In a study of the overall success of advanced cardiac life support (ACLS) and cardiopulmonary resuscitation, Pepe et al58 evaluated the effective-

16

SRPS Volume 9, Number 4

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 and efficiency 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 regularly 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 hospital ER before starting to do surgeries in your office. The algorithms appended to this booklet represent current guidelines for cardiopulmonary resuscitation in various cardiac conditions.59,60 We suggest that you copy these pages and display them prominently in your work environment.

BIBLIOGRAPHY
LOCAL ANESTHETICS 1. Fleming JA, Byck R, Barash PG: Pharmacology and therapeutic applications of cocaine. Anesthesiology 73:518, 1990. 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. VanDyke C, Beck R: Cocaine. Sci Am 246:128, 1982. Cousins MJ, Bridenbaugh PO (eds): Neural Blockade in Clinical Anesthesia and Management of Pain. 2nd ed. Philadelphia, JB Lippincott, 1988. Butterworth JF IV and Strichartz GR: Molecular mechanisms of local anesthesia: a review. Anesthesiology 72:711, 1990. Reiz S, Nath S: Cardiotoxicity of local anesthetic agents. Br J Anaesth 58:736, 1986. Hille B: Local anesthetics: hydrophilic and hydrophobic pathways for the drug receptor reaction. J Gen Physiol 69:497, 1977. Seelig A: The use of monolayers for simple and quantitative analysis of lipid-drug interactions exemplified with dibucaine and substance P. Cell Biol Intl Rep 14:369, 1990. Smith ICP, Auger M, Jarrell HC: Molecular details of anesthetic-lipid interaction. Ann NY Acad Sci 625:668, 1991. Khodorov BI: Role of inactivation in local anesthetic action. Ann NY Acad Sci 625:224, 1991. Leonard RJ et al: Reverse pharmacology of the nicotinic acetylcholine receptor. Ann NY Acad Sci 625:588, 1991. Covino BG: Local anesthesia (Part 1). N Engl J Med 286:975, 1972. Cousins MJ, Mather LE: Clinical pharmacology of local anesthetics. Anaesth Intensive Care 8:257, 1980. Covino BG: Pharmacology of local anesthetic agents. Ration Drug Ther 21:1, 1987. Covino BG: Physiology and pharmacology of local anesthetic 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. Tucker GT: Binding of anilide-type local anesthetic in human plasma: I. Relationships between binding, physicochemical properties, and anesthetic activity. Anesthesiology 33:287, 1970. Brown RD: The failure of local anesthesia in acute inflammationSome recent concepts. Br Dent J 151:47, 1981. 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. Weinberg GL, Laurito CE, Geldner P, et al: Malignant ventricular dysrhythmias in a patient with isovaleric acidemia receiving general and local anesthesia for suction lipectomy. J Clin Anesthesiol 9:668, 1997. Klein JA: Anesthesia: modified liposuction technique. Dermatol Clin 8(3):421, 1990. Siegel RJ, Vistnes LM, Iverson RE: Effective hemostasis with less epinephrine. An experimental and clinical study. Plast Reconstr Surg 51:129, 1973. Cederholm I, Evers H, Lofstrom JB: Skin blood flow after intradermal injection of ropivacaine in various concentrations with and without epinephrine evaluated by laser Doppler flowmetry. Reg Anesth 17:322, 1992. Reinisch J, Myers B: The effect of local anesthesia with epinephrine on skin flap survival. Plast Reconstr Surg 54:324, 1974. Wu G, Calamel PM, Shedd DP: The hazards of injecting local anesthetic solutions with epinephrine in flaps. Plast Reconstr Surg 62:396, 1978. Bromage PR: Improved conduction blockade in surgery and obstetrics: carbonated local anesthetics. Can Med Assoc J 97(23):1377, Dec 2, 1967. Morison DH: A double-blind comparison of carbonated lidocaine and lidocaine hydrochloride in epidural anaesthesia. Can Anaesth Soc J 28(4):387, 1981.

17.

2.

18.

3. 4.

19.

5.

20.

6. 7.

21. 22.

8.

23.

9.

10. 11. 12. 13. 14. 15.

24.

25.

26.

27.

17

SRPS Volume 9, Number 4

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38. 39.

40.

41. 42.

43.

