Cardiovascular and Central Nervous System Toxicity of Local Anesthetics

Parvinder Singh and Jeffrey S. Lee

E VER SINCE the introduction of cocaine as a local anesthetic into medical practice by

Keller, 1 it has been known that these agents are a double-edged sword providing immense bene- fits as well as a potential for toxicity. While de- scribing the effects of cocaine, and also acting as guinea pigs for their research, Halsted and Hall in New York became cocaine addicts. 2

The quest for safer local anesthetics began to- ward the end of the 19th century, soon after the toxic effects of cocaine became known. Around the dawn of the 20th century, three cocaine sub- stitutes, tropocaine, stovaine, and novocaine, were tried. In 1943, Lofgren 1 synthesized the am- ide-linked local anesthetic lidocaine; this started the practice of regional anesthesia with which we are familiar today. Lidocaine had a short du- ration of action; thus, the longer-acting bupiva- caine and etidocaine were introduced in clinical practice (in the 1970s in the United States). The latter two had their own problems, and the search for a safe and efficacious local anesthetic contin- ues with the introduction of ropivacaine. This review will focus on the factors influencing local anesthetic toxicity: the manifestations, underly- ing mechanisms, and prevention and treatment of central nervous system (CNS) and cardiovascular system toxicity.

The incidence of toxic events is not well docu- mented. However, it is reasonable to state that in performing a major nerve block (exclusive of spinal anesthesia), the patient is more likely to experience a CNS or cardiovascular reaction than to suffer permanent nerve damage, but is far less likely to experience one of these events than to have a failed anesthetic.

We now know that these anesthetics exert their

From the Department of Anesthesiology, University of Southern California, Los Angeles, CA.

Address to reprint requests Jeffrey S. Lee, MD, Los Angeles County + University of Southern California Medical Center, Women's and Children's Hospital, 1240 N Mission Rd, Room 5K17, Los Angeles, CA 90033.

Copyright �9 1998 by W.B. Saunders Company 0277-0326/98/1701-000958. 00/0

effect by deformation of the sodium channels on the membranes of cells. This change in configu- ration of the sodium channel inhibits sodium in- flux and thus depolarization of the cell mem- brane. Without depolarization, conduction of afferent or efferent impulses cannot occur.

Thus, it is not surprising that local anesthetics whose desired effect is blockade of impulse transmission in selected nerves can cause un- wanted, even dangerous, effects when other ex- citable tissues (ie, the heart and brain) are ex- posed to significant concentrations. Indeed, regional anesthesia is "regional" because we place these agents close to the site where nerve block is desired rather than distributing them throughout the body.

FACTORS INFLUENCING TOXICITY

The toxicity of local anesthetics is a result of a relative or absolute overdose of the drug being used. This in turn is affected by other factors, such as

1. Total amount o f drug used: the greater the mass of the drug deposited, the greater the diffusion gradient for the drug to enter the circulation.

2. Presence or absence o f epinephrine: the presence of vasoconstrictors delays the absorption of the drug into the circula- tion and therefore reduces toxicity.

3. Vascularity o f the site o f injection: when local anesthetics are deposited at more vascular sites, such as the intercostal or epidural space, a higher blood level of the drug is achieved than when injected into the brachial plexus or subcutaneous tissue. For example, a 400 mg dose of lidocaine for intercostal nerve block re- sulted in a toxic plasma level of 7 #g/ mL, whereas the same amount when used for brachial plexus block resulted in a plasma level of 3 #g/mL 2.

4. Type o f local anesthetic used: except co- caine, all local anesthetics are vasodila-

1 8 Seminars in Anesthesia, Perioperative Medicine and Pain, Vol 17, No 1 (March), 1998: p 18-23

CVS AND CNS TOXICITY OF LOCAL ANESTHETICS 19

tots to a varying degree. For example, lidocaine is more rapidly absorbed than prilocaine, a less potent vasodilator than lidocaine. In addition, lipid solubility of the drug used influences its rate of ab- sorption. Thus, etidocaine, a more lipid soluble drug than bupivacaine, tends to be sequestered by the adipose tissue, re- sulting in a decreased rate of absorption and lower plasma le.vels than bupiva- caine.

5. Rate of destruction of drug: the faster metabolized drugs will cause less cumu- lative toxicity. In acute toxicity, this fac- tor is irrelevant.

