Cardiovascular and central nervous system toxicity of local anesthetics

Cardiovascular and Central Nervous System Toxicity of Local Anesthetics Parvinder Singh and Jeffrey S. Lee 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 benefits as well as a potential for toxicity. While describing 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 toward the end of the 19th century, soon after the toxic effects of cocaine became known. Around the dawn of the 20th century, three cocaine substitutes, tropocaine, stovaine, and novocaine, were tried. In 1943, Lofgren 1 synthesized the amide-linked local anesthetic lidocaine; this started the practice of regional anesthesia with which we are familiar today. Lidocaine had a short duration of action; thus, the longer-acting bupivacaine 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 continues with the introduction of ropivacaine. This review will focus on the factors influencing local anesthetic toxicity: the manifestations, underlying mechanisms, and prevention and treatment of central nervous system (CNS) and cardiovascular system toxicity. The incidence of toxic events is not well documented. 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

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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 18

effect by deformation of the sodium channels on the membranes of cells. This change in configuration of the sodium channel inhibits sodium influx and thus depolarization of the cell membrane. 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 unwanted, even dangerous, effects when other excitable tissues (ie, the heart and brain) are exposed 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. P r e s e n c e or absence o f epinephrine: the presence of vasoconstrictors delays the absorption of the drug into the circulation 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 resulted 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 cocaine, all local anesthetics are vasodila-

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

CVS AND CNS TOXICITY OF LOCAL ANESTHETICS 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 absorption. Thus, etidocaine, a more lipid soluble drug than bupivacaine, tends to be sequestered by the adipose tissue, resulting in a decreased rate of absorption and lower plasma le.vels than bupivacaine. 5. Rate of destruction of drug: the faster metabolized drugs will cause less cumulative toxicity. In acute toxicity, this factor 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 proteinbinding sites may increase the unbound local anesthetic concentration. Likewise, patients with advanced liver disease have at least a theoretical risk of toxicity at a lower dose of local anesthetic drug than normal patients because of decreased synthesis of plasma proteins. With advancing age, the volume of distribution 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 reducing hepatic blood flow and inhibiting mixed function oxidases, cimetidine and propranolol lead to reduced hepatic clearance of local anesthetics. All inhalational anesthetics also reduce hepatic blood flow and probably reduce clearance. The clinical significance of these interactions is not clear, and how individual patients are affected also varies considerably. CENTRAL NERVOUS SYSTEM TOXICITY Central nervous system toxicity is a relatively early manifestation of toxicity from local anesthetic drugs and can occur at plasma levels of the drug that may well be within the therapeutic range. The incidence varies according to the indication for which local anesthetic is being used.

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When lidocaine is used intravenously, as an antiarrhythmic 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 r o u t e Y Toxic levels are most often achieved by unintentional intravascular injection, although slow absorption from a peripheral site can have the same undesirable end result. Local anesthetics are CNS depressants, although 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 unopposed. 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 complain 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, finally, 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 elevated Paco2, decreases the convulsive threshold. 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 cardiovascular toxicity, and can be lethal in this setting. Conversely, oxygen per se does not prevent 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 during convulsions, but this is compensated by autoregulatory 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-

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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 providing 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 shortacting muscle relaxants (succinylcholine or mivacurium) 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 anesthetic practice, most patients will likely have been given a benzodiazepine premedication, either orally or intravenously. Oxygen should be administered before initiating the regional anesthetic 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 depressant, 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 address this problem. Whether the surgical procedure should proceed once the patient is asleep and intubated is best decided in the individual situation after discussion 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 effects 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 11editorial in Anesthesiology described six cases of sudden cardiovascular collapse that were not always preceded by seizures. Another common denominator was that all patients received potent, lipidsoluble drugs: bupivacaine (five cases) or etidocaine (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 editorial was replaced by mounting clinical evidence of an enhanced cardiotoxicity of bupivacaine and etidocaine. In 1983, the Food and Drug Administration ruled that 0.75% bupivacaine concentration "was no longer recommended for obstetric anesthesia. ''9'1~ After this rather unconventional recommendation, a plethora of animal and human investigations was launched; the majority of the evidence favored Albright's opinion that etidocaine and the far more commonly used bupivacaine are different from lidocaine in their effect 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 impulses 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 Purkinje 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, making 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 logic effects make bupivacaine a more cardiotoxic 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 surprising that an overdose of local anesthetics can cause hypotension, prolongation of QT interval, reentrant arrythmias, and cardiac arrest. Although initial case reports alluded to failed resuscitation following bupivacaine toxicity, successful resuscitation has been accomplished, 18'~9 and bretylium 2~ was better than lidocaine for reversing these cardiac effects in a dog model. The treatment is oxygenation and restoration of hemodynamics. In the face of unstable hemodynamics, external cardiac massage should be instituted, followed by, if necessary, inotropic support. Persistent ventricular tachycardia or fibrillation 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 volume 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 maxim u m 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).

