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Neurally-mediated Cardiotoxicity of Local Anesthetics: Direct Effect of Seizures or of Local Anesthetics?

de La Coussaye, Jean E. M.D., Ph.D.*; Aya, A.Guy M. M.D., Ph.D.; Eledjam, Jean-Jacques M.D.

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To the Editor:—
Ladd et al.1 showed in conscious sheep that the administration of incremental doses of local anesthetics in the central nervous system bloodstream induces minimal systemic recirculation, dose-dependent central nervous system excitatory behavior, and electroencephalographic changes. These authors also observed that bupivacaine is more neurotoxic than levobupivacaine, which is also more neurotoxic than ropivacaine. Finally, they stated that there are no differences among the drugs concerning their arrhythmogenicity.
It is well established that large doses of local anesthetics slow cardiac conduction velocity in a dose- and use-dependent manner by inhibiting the fast-inward sodium current. 2 The slowing of ventricular conduction velocity is responsible for a proportional QRS widening 3,4 and facilitates the occurrence of reentrant ventricular arrhythmias around arcs of conduction block. 5,6 In other words, the increase in heart rate by enhancing the slowing of ventricular conduction is one of the main mechanisms facilitating the occurrence of serious reentrant ventricular arrhythmias in the case of high plasma concentration. Moreover, Mazoit et al.7 and our team 8 reported that bupivacaine is more use-dependent than levobupivacaine and ropivacaine. This fact explains at least in part the differences in direct cardiotoxicity in these three local anesthetics. As demonstrated by Bernards and Artru 9,10 and our team, 11 an overdose of local anesthetics induces an increase in the sympathetic outflow by their direct neurotoxicity and therefore an increase in heart rate, facilitating the occurrence of serious reentrant arrhythmias when toxic cardiac concentrations are reached.
In the elegant study published by Ladd et al., 1 RR and PR intervals are obviously shortened. In contrast and surprisingly, QRS is shortened by the administration of any local anesthetics at any dose. One might argue that the baseline values are somewhat widened and that the method of measurement, including the paper speed, is not specified in the method section. Nevertheless, because QRS is not widened, one could specially argue that there is no direct cardiotoxicity and that the observed arrhythmias are only due to the pre- and convulsant effects of local anesthetics as any seizures can provoke. In conclusion, the sentence in the summary that “no differences were found in their arrhythmogenic potential”1 may be confusing because the analyzed arrhythmogenicity in the present study is only in terms of indirect and neurally mediated cardiotoxicity and not in terms of direct cardiotoxicity.
Jean E. de La Coussaye, M.D., Ph.D.*
A.Guy M. Aya, M.D., Ph.D.
Jean-Jacques Eledjam, M.D.
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References

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5. Brugada J, Boersma L, Kirchhof C, Allessie MA: Proarrhythmic effects of flecainide: Experimental evidence for increased susceptibility to reentrant arrhythmias. Circulation 1991; 84: 1808–18

6. de La Coussaye JE, Brugada J, Allessie MA: Electrophysiologic and arrhythmogenic effects of bupivacaine. A study with High-resolution ventricular epicardial mapping in rabbit heart. A nesthesiology 1992; 77: 132–41

7. Mazoit JX, Decaux A, Bouaziz H, Edouard A: Comparative ventricular electrophysiologic effect of racemic bupivacaine, levobupivacaine, and ropivacaine on the isolated rabbit heart. A nesthesiology 2000; 93: 784–92

8. Aya AG, de La Coussaye JE, Robert E, Ripart J, Cuvillon P, Mazoit JX, Jeannes P, Fabbro-Péray P, Eledjam JJ: Comparison of the effects of racemic bupivacaine, levobupivacaine, and ropivacaine on ventricular conduction, refractoriness and wavelength. An epicardial mapping study. A nesthesiology 2002; 96: 641–50

9. Bernards CM, Artru AA: Hexamethonium and midazolam terminate dysrhythmias and hypertension caused by intracerebroventricular bupivacaine in rabbits. A nesthesiology 1991; 74: 89–96

10. Bernards CM, Artru AA: Effects of intracerebroventricular picrotoxin and muscimol on intravenous bupivacaine toxicity: Evidence supporting central nervous system involvement in bupivacaine cardiovascular toxicity. A nesthesiology 1993; 78: 902–10

11. de La Coussaye JE, Eledjam JJ, Bruelle P, Lefrant JY, Bassoul B, Peray PA, Desch G, Sassine A: Mechanisms of the putative cardioprotective effect of hexamethonium in anesthetized dogs given a large dose of bupivacaine. A nesthesiology 1994; 80: 595–605

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