6. Age and physical status of the patient: in neonates, toxicity can occur because competition between bilirubin and local anesthetics for the same plasma protein- binding sites may increase the unbound local anesthetic concentration. Like- wise, patients with advanced liver dis- ease have at least a theoretical risk of toxicity at a lower dose of local anesthe- tic drug than normal patients because of decreased synthesis of plasma proteins. With advancing age, the volume of dis- tribution and clearance is reduced. This has more implications when repeated doses of the drug are used. Thus, the initial dose will be relatively unchanged in the elderly, whereas subseguent doses should be smaller and less frequent.

7. Interaction with other drugs: by reduc- ing hepatic blood flow and inhibiting mixed function oxidases, cimetidine and propranolol lead to reduced hepatic clearance of local anesthetics. All inha- lational anesthetics also reduce hepatic blood flow and probably reduce clear- ance. The clinical significance of these interactions is not clear, and how indi- vidual patients are affected also varies considerably.

CENTRAL NERVOUS SYSTEM TOXICITY

Central nervous system toxicity is a relatively early manifestation of toxicity from local anes- thetic drugs and can occur at plasma levels of the drug that may well be within the therapeutic range. The incidence varies according to the indi- cation for which local anesthetic is being used.

When lidocaine is used intravenously, as an anti- arrhythmic agent, the incidence of convulsions is 5.7 per 1,000 versus 0.7 to 4.4 per 1,000 when it is used via the epidural rou teY Toxic levels are most often achieved by unintentional intra- vascular injection, although slow absorption from a peripheral site can have the same undesir- able end result.

Local anesthetics are CNS depressants, al- though clinically they have a biphasic response. 6 The initial excitatory phase is brought about by blockade of inhibitory pathways in the cerebral cortex, leaving the facilitatory neurons to fire un- opposed. Later, facilitatory pathways are also blocked, resulting in respiratory depression and coma. A continuum of symptoms of CNS toxicity is produced depending on the concentration of local anesthetic in plasma. Patients initially com- plain of a metallic taste in the mouth, ringing in the ears, circumoral tingling, dizziness, and feeling light headed. This is followed by tremors, muscle twitches, tonic-clonic seizures, and, fi- nally, coma. In general, the more rapidly a blood level is attained and the higher it is, the more severe the symptoms. The early symptoms should caution the clinician to cease the local anesthetic injection if it is still ongoing or, if it has been completed, to be ready for the treatment of seizures if the blood level continues to rise.

The threshold for convulsions is affected by the acid-base status, by hypoxia, and by cerebral metabolism. Acidosis, particularly that due to el- evated Paco2, decreases the convulsive thresh- old. By increasing cerebral blood flow, elevated Paco2 delivers a larger amount of the drug to the brain. CO2 also diffuses into neuronal cells, causing intracellular acidosis, which ionizes the drugs, leading to ion trapping and increased CNS toxicity. 7 Hypoxia enhances both CNS and car- diovascular toxicity, and can be lethal in this setting. Conversely, oxygen per se does not pre- vent CNS toxicity, but can be critical to meet the increased metabolic demands of the CNS, skeletal muscles, and heart during the period of convulsion. 8 Cerebral metabolism increases dur- ing convulsions, but this is compensated by auto- regulatory mechanisms by which blood flow to the brain is also increased.

There is the potential for bone and soft tissue trauma secondary to the tonic-clonic movements, including biting the tongue and/or lip. Finally, airway obstruction, apnea, and aspiration of gas-

20 SINGH AND LEE

tric contents may further decrease the oxygen supply to the overactive brain and may be lethal.

Taking into account the above factors, the treatment of convulsions logically includes pro- viding an adequate supply of oxygen and control of seizures. Initial treatment should be directed toward preventing physical injury to the patient and oxygenation. In an unresponsive patient, manual ventilation with oxygen is started, both to raise the oxygen tension.and lower the carbon dioxide tension. If the seizures still persist, a small dose of thiopental (1 to 2 mg/kg), propofol (0.5 to 1 mg/kg), or midazolam (0.05 mg/kg) is given. The drug of choice is the one on hand. If seizures are prolonged and are interfering with effective maintenance of the airway, then short- acting muscle relaxants (succinylcholine or mi- vacurium) become necessary. A muscle relaxant stops the overt manifestation of seizure activity, allows the airway to be secured, and allows for easy oxygen delivery, although seizure activity in the brain is not abated.

Serendipitously, due to current fashions in an- esthetic practice, most patients will likely have been given a benzodiazepine premedication, ei- ther orally or intravenously. Oxygen should be administered before initiating the regional anes- thetic and continuously thereafter.