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There are only two ways for local anesthetics to gain access to the blood: absorption from tissue or direct deposition through a needle either intentionally (a Bier block) or unintentionally while performing the block. When performing intravenous regional anesthesia (Bier block), potentially 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, realizing that a large volume of agent must be injected to have a successful anesthetic, the practitioner should use the minimum concentration of local anesthetic estimated to cause satisfactory anesthesia. The most likely cause of a toxic reaction during 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 tourniquet is working and inflated before the proximal tourniquet is released. At the end of the procedure, 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. If 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 patient 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 further, more dangerous, manifestations can be avoided. Indeed, in one study in 12 unpremedicated male volunteers given 100 mg/min intravenous lidocaine, all reported early, non-lifethreatening 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 strategy is to stay below the maximum recommended dose. This admonition falls by the wayside when

22 a very small volume of local anesthetic is injected into a carotid or a vertebral artery. Frequent aspiration and injection of local anesthetic in small incremental aliquots is the mainstay of preventing toxicity. Even this method is not foolproof, however. A needle or catheter can be in a vessel lumen and not deliver blood on aspiration if, for example, the negative pressure of aspiration pulls the intima against the cannula opening. Adjuvants added to the local anesthetic to enhance the quality of anesthesia also have been advocated as early markers of intravascular injection. 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 medications or general anesthesia. Small doses of epinephrine (10 to 20 #g) have been shown to cause a rapid but evanescent increase 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-blockers) 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 patients, the potential for vasoconstriction with small doses of intravascular epinephrine has been considered risky, eg, mothers and fetuses with compromised placental function. Once intravascular 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 absorption 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 peripheral vasoconstriction but not of tachycardia. Injection of small quantities of air along with precordial doppler monitoring, as is done in sitting 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

SINGH AND LEE at the site where regional anesthesia is being delivered. 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 reports 10 to 15 years ago heightened the awareness of the anesthesia community such that the reports of death due to this agent have waned considerably. Nevertheless, the potential cardiotoxicity of bupivacine and etidocaine have led to a search for a less toxic agent. In 1996, ropivacaine was introduced into clinical practice in the United States. Ropivacaine and bupivacaine (and mepivacaine for that matter) share a common chemical structure, except that a propyl group in ropivacaine replaces a butyl 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 demonstrated 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 bupivacaine. 23 In a human study, ropivacaine produced less CNS symptoms at a dose 25% greater than bupivacaine) 2 Cardiovascular effects of bupivacaine appeared at a lower dose and lower plasma concentration. Although ropivacaine and bupivacaine 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 accidental intravenous injection of 75 to 200 mg ropivacaine. Only one patient (male) convulsed; the other patients reported mild CNS symptoms. No patient showed signs or symptoms of cardiovascular toxicity.

CVS AND CNS TOXICITY OF LOCAL ANESTHETICS 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 f o r fut u r e u s e is t h e 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 caine, which may offer most of this agent' s anest h e t i c a d v a n t a g e s w i t h r e d u c e d c a r d i a c risk.

CONCLUSION Regional anesthetic techniques offer many adv a n t a g e s to o u r p a t i e n t s , d o c u m e n t e d e l s e w h e r e in this issue, and better and, hopefully, safer agents continue to be developed. Nevertheless, vigilance, t h e m o t t o o f t h e 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 still t h e w a t c h w o r d i n s a f e 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 o c a l a n e s t h e t i c s or, f o r t h a t m a t t e r , f r o m a n y o f t h e drugs in our armamentarium.

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, England, Wright Publications, 1987, pp 593-622 3. Covino BG: Pharmacokinetics of local anesthetic drugs, in Prys Roberts C, Hug C (eds): Pharmacokinetics of Anesthesia. 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 lidocaine on the central nervous system. Anesthesiology 28:155172, 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 hypoxia enhances central nervous system and cardiovascular system toxicity of bupivacaine in lightly anesthetised pigs. Anesthesiology 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 anesthesia with etidocaine or bupivacaine. Anesthesiology 51:285287, 1979 12. Arlock P: Actions of three local anesthetics: Lidocaine, bupivacaine and ropivacaine on guinea pig papillary muscle sodium channels (Vm~,). Pharmacol Toxicol 63:96104, 1988 13. Nath S, H~ggmark S, Johansson G, et al: Differential

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depressant and electrophysiologic cardiotoxicity of local anesthetics: 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 effects of lidocalne and bupivacaine. Anesth Analg 67:107114, 1988 16. Crandell J, Kotelko D: Cardiotoxicity of local anesthetics 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 nonpregnant and pregnant ewes. Anesthesiology 82:734-740, 1995 18. Mallampati S, Liu P, Knapp R: Convulsions and ventricular tachycardia from bupivacaine and epinephrine: Successful 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. Anesthesiology 86:34A, 1997 21. Kasten G, Martin S: Bupivacaine cardiovascular toxicit5,: 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 systemic 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: Cardiotoxicity of ropivacaine--A new amide local anesthetic agent. Acta Anaesthesiol Scand 33:93-98, 1989 25. Moller R, Covino B: Cardiac electrophysiologic properties of bupivacaine and lidocaine compared with those of ropivacaine, a new amide local anesthetic agent. Anesthesiology 72:322-329, 1990 26. Moller R, Covino B: Effect of progesterone on the cardiac electrophysiologic alterations produced by ropivacaine 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 channels 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 Anaesth 59:78-95, 1987