44.

45. 46.

Hickey R, Knape KG, Blanchard J, et al: Lidocaine hydrocarbonate is not superior to lidocaine hydrochloride in interscalene brachial plexus block. Reg Anesth 15(4):194, 1990. Tezlaff JE, Yoon HJ, Brems J, Javorsky T: Alkalinization of mepivacaine improves the quality of motor block associated with interscalene brachial plexus anesthesia for shoulder surgery. Reg Anesth 20(2):128, 1995. Capogna G, Celleno D, Laudano D, Giunta F: Alkalinization of local anesthetics. Which block, which local anesthetic? Reg Anesth 20(5):369, 1995. Bedder MD, Kozody R, Craig DB: Comparison of bupivacaine and alkalinized bupivacaine in brachial plexus anesthesia. Anesth Analg 67(1):48, 1988. Benlabed M, Jullien P, Guelmi K, et al: Alkalinization of 0.5% lidocaine for intravenous regional anesthesia. Reg Anesth 15(2):59, 1990. Candido KD, Winnie AP, Covino BG, et al: Addition of bicarbonate to plain bupivacaine does not significantly alter the onset or duration of plexus anesthesia. Reg Anesth 20(2):133, 1995. Chow MY, Sia AT, Koay CK, Chan YW: Alkalinization of lidocaine does not hasten the onset of axillary brachial plexus block. Anesth Analg 86(3):566, 1998. Moore DC et al: Does compounding of local anesthetic agents increase their toxicity in humans? Anesth Analg 51:579, 1972. Cohen SE, Thurlow A: Comparison of a chloroprocaine bupivacaine mixture with chloroprocaine and bupivacaine used individually for obstetric epidural analgesia. Anesthesiology 51(4):288, 1979. De Jong RH, Bonin JD: Mixtures of local anesthetics are no more toxic than the parent drugs. Anesthesiology 54:177, 1981. Kennedy KS, Cave RH: Anaphylactic reaction to lidocaine. Arch Otolaryngol Head Neck Surg 112:671, 1986. Tucker GT, Mather LE: Properties, absorption, and disposition of anesthetic agents. In: Cousins MJ, Bridenbaugh PO (eds), Neural Blockade in Clinical Anesthesia and Management of Pain, 3rd Ed. Philadelphia, LippincottRaven, 1998. Part 1, Ch 3, p 55-96. Momota Y, Artru AA, Powers KM, et al: Posttreatment with propofol terminates lidocaine-induced epileptiform electroencephalogram activity in rabbits: effects on cerebrospinal fluid dynamics. Anesth Analg 87:900, 1998. Mehra P, Caiazzo A, Maloney P: Lidocaine toxicity. Anesth Prog 45:38, 1998. Englesson S: The influence of acid-base changes on central nervous system toxicity of local anaesthetic agents. I. An experimental study in cats. Acta Anaesthesiol Scand 18(2):79, 1974. Englesson S, Grevsten S: The influence of acid-base changes on central nervous system toxicity of local anaesthetic agents. II. Acta Anaesthesiol Scand 18(2):88, 1974. Bernards CM, Carpenter RL, Kenter ME, et al: Effect of epinephrine on central nervous system and cardiovascular system toxicity of bupivacaine in pigs. Anesthesiology 71(5):711, 1989. [No authors listed]: Cardiotoxicity of local anaesthetic drugs. Lancet 2(8517):1192, Nov 22, 1986. Morishima HO, Pedersen H, Finster M, et al: Bupivacaine toxicity in pregnant and nonpregnant ewes. Anesthesiology 63:134, 1985.

47.

48.

49.

50.

51.

52. 53.

54.

55. 56.

57.

58.

59.

60. 61.

62.

63.

64.

65.