In the clinical setting of an unexpected sudden adverse reaction, it is easy to overtreat. Most convulsions are self-limiting and require no more than oxygenation. Too much 9f a.CNS depres- sant, superimposed on postictal depression, will only delay recovery. In the rare circumstance in which the local anesthetic is manifesting cardiac effects, it is wise to stop the seizure focus, secure the airway, guarantee oxygenation, and then ad- dress this problem.

Whether the surgical procedure should pro- ceed once the patient is asleep and intubated is best decided in the individual situation after dis- cussion with the surgeon. In a purely elective operation, it seems prudent to allow the patient to awaken and to assess any mental or physical damage rather than proceeding.

CARDIOVASCULAR SYSTEM TOXICITY

Local anesthetics can have three adverse ef- fects on the cardiovascular system. They may have a direct effect on the myocardium, they may act by blocking the autonomic nervous system as during spinal or epidural blockade, or the car-

diovascular system toxicity may be an allergic response. This discussion will focus on the direct effects of local anesthetics on the myocardium.

Conventional wisdom has been that the signs of CNS toxicity precede cardiovascular system toxicity. This is still true for lidocaine, but it does not carry over to the more potent agents, such as bupivacaine and etidocaine. Albright' s 11 editorial in Anesthesiology described six cases of sudden cardiovascular collapse that were not always preceded by seizures. Another common denomi- nator was that all patients received potent, lipid- soluble drugs: bupivacaine (five cases) or etido- caine (one case). Furthermore, the majority of adverse events were noted in term pregnant women. Albright cautioned that these agents may be different from and may not have the same sequence of toxicity as lidocaine.

The initial skepticism directed toward this edi- torial was replaced by mounting clinical evidence of an enhanced cardiotoxicity of bupivacaine and etidocaine. In 1983, the Food and Drug Adminis- tration ruled that 0.75% bupivacaine concentra- tion "was no longer recommended for obstetric anesthesia. ''9'1~ After this rather unconventional recommendation, a plethora of animal and hu- man investigations was launched; the majority of the evidence favored Albright's opinion that etidocaine and the far more commonly used bupi- vacaine are different from lidocaine in their ef- fect on the myocardium.

Local anesthetics directly affect the heart in two ways: by a negative inotropic effect on the myocardium and by delaying transmission of im- pulses through the cardiac conduction system. At the electrophysiologic level, both effects are mediated by blocking the sodium channels, thereby effecting a decrease in the maximum rate of depolarization in ventricular muscle and Pur- kinje fibers. Sodium channels are blocked during systole, and the block starts to dissipate during diastole. However, bupivacaine displaces much more slowly than lidocaine during diastole. The dissociation time constant is 0.15 seconds for lidocaine and 1.5 seconds for bupivacaine, mak- ing the latter 10-fold slower. I2

These effects are not only dose dependent, but are also related to the potency of drugs. It may be that because of its high lipophilicity, bupivacaine gains direct transmembrane access to sodium channels, which is independent of voltage-gated access. These differences in the electrophysio-

CVS AND CNS TOXICITY OF LOCAL ANESTHETICS 21

logic effects make bupivacaine a more cardio- toxic agent, a finding supported by the results of numerous animal studies.1315 These effects may 16 or may not 17 be greater in pregnancy, at least in the animal model.

Based on the above physiology, it is not sur- prising that an overdose of local anesthetics can cause hypotension, prolongation of QT interval, reentrant arrythmias, and cardiac arrest. Al- though initial case reports alluded to failed resus- citation following bupivacaine toxicity, success- ful resuscitation has been accomplished, 18'~9 and bretylium 2~ was better than lidocaine for re- versing these cardiac effects in a dog model. The treatment is oxygenation and restoration of he- modynamics. In the face of unstable hemody- namics, external cardiac massage should be insti- tuted, followed by, if necessary, inotropic support. Persistent ventricular tachycardia or fi- brillation should be treated with defibrillation or intravenous bretylium (5 mg/kg slowly up to a maximum of 30 mg/kg).

PREVENTION OF SYSTEMIC TOXICITY

Presuming the agent is placed in the proper location for the intended regional technique, it is not easy to decide what number of milligrams of a given local anesthetic will safely anesthetize the nerve and not, through absorption, result in a blood level that is unsafe. While we may know the relative vascularity of different sites, there is no way to ascertain the absolute blood flow to a given site in a given patient and to predict the ultimate blood level. More rapid absorption of a smaller mass of drug may result in higher blood levels than slower absorption of a larger mass. Ultimately, one needs to deposit a sufficient vol- ume and mass of local anesthetic to satisfactorily attain conduction block. If there is any question about the safety of what is calculated to be the necessary number of milligrams to accomplish satisfactory regional anesthesia, perhaps the practitioner should abandon plans for this type of anesthesia.

