Comparative Cardiovascular Toxicity (also see Chapter 43 , Chapter 44 , Chapter 45 , and Chapter 58 )

In recent years, the more potent drugs (i.e., bupivacaine and etidocaine) have been reported to cause rapid and profound cardiovascular depression.

The cardiotoxicity of the more potent drugs such as bupivacaine appears to differ from that of lidocaine in the following manner^[139] :

1. The ratio of the dosage required for irreversible cardiovascular collapse (CC) and the dosage that will produce CNS toxicity (convulsions) (i.e., the CC/CNS ratio) is lower for bupivacaine and etidocaine than for lidocaine.
2. Ventricular arrhythmias and fatal ventricular fibrillation may occur more often after rapid intravenous administration of a large dose of bupivacaine but far less frequently with lidocaine.
3. A pregnant animal or patient may be more sensitive than a nonpregnant animal or patient to the cardiotoxic effects of bupivacaine.
4. Cardiac resuscitation is more difficult after bupivacaine-induced cardiovascular collapse.
5. Acidosis and hypoxia markedly potentiate the cardiotoxicity of bupivacaine.

CC/CNS Ratio

In sheep, the CC/CNS dose and blood level ratios for bupivacaine and etidocaine were found to be lower than those for lidocaine.^[140] A CC/CNS dose ratio of 7.1 ± 1.1 was found for lidocaine, which indicates that seven times as much drug was required to induce irreversible cardiovascular collapse as was needed to produce convulsions. The CC/CNS dose ratio for bupivacaine was 3.7 ± 0.5 whereas that for etidocaine was 4.4 ± 0.9, and the CC/CNS blood level ratio for lidocaine was 3.6 ± 0.3 versus 1.6 to 1.7 for bupivacaine and etidocaine. At the time of cardiovascular collapse, higher concentrations of bupivacaine and etidocaine than lidocaine were present in the myocardium, which suggests that some of the enhanced cardiac toxicity of these more potent drugs is due to greater myocardial uptake.

Ventricular Arrhythmias

Bupivacaine and to a lesser degree etidocaine may induce severe cardiac arrhythmias, including ventricular fibrillation, in various animal species. ^{[134] [141] [142] [143] [144] [145]} Ventricular arrhythmias were rarely seen with lidocaine, mepivacaine, or tetracaine. ^[146] These electrophysiologic effects of bupivacaine may result in conduction abnormalities leading

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Enhanced Cardiotoxicity in Pregnancy (also see Chapter 58 )

A number of the cardiotoxic reactions that have been reported after the use of bupivacaine occurred in pregnant patients. As a result, the 0.75% solution is no longer recommended for use in obstetric anesthesia in the United States. In studies of pregnant and nonpregnant sheep, the CC/CNS dose ratio of bupivacaine decreased from 3.7 ± 0.5 in nonpregnant to 2.7 ± 0.4 in pregnant animals.^[140] However, little difference was observed in the CC/CNS blood level ratio, which varied from 1.6 ± 1.0 in nonpregnant animals to 1.4 ± 0.1 in pregnant ewes. The blood level of bupivacaine at which circulatory collapse occurred was lower in pregnant animals, but no difference in the myocardial uptake of bupivacaine in pregnant and nonpregnant sheep was observed at the time of cardiovascular collapse.

Cardiac Resuscitation (also see Chapter 78 )

Studies in acidotic and hypoxic sheep have demonstrated that cardiac resuscitation after bupivacaine-induced toxicity is difficult.^[149] Studies in cats and hypoxic dogs rendered toxic with bupivacaine indicate that resuscitation is possible if massive doses of epinephrine and atropine are administered.^{[150] [151]} In addition, bretylium but not lidocaine could raise the ventricular tachycardia threshold that was lowered by bupivacaine.^[152] Other drugs have also been tested for their effects on resuscitation from bupivacaine cardiotoxicity. Amrinone was found to be effective in two studies in dogs but ineffective in a study in rats. Case reports have suggested that either bretylium or phenytoin ^[153] may be effective.

The clinical implications for cardiac resuscitation after an intravascular injection or overdose of local anesthetic are the following:

1. No medications are uniformly effective in facilitating resuscitation from bupivacaine-induced cardiac arrest or severe ventricular tachycardia. The basic principles of cardiopulmonary resuscitation should be emphasized first, including attention to securing the airway, providing oxygenation and ventilation, and instituting chest compressions if needed. Epinephrine remains a first-line choice of medication in the event of circulatory collapse.
2. Because resuscitation after local anesthetic-induced circulatory collapse is so difficult, prevention of massive intravascular injection or excessive dosing is crucial.
3. Negative aspiration of the syringe does not always exclude intravascular placement. Incremental, fractionated dosing should be the rule for all patients undergoing major conduction blockade. Although changes in the ECG are not always present before circulatory collapse, they often are, and continuous attention to the ECG (including changes in QRS morphology, rate, rhythm, or ectopy) may be lifesaving by terminating injection before a lethal dose is administered.