Solomon D, Bunegin L, Albin M: The effect of magnesium sulfate administration on cerebral and cardiac toxicity of bupivacaine in dogs. Anesthesiology 72:341, 1990. Albright GA: Cardiac arrest following regional anesthesia with etidocaine or bupivacaine. Anesthesiology 51:285, 1979. 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. Moller RA, Covino BG: Cardiac electrophysiologic effects of articaine compared with bupivacaine and lidocaine. Anesth Analg 76:1266, 1993. Clarkson C, Hondeghem L: Mechanism 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. Atlee JL III, Bosnjak ZJ: Mechanisms for cardiac dysrhythmias during anesthesia. Anesthesiology 72:347, 1990. Thomas RD, Behbehani MM, Coyle DE, et al: Cardiovascular toxicity of local anesthetics: an alternative hypothesis. Anesth Analg 65:444, 1986. Feldman HS, Arthur GR, Pitkanen M, et al: Treatment of acute systemic toxicity after the rapid intravenous injection of ropivacaine and bupivacaine in the conscious dog. Anesth Analg 73:373, 1991. Chen AH: Toxicity and allergy to local anesthesia. CDAJ 26(9):683, 1998. Bernards CM, Artru AA: Effect of intracerebroventricular picrotoxin and muscimol on intravenous bupivacaine toxicity. Evidence supporting central nervous system involvement in bupivacaine cardiovascular toxicity. Anesthesiology 78:902, 1993. Bernards CM, Carpenter RL, Rupp SM, et al: Effect of midazolam and diazepam premedication on central nervous system and cardiovascular toxicity of bupivacaine in pigs. Anesthesiology 70(2):318, 1989. Bernards CM, Artru AA: Hexamethonium and midazolam terminate dysrhythmias and hypertension caused by intracerebroventricular bupivacaine in rabbits. Anesthesiology 74:89, 1991. Scott DB, Lee A, Fagan D, et al: Acute toxicity of ropivacaine compared with that of bupivacaine. Anesth Analg 69:563, 1989. McClure JH: Ropivacaine. Br J Anaesth 76:300, 1996. Knudsen K, Beckman Suurkula M, Blomberg S, et al: Central nervous and cardiovascular effects of i.v. infusions of ropivacaine, bupivacaine and placebo in volunteers. Br J Anaesth 78:507, 1997. Klein SM, Greengrass RA, Steele SM, et al: A comparison of 0.5% bupivacaine, 0.5% ropivacaine, and 0.75% ropivacaine for interscalene brachial plexus block. Anesth Analg 87(6):1316, 1998. Sia AT, et al: Epidural 0.2% ropivacaine for labour analgesia: parturient-controlled or continuous infusion? Anaesth Intensive Care 27(2):154, 1999. Arlock P: Actions of three local anaesthetics: lidocaine, bupivacaine and ropivacaine on guinea pig papillary muscle sodium channels (Vmax). Pharmacol Toxicol 63(2):96, 1988. Kohane DS, Sankar WN, Shubina M, et al: Sciatic nerve blockade in infant, adolescent, and adult rats: a comparison of ropivacaine with bupivacaine. Anesthesiology 89(5):1199, 1998.

18

SRPS Volume 9, Number 4

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78. 79.

80.

81. 82. 83.

84.

85.