Calculation of a clinically appropriate maxi- mum dose than can be safely administered at one time should be based on lean body mass. For the two most commonly used local anesthetics, reasonable guidelines seem to be lidocaine 7 mg/ kg (500 mg in a 70-kg patient) and bupivacaine 2.5 to 3.0 mg/kg (175 to 210 mg in a 70-kg patient).

There are only two ways for local anesthetics to gain access to the blood: absorption from tis- sue or direct deposition through a needle either intentionally (a Bier block) or unintentionally while performing the block. When performing intravenous regional anesthesia (Bier block), po- tentially dangerous levels of local anesthetic are intentionally placed in the venous circulation. Absorption of such an agent does occur, and blood levels of local anesthetic can be detected from blood drawn from the general circulation while the tourniquet is inflated. Once again, real- izing that a large volume of agent must be in- jected to have a successful anesthetic, the prac- titioner should use the minimum concentration of local anesthetic estimated to cause satisfactory anesthesia.

The most likely cause of a toxic reaction dur- ing a Bier block is tourniquet failure. The best way to prevent trouble obviously is to ascertain that the tourniquet functions normally, that it is inflated before the intravenous injection, and, if a double tourniquet is used, that the distal tourni- quet is working and inflated before the proximal tourniquet is released. At the end of the proce- dure, particularly if surgery has been brief, it is a good practice to repeatedly inflate and deflate the tourniquet in an attempt to avoid rapid washin of local anesthetic from the isolated limb to the general circulation.

I f enough major nerve blocks are performed, an intravascular injection will eventually occur. Several strategies have been devised to detect this event. First and foremost is careful patient education and close verbal contact with the pa- tient while performing the block. Presumably, if the patient knows what symptoms to report and the practitioner can elicit early symptoms of CNS toxicity, the procedure can be aborted and fur- ther, more dangerous, manifestations can be avoided. Indeed, in one study in 12 unpremedi- cated male volunteers given 100 mg/min intrave- nous lidocaine, all reported early, non- l i fe- threatening symptoms (lightheadedness, tinnitus, numbness of the tongue) by the time 200 mg had been administered. 22

Unfortunately, in the time-urgent operating rooms in which we practice today, particularly in our multilingual society, such close patient rapport may not always occur. One obvious strat- egy is to stay below the maximum recommended dose. This admonition falls by the wayside when

22 SINGH AND LEE

a very small volume of local anesthetic is injected into a carotid or a vertebral artery. Frequent aspi- ration and injection of local anesthetic in small incremental aliquots is the mainstay of pre- venting toxicity. Even this method is not fool- proof, however. A needle or catheter can be in a vessel lumen and not deliver blood on aspira- tion if, for example, the negative pressure of aspi- ration pulls the intima against the cannula open- ing.

Adjuvants added to the local anesthetic to en- hance the quality of anesthesia also have been advocated as early markers of intravascular injec- tion. Narcotics like fentanyl or sufentanil may cause changes in sensorium when small doses are administered intravascularly. This requires the close patient contact already mentioned as well as a patient unobtunded by other medica- tions or general anesthesia.

Small doses of epinephrine (10 to 20 #g) have been shown to cause a rapid but evanescent in- crease in heart rate when given intravascularly, and epinephrine has been recommended as a test dose or part of the total dose of injected local anesthetic. This increase in heart rate may not always occur (patients treated with beta-block- ers) or may be hard to detect in some patients with pre-existing tachycardia or with fluctuating heart rates (women in active labor). In addition, the increase in heart rate, if it does occur, may be dangerous in some patients, eg, those with significant coronary artery disease. In other pa- tients, the potential for vasoconstriction with small doses of intravascular epinephrine has been considered risky, eg, mothers and fetuses with compromised placental function. Once intravas- cular injection has been ruled out, epinephrine (1/200,000 to 1/800,000) included in the full dose of local anesthetic may be useful in slowing ab- sorption from the site of injection and reducing peak blood levels.

Isoproterenol, not as widely used and not yet shown to be safe for epidnral administration, has been advocated as an alternative to epinephrine. Theoretically, it would avoid the hazard of pe- ripheral vasoconstriction but not of tachycardia.