Ropivacaine

In response to reports of cardiovascular toxicity from accidental intravenous injection of bupivacaine,^[75] a new long-lasting amide local anesthetic was developed. Ropivacaine (Naropin) differs from bupivacaine both in the substitution of a propyl for the butyl group on the piperidine ring's tertiary nitrogen atom and the fact that it consists of a single enantiomer, the (S)-stereoisomer (see Fig. 14-2 ). Commercial bupivacaine is a racemic mixture of both isomers, whereas lidocaine, which lacks a chiral center, has no stereosymmetry. With these designed changes in molecular structure, it was hoped that ropivacaine would be less intrinsically cardiotoxic. The hope that it would be cleared more rapidly from the circulation if injected intravenously has, however, been confounded by evidence that the (S)-enantiomers of mepivacaine and bupivacaine are metabolized by the liver more slowly than the corresponding (R)-enantiomers, as well as having a slower rate of total-body clearance. ^{[154] [155]}

The cardiovascular toxicity of local anesthetics is complex and involves direct effects on the myocardium,^[129] on vascular tissue^[138] (both smooth muscle and its neuronal supply), and on the central innervation of the heart.^{[147] [156]} In both neuronal and cardiac Na⁺ channels, the (S)-isomers of these piperidine-containing local anesthetics are less potent than the (R)-isomers,^{[157] [158]} but the stereopotency of the cardiovascular effects mediated through vascular tissue and the CNS is not known. Because of the smaller propyl substituent, (S)-ropivacaine is slightly less potent than (S)-bupivacaine in its effect on single sodium channels ^[159] and isolated nerve action potentials. More germane to the direct cardiotoxic actions is that the very slow reversal of Na⁺ channel blockade after a cardiac action potential, which is a hallmark of bupivacaine, is considerably faster with ropivacaine.^[160] Such slow drug reversal has been related to persistent conduction slowing, reentry circuits, and the development of ventricular tachycardias leading to fibrillation.^[127] In addition to these electrical differences, the negative inotropic potency of ropivacaine on isolated cardiac tissue appears to be considerably less than that of bupivacaine. ^{[160] [161]} Both electrical and mechanical differences in the toxic profiles may arise from the selective inhibition of Ca²⁺ currents by bupivacaine.^{[128] [146] [162]}

Do the data thus far support the claim of a greater therapeutic index for ropivacaine than bupivacaine, particularly with regard to cardiotoxicity? In clinical studies comparing potencies of ropivacaine and bupivacaine administered for brachial plexus^[163] or lumbar epidural block, ^{[164] [165]} the anesthetic profiles of the drugs were almost identical. A third study comparing lumbar epidural 0.5% bupivacaine with 0.75% ropivacaine also found no significant differences in motor or sensory effects betweenthe drugs at these different concentrations.^[166] Overall, it appears that ropivacaine is slightly less potent than (1:1.3 to 1:1.5) or equally as potent as bupivacaine for regional anesthesia. In some laboratory animal studies

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At the projected equipotent doses for nerve block, are the drugs equally toxic? The overall impression is that ropivacaine is less cardiotoxic than bupivacaine. Studies in animals have generally found that bupivacaine more readily produces conduction disturbances, cardiac collapse, or ventricular fibrillation than ropivacaine does.

Chirality rather than the difference between the propyl- and butyl-N-piperidine substituent may account for the greater safety of ropivacaine, for many fewer cardiotoxic events also occur when (S)-bupivacaine (levobupivacaine) rather than racemic bupivacaine is administered to sheep. In contrast, death from ventricular arrhythmias is comparable between ropivacaine and bupivacaine at equipotent doses in sheep. Convulsant doses of ropivacaine are larger than those of bupivacaine but less than those of lidocaine. ^{[170] [171]} Levobupivacaine has been developed for clinical use,^[172] and studies are in progress to determine whether it will have unique clinical benefits.

Perhaps the most notable difference between ropivacaine and bupivacaine is that aggressive cardiac resuscitation after an intentional intravenous bolus in dogs led to effective reversal of the toxic effects far more frequently with ropivacaine than with bupivacaine.^[173] Furthermore, intravenous ropivacaine is cleared from the circulation more rapidly than intravenous bupivacaine. ^[174] This feature will enhance the safety of ropivacaine relative to bupivacaine when the drugs are used for repeated dosing or by infusion. In contrast to bupivacaine, the cardiotoxic profile of ropivacaine in pregnant ewes is the same as the corresponding profile in nonpregnant ewes.^[175] These studies would suggest that ropivacaine may have slightly greater safety than bupivacaine for local and regional anesthesia.

Acidosis and Hypoxia

Hypercapnia, acidosis, and hypoxia potentiate the negative chronotropic and inotropic action of lidocaine and bupivacaine in isolated cardiac tissue, and the combination of hypoxia and acidosis markedly potentiates the cardiodepressant effects of bupivacaine. Hypoxia and acidosis also increased the frequency of cardiac arrhythmias and the mortality rate in sheep after the intravenous administration of bupivacaine.^{[149] [176]} Hypercapnia, acidosis, and hypoxia occur very rapidly in some patients after seizure activity induced by the rapid accidental intravascular injection of local anesthetics. ^[177] Thus, the cardiovascular depression observed in some patients after the accidental intravenous injection of bupivacaine may be related in part to the severe acid-base changes that occur during toxic reactions to this drug.

Indirect Cardiovascular Effects

High levels of spinal or epidural blockade can produce severe hypotension. In a review of closed claims of patients who suffered perioperative cardiac arrest, a series of cases were identified that involved generally healthy patients undergoing spinal anesthesia.^[178] Common features of these cases and subsequent case series^[179] included high dermatomal levels of spinal anesthesia, liberal use of sedatives, and hypotension accompanied by bradycardia. The authors noted that adverse outcomes seemed to be associated with delays in recognition of the problem, delays in instituting airway support (particularly in sedated patients), and delays in administration of direct-acting combined α- and β-adrenergic agonists such as epinephrine. Although mild degrees of hypotension generally respond well to indirect-acting sympathomimetics such as ephedrine or incremental dosing of phenylephrine, the combination of severe hypotension and significant bradycardia under spinal anesthesia should in most clinical settings be treated promptly with incremental dosing of epinephrine.