Feldman HS, Dvoskin S, Arthur GR, Doucette AM: Antinociceptive and motor-blocking efficacy of ropivacaine and bupivacaine after epidural administration in the dog. Reg Anesth 21(4):318, 1996. Da Conceicao MJ, Coelho L, Khalil M: Ropivacaine 0.25% compared with bupivacaine 0.25% by the caudal route. Paediatr Anaesth 9(3):229, 1999. Liu PL, Feldman HS, Covino BM, et al: Acute cardiovascular toxicity of intravenous amide local anesthetics in anesthetized ventilated dogs. Anesth Analg 61:317, 1982. Korman B, Riley RH: Convulsions induced by ropivacaine during interscalene brachial plexus block. Anesth Analg 85:1128, 1997. Norris MC, Ferrenbach D, Dalman H, et al: Does epinephrine improve the diagnostic accuracy of aspiration during labor epidural analgesia? Anesth Analg 88(5):1073, 1999. Nystrom EU, Heavner JE, Buffington CW: Blood pressure is maintained despite profound myocardial depression during acute bupivacaine overdose in pigs. Anesth Analg 88(5):1143, 1999. Heavner JE, Dryden CF Jr, Sanghani V, et al: Severe hypoxia enhances central nervous system and cardiovascular toxicity of bupivacaine in lightly anesthetized pigs. Anesthesiology 77(1):142, 1992. Benoit PW, Belt WD: Destruction and regeneration of skeletal muscle after treatment with a local anaesthetic, bupivacaine (Marcaine). J Anat 107(3):547, 1970. Hjelm M, Holmdahl MH: Clinical chemistry of prilocaine and clinical evaluation of methaemoglobinaemia induced by this agent. Acta Anaesthesiol Scand Suppl 16:161, 1965. Lund PC, Cwik JC: A correlation of the differential penetration and the systemic toxicity of lidocaine, mepivacaine and prilocaine in man. Acta Anaesthesiol Scand Suppl 23:475, 1966. Feehan HF, Mancusi-Ungaro A: The use of cocaine as a topical anesthetic in nasal surgery: A survey report. Plast Reconstr Surg 57:62, 1976. Johns ME, Henderson RL: Cocaine use by the otolaryngologist: a survey. Trans Am Acad Ophthalmol Otolaryngol 84:969, 1977. Isner JM et al: Acute cardiac events temporally related to cocaine abuse. N Engl J Med 315:1438, 1986. Mathias DW: Cocaine-associated myocardial ischemia: review of clinical and angiographic findings. Am J Med 81:675, 1986. Dackis CA, Gold MS: The new concept in cocaine addiction. The dopamine depletion hypothesis. Neurosci Biobehav Rev 9:496, 1985. Miller RD (ed): Anesthesia, 4th ed. New York, Churchill Livingstone, 1994. White PF (ed): Outpatient Anesthesia. New York, Churchill Livingstone, 1990. Kohane DS, Yieh J, Lu NT, et al: A re-examination of tetrodotoxin for prolonged duration local anesthesia. Anesthesiology 89:119, 1998. Curley J, Castillo J, Hotz J, et al: Prolonged regional nerve blockade. Injectable biodegradable bupivacaine/polyester microspheres. Anesthesiology 84(6):1401, 1996. Castillo J, Curley J, Hotz J, et al: Glucocorticoids prolong rat sciatic nerve blockade in vivo from bupivacaine microspheres. Anesthesiology 85(5):1157, 1996.

CPR and ACLS 1. 2. 3. 4. Redding JS: Cardiopulmonary resuscitation. The essentials. Clin Plast Surg 12:137, 1985. Jaffe AS (ed): Textbook on Advanced Cardiac Life Support. Dallas, American Heart Association, 1987. Sanders AB: Cardiopulmonary resuscitation. Acad Emerg Med 1:136, 1994. Tucker KJ, Redberg RF, Schiller NB, Cohen TJ: Active compression-decompression resuscitation: analysis of transmitral flow and left ventricular volume by transesophageal echocardiography in humans. Cardiopulmonary Resuscitation Working Group. J Am Coll Cardiol 22:1485, 1993. Tucker KJ, Galli F, Savitt MA, et al: Active compressiondecompression resuscitation: effect on resuscitation success after in-hospital cardiac arrest. J Am Coll Cardiol 24:201, 1994. Tucker KJ, Savitt MA, Idris A, Redberg RF, et al: Cardiopulmonary resuscitation. Historical perspectives, physiology, and future directions. Arch Intern Med 154:2141, 1994. Niemann JT: Cardiopulmonary resuscitation. N Engl J Med 327:1075, Oct 8, 1992. Haynes BE, Mendoza A, McNeil M, et al: A statewide early defibrillation initiative, including laypersons and outcome reporting. JAMA 266:545, 1991. Kellermann AL, Staves DR, Hackman BB: In-hospital resuscitation following unsuccessful prehospital advanced cardiac life support: heroic efforts or an exercise in futility? Ann Emerg Med 17:589, 1988. Shimazu S, Shatney CH: Outcomes of trauma patients with no vital signs on hospital admission. J Trauma 23:213, 1983. Gray WA, Capone RJ, Most AS: Unsuccessful emergency medical resuscitationAre continued efforts in the emergency department justified? N Engl J Med 325:1393, Nov 14, 1991. de Bono D: ResuscitationTime for a re-think? Q J Med 81(296):959, 1991. Gonzalez ER, Ornato JP: The dose of epinephrine during cardiopulmonary resuscitation in humans: What should it be? DICP 25:773, 1991. Pepe PE, Levine RL, Fromm RE Jr, et al: Cardiac arrest presenting with rhythms other than ventricular fibrillation: contribution of resuscitative efforts toward total survivorship. Crit Care Med 21:1838, 1993. Hine LK, Pedone M: On-site first aid, CPR responders need to make fast, vital decisions. Occup Health Saf 62:74, 1993. Advanced Cardiac Life Support Subcommittee and Emergency Cardiac Care Committee: Improving survival from sudden cardiac arrest: the chain of survival. Circulation 83:1832, 1991. Cummins RO, Eisenberg MS, Litwin PE, et al: Automatic external defibrillators used by emergency medical technicians. A controlled clinical trial. JAMA 257:1605, Mar 27, 1987. Weaver WD, Hill D, Fahrenbruch CE, et al: Use of the automatic external defibrillator in the management of out-of-hospital cardiac arrest. N Engl J Med 319:661, Sep 15, 1988.