Injection of small quantities of air along with precordial doppler monitoring, as is done in sit- ting neurosurgical cases, has been advocated as a method for detecting intravascular placement of an epidural catheter. This may not be practical because a doppler probe is not always available

at the site where regional anesthesia is being de- livered.

The above precautions may help to prevent, but not eliminate, toxicity from local anesthetic agents. Eventually, however, a practitioner will take care of a patient whose blood level of local anesthetic increases to unsafe levels.

RECENT ADVANCES AND THE FUTURE

Bupivacaine has been and is a valuable local anesthetic agent. It seems that the flurry of re- ports 10 to 15 years ago heightened the aware- ness of the anesthesia community such that the reports of death due to this agent have waned considerably. Nevertheless, the potential cardio- toxicity of bupivacine and etidocaine have led to a search for a less toxic agent.

In 1996, ropivacaine was introduced into clini- cal practice in the United States. Ropivacaine and bupivacaine (and mepivacaine for that mat- ter) share a common chemical structure, except that a propyl group in ropivacaine replaces a bu- tyl group in bupivacaine (or a methyl group in the case of mepivacaine) on the tertiary amine. 9'2~ Ropivacaine also has been released solely as the s (or l) stereoisomer, whereas bupivacaine is a racemic mixture of the r and s forms. It seems that the r(d) and s(l) enantiomer has a much more prolonged presence on the sodium channel than the s form; indeed, ropivacaine has been demon- strated as less likely to cause malignant rhythm disturbances than bupivacaine. 17'2>27

In dogs, even at twice the convulsive dose, ropivacaine was less arrythmogenic than bupiva- caine. 23 In a human study, ropivacaine produced less CNS symptoms at a dose 25% greater than bupivacaine) 2 Cardiovascular effects of bupiva- caine appeared at a lower dose and lower plasma concentration. Although ropivacaine and bupiva- caine have a similar effect on the maximum rate of depolarization of Purkinje fibers, ropivacaine differs in that it dissociates more easily from the receptors than bupivacaine. .2

A recent survey 27 involving 3,000 patients in 60 clinical studies further bears testimony to the relative safety of ropivacaine. Five females (two of them pregnant) and one male received acci- dental intravenous injection of 75 to 200 mg ropi- vacaine. Only one patient (male) convulsed; the other patients reported mild CNS symptoms. No patient showed signs or symptoms of cardiovas- cular toxicity.

CVS AND CNS TOXICITY OF LOCAL ANESTHETICS 23

A n o t h e r p o t e n t i a l a n e s t h e t i c a v a i l a b l e fo r fu-

tu re u s e is the p u r e s(l) e n t a n t i o m e r o f b u p i v a -

ca ine , w h i c h m a y o f f e r m o s t o f th i s a g e n t ' s anes -

t he t i c a d v a n t a g e s w i t h r e d u c e d ca r d i ac r isk .

CONCLUSION

R e g i o n a l a n e s t h e t i c t e c h n i q u e s o f f e r m a n y ad-

v a n t a g e s to o u r pa t i en t s , d o c u m e n t e d e l s e w h e r e

in th i s i s sue , a n d b e t t e r and , h o p e f u l l y , s a fe r

a g e n t s c o n t i n u e to b e d e v e l o p e d . N e v e r t h e l e s s ,

vigilance, t he m o t t o o f t he A m e r i c a n S o c i e t y o f

A n e s t h e s i o l o g i s t s , is s t i l l t he w a t c h w o r d in safe-

g u a r d i n g p a t i e n t s f r o m a d v e r s e r e s p o n s e s to l oca l

a n e s t h e t i c s or, fo r t ha t ma t t e r , f r o m a n y o f t he

d r u g s in o u r a r m a m e n t a r i u m .

REFERENCES L de Jong R: Local Anesthetics. Lancet 2:990-991, 1994 2. Atkinson RS, Rushman GB, Alfred Lee J: Regional

Analgesia. A Synopsis of Anaesthesia (ed 10). Bristol, En- gland, Wright Publications, 1987, pp 593-622

3. Covino BG: Pharmacokinetics of local anesthetic drugs, in Prys Roberts C, Hug C (eds): Pharmacokinetics of Anes- thesia. Oxford, UK, Blackwell Scientific, 1984, pp 202-208

4. Boston collaborative drug surveillance program: Drug induced convulsions. Lancet 2:677-679, 1972

5. Moore DC, Bridenbaugh LD, Bridenbaugh PO, et al: Does compounding of local anesthetics increase their toxicity in humans? Anesth Analg 51:579-585, 1972

6. Wagman IH, de Jong RH, Prince DA: Effects of lido- caine on the central nervous system. Anesthesiology 28:155- 172, 1967

7. Engelsson S: The influence of acid base changes on central nervous system toxicity of local anesthetic agents. I. An experimented study in cats. Acta Anaesthesiol Scand 18:79, 1974

8. Heavner JE, Dryden CF, Sanghani V, et al: Severe hyp- oxia enhances central nervous system and cardiovascular sys- tem toxicity of bupivacaine in lightly anesthetised pigs. Anes- thesiology 77:142-147, 1992

9. McClure J: Ropivacaine. Br J Anaesth 76:300-307, 1996

10. Reiz S, Nath S: Cardiotoxicity of local anesthetic agents. Br J Anaesth 58:736-746, 1986

11. Albright G: Cardiac arrest following regional anesthe- sia with etidocaine or bupivacaine. Anesthesiology 51:285- 287, 1979

12. Arlock P: Actions of three local anesthetics: Lido- caine, bupivacaine and ropivacaine on guinea pig papillary muscle sodium channels (Vm~,). Pharmacol Toxicol 63:96- 104, 1988

13. Nath S, H~ggmark S, Johansson G, et al: Differential

depressant and electrophysiologic cardiotoxicity of local an- esthetics: An experimental study with special reference to lidocalne and bupivacaine. Anesth Analg 65:1263-1270, 1986

14. Moller R, Covino B: Toxic cardiac electrophysiologic effects of bupivacalne and lidocaine at high concentrations. Anesthesiology 63:A223, 1985 (abstr)

15. Moller R, Covino B: Cardiac electrophysiologic ef- fects of lidocalne and bupivacaine. Anesth Analg 67:107- 114, 1988

16. Crandell J, Kotelko D: Cardiotoxicity of local anes- thetics during late pregnancy. Anesth Analg 64:204, 1985 (abstr)

17. Santos A, Arthur G, Wlody D, et al: Comparative systemic toxicity of ropivacaine and bupivacaine in nonpreg- nant and pregnant ewes. Anesthesiology 82:734-740, 1995

18. Mallampati S, Liu P, Knapp R: Convulsions and ven- tricular tachycardia from bupivacaine and epinephrine: Suc- cessful resuscitation. Anesth Analg 63:856-859, 1984

19. Davis N, de Jong R: Successful resuscitation following massive bupivacaine overdose. Anesth Analg 61:62-64, 1982

20. Palmisano B, Landow L: From the FDA. Anesthesiol- ogy 86:34A, 1997

21. Kasten G, Martin S: Bupivacaine cardiovascular toxic- it5,: Comparison of treatment with bretylium and lidocaine. Anesth Analg 64:911-916, 1985

22. Scott D, Lee A, Fagan D, et al: Acute toxicity of ropivacaine compared with that of bupivacaine. Anesth Analg 69:563-569, 1989

23. Feldman H, Arthur G, Covino B: Comparitive sys- temic toxicity of convulsant and supraconvulant doses of intravenous ropivacalne, bupivacedne and lidocaine in the conscious dog. Anesth Analg 69:794-801, 1989

24. Reiz S, H~iggmark S, Johansson G, et al: Cardiotoxic- ity of ropivacaine--A new amide local anesthetic agent. Acta Anaesthesiol Scand 33:93-98, 1989

25. Moller R, Covino B: Cardiac electrophysiologic prop- erties of bupivacaine and lidocaine compared with those of ropivacaine, a new amide local anesthetic agent. Anesthesiol- ogy 72:322-329, 1990

26. Moller R, Covino B: Effect of progesterone on the cardiac electrophysiologic alterations produced by ropiva- caine and bupivacaine. Anesthesiology 77:735-741, 1992

27. Selander D, Sjovli J, Waldenlind L: Accidental i.v. injections of ropivacaine: Clinical experience of six cases. Reg Anesth 22:2S, 70, 1997

SUGGESTED READING Clarkson C, Hondeghem L: Mechanism for bupivacaine

depression of cardiac conduction: Fast block of sodium chan- nels during the action potential with slow recovery from block during diastole. Anesthesiology 62:396-405, 1985

Reiz S, Nath S: Cardiotoxicity of local anesthetic agents. Br J Anaesth 58:736 746, 1986

Reynolds F: Adverse effects of local anesthetics. Br J An- aesth 59:78-95, 1987