5.

6.

7. 8.

9.

10.

11.

12. 13.

14.

15.

16.

17.

18.

19

SRPS Volume 9, Number 4

19.

20. 21. 22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

OKeeffe S, Radahan C, Keane P, Daly K: Age and other determinants of survival after in-hospital cardiopulmonary resuscitation. Q J Med 81(296):1005, 1991. Tresch DD: CPR in the elderly: When should it be performed? Geriatrics 46:47, 1991. Stauffer JL: Medical management of the airway. Clin Chest Med 12:449, 1991. Melker RJ: Recommendations for ventilation during cardiopulmonary resuscitation: time for change? Crit Care Med 13:882, 1985. Cohen TJ, Tucker KJ, Lurie KG, et al: Active compressiondecompression: a new method of cardiopulmonary resuscitation. Cardiopulmonary Resuscitation Working Group. JAMA 267:2916, Jun 5, 1992. Cohen TJ, Goldner BG, Maccaro PC, et al: A comparison of active compression-decompression cardiopulmonary resuscitation with standard cardiopulmonary resuscitation for cardiac arrests occurring in the hospital. N Engl J Med 329:1918, Dec 23, 1993. Shultz JJ, Coffeen P, Sweeney M, et al: Evaluation of standard and active compression-decompression CPR in an acute human model of ventricular fibrillation. Circulation 89:684, 1994. Lurie KG, Shultz JJ, Callaham ML, et al: Evaluation of active compression-decompression CPR in victims of out-of-hospital cardiac arrest. JAMA 271:1405, May 11, 1994. Schwab TM, Callaham ML, Madsen CD, Utecht TA: A randomized clinical trial of active compression-decompression CPR vs standard CPR in out-of-hospital cardiac arrest in two cities. JAMA 273:1261, Apr 26, 1995. Guly UM, Robertson CE: Active decompression improves the haemodynamic state during cardiopulmonary resuscitation. Br Heart J 73:372, 1995. Babbs CF: Interposed abdominal compression-CPR: a case study in cardiac arrest research. Ann Emerg Med 22:24, 1993. Babbs CF: Interposed abdominal compression-cardiopulmonary resuscitation: Are we missing the mark in clinical trials? Am Heart J 126:1035, 1993. Babbs CF, Sack JB, Kern KB: Interposed abdominal compression as an adjunct to cardiopulmonary resuscitation. Am Heart J 127:412, 1994. Sack JB, Kesselbrenner MB, Bregman D: Survival from inhospital cardiac arrest with interposed abdominal counterpulsation during cardiopulmonary resuscitation. JAMA 267:379, Jan 15, 1992. Sack JB, Kesselbrenner MB: Hemodynamics, survival benefits, and complications of interposed abdominal compression during cardiopulmonary resuscitation. Acad Emerg Med 1:490, Sep-Oct 1994. Halperin HR, Tsitlik JE, Gelfand M, et al: A preliminary study of cardiopulmonary resuscitation by circumferential compression of the chest with use of a pneumatic vest. N Engl J Med 329, 762, Sep 9, 1993. Eorgan PA, Greer JL: Cough CPR: a consideration for highrisk cardiac patient discharge teaching. Crit Care Nurs 12:21, 1992. Ward KR, Menegazzi JJ, Zelenak RR, et al: A comparison of chest compressions between mechanical and manual CPR by monitoring end-tidal PCO2 during human cardiac arrest. Ann Emerg Med 22:669, 1993.

37.

38. 39.

40. 41. 42. 43. 44. 45. 46.

47.

48.

49.

50.

51. 52. 53.

54.

55. 56.

57. 58. 59. 60.

Leuthner SR, Jansen RD, Hageman JR: Cardiopulmonary resuscitation of the newborn. An update. Pediatr Clin North Am 41:893, 1994. Orlowski JP: Pediatric cardiopulmonary resuscitation. Emerg Med Clin North Am 1:3, 1983. Hozinski MF: Is pediatric resuscitation unique? Relative merits of early CPR and ventilation versus early defibrillation for young victims of prehospital cardiac care. Ann Emerg Med 25:540, 1995. Tonkin SL, Davis SL, Gunn TR: Nasal route for infant resuscitation by mothers. Lancet 345:1353, 1995. Segedin E, Torrie J, Anderson B: Nasal airway versus oral route for infant resuscitation. Lancet 346:382, 1995. Chameides L: CPR challenges in pediatrics. Ann Emerg Med 22:338, 1993. Goetting MG: Mastering pediatric cardiopulmonary resuscitation. Pediatr Clin North Am 41:1147, 1994. Zaritsky A: Pediatric resuscitation pharmacology. Ann Emerg Med 22:445, 1993. Tibballs J: Endotracheal and intraosseous drug administration for paediatric CPR. Aust Fam Physician 21:1147, 1992. Spivey WH, Crespo SG, Fuhs LR, Schoffstall JM: Plasma catecholamine levels after intraosseous epinephrine administration in a cardiac arrest model. Ann Emerg Med 21:127, 1992. Gonzalez ER, Ornato JR, Garnett AR, et al: Dose-dependent vasopressor response to epinephrine during CPR in humans. Ann Emerg Med 18:920, 1989. Hebert P, Weitzman BN, Stiell IG, Stark RM: Epinephrine in cardiopulmonary resuscitation. J Emerg Med 9:487, 1991. Berkowitz ID, Gervais H, Schleien CL, et al: Epinephrine dosage effects on cerebral and myocardial blood flow in infant swine model of cardiopulmonary resuscitation. Anesthesiology 75:1041, 1991. Cipolotti G, Paccagnella A, Simini G: Successful cardiopulmonary resuscitation using high doses of epinephrine. Int J Cardiol 33:430, 1991. Shafer AL: Cardiopulmonary resuscitation drug therapy. AORN J 54:1070, 1991. Pearson JW, Redding JS: Influence of peripheral vascular tone on cardiac resuscitation. Anesth Analg 44:746, 1965. Michael JR, Guerci AD, Koehler RC, et al: Mechanisms by which epinephrine augments cerebral and myocardial perfusion during cardipoulmonary resuscitation in dogs. Circulation 69:822, 1984. Koehler RC, Michael JR, Guerci AD, et al: Beneficial effect of epinephrine infusion on cerebral and myocardial blood flow during CPR. Ann Emerg Med 14:744, 1985. Otto CW, Yakaitis RW: The role of epinephrine in CPR: a reappraisal. Ann Emerg Med 13:840, 1984. Kette F, Weil MH, Gazmuri RJ: Buffer solutions may compromise cardiac resuscitation by reducing coronary perfusion pressure. JAMA 266:2121, 1991. Weisfeldt ML, Guerci AD: Sodium bicarbonate in CPR. JAMA 266:2129, 1991. Pepe PE, Abramson NS, Brown CG: ACLSDoes it really work? Ann Emerg Med 23:1037, 1994. Cummins RO: Advanced Cardiac Life Support. Dallas, American Heart Association, 1997. Hazinski MF, Cummins RO (eds): 1997-99 Handbook of Emergency Cardiovascular Care for Healthcare Providers. Dallas, American Heart Association, 1997.

20

SRPS Volume 9, Number 4

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

21

SRPS Volume 9, Number 4

Fig 1B-1. Treatment of Ventricular Fibrillation.

22

SRPS Volume 9, Number 4

Fig 1B-2. Additional Antifibrillatory Measures.

23

SRPS Volume 9, Number 4

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

24

SRPS Volume 9, Number 4

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

25

SRPS Volume 9, Number 4

Fig 1E-1. Treatment of Supraventricular Tachyarrhythmias.

26

SRPS Volume 9, Number 4

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

27