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LETTERS TO THE EDITOR

Local Anesthetic Toxicity: Different Mechanisms for Different End Points

University of Illinois, Chief, Anesthesia, Chicago VA, Westside Division, Chicago, IL

To the Editor:

Ohmura et al. (1) report that after IV infusion in rats different serum concentrations of bupivacaine, levobupivacaine, and ropivacaine were achieved at the start of dysrhythmias, whereas nearly identical serum concentrations of the three were measured at the time of asystole. This suggests there are probably different sites of anesthetic action underlying the two clinical end points. Local anesthetics interfere with a wide range of cellular activities and the clinical phenotype of local anesthetic cardiac toxicity is correspondingly complex (e.g., various arrhythmias, conduction abnormalities, contractile dysfunction).

Notably, the anesthetic concentrations found by Ohmura et al. (1) at the time of cardiovascular collapse were more than 100-fold more than those reported to block sodium ion channels (2), but were the same order of magnitude (0.1 mM) as inhibits mitochondrial transport of fatty acids, the heart’s preferred fuel in aerobic metabolism (3). Furthermore, their findings support a bupivacaine site of action leading to the end point of asystole that is neutral with respect to chirality. Sztark et al. (4) showed adverse effects on mitochondrial respiration at the same concentration for both isomers of bupivacaine.

I believe the findings of Ohmura et al. (1) support the potential relevance of a mitochondrial mechanism in severe local anesthetic-induced cardiac toxicity.

References

1. Ohmura S, Kawada M, Ohta T, et al. Systemic toxicity and resuscitation in Bupivacaine-, levobupivacaine-, or ropivacaine-infused rats. Anesth Analg 2001; 93: 743–8.[Abstract/Free Full Text]
2. Clarkson CW, Hondeghem LM. Mechanism for bupivacaine depression of cardiac conduction: fast block of sodium channels during the action potential with slow recovery from block during diastole. Anesthesiology 1985; 62: 396–405.[Web of Science][Medline]
3. Weinberg GL, Palmer JW, VadeBoncouer TR, et al. Bupivacaine inhibits acylcarnitine exchange in cardiac mitochondria. Anesthesiology 2000; 92: 523–8.[Web of Science][Medline]
4. Sztark F, Nouette-Gaulain K, Malgat M, et al. Absence of stereospecific effects of bupivacaine isomers on heart mitochondrial bioenergetics. Anesthesiology 2000; 93: 456–62.[Web of Science][Medline]

Response

Department of Anesthesiology and Intensive Care Medicine, Kanazawa University School of Medicine, Kanazawa, Japan

In Response:

We thank Dr. Weinberg for his interest in our recent publication (1) and appreciate the opportunity to respond to his comments. Dr. Weinberg and colleagues (2) proposed the inhibition of mitochondrial transport of fatty acid as a mechanism underlying the cardiovascular toxicity of local anesthetics. They calculated the half- inhibitory concentrations (IC₅₀) for bupivacaine and ropivacaine as 0.26 mM and 0.65 mM, respectively. It seems that these IC₅₀ values are still higher than the corresponding plasma concentrations of bupivacaine and ropivacaine at the onset of asystole reported in our paper (0.13 mM and 0.15 mM, respectively). However, care must be taken in interpreting our data because the plasma concentrations of local anesthetics at the onset of asystole are considerably affected by the rate of infusion (3). In addition, isoflurane, which has been reported to affect different mitochondrial functions (4), was used for basal anesthesia in our study.

We suppose that the cardiovascular toxicity induced by local anesthetics may be explained in part by the mitochondrial mechanism. However, the clinical relevance of the mechanism is yet to be determined.

References

1. Ohmura S, Kawada M, Ohta T, et al. Systemic toxicity and resuscitation in bupivacaine-, levobupivacaine-, or ropivacaine-infused rats. Anesth Analg 2001; 93: 743–8.
2. Weinberg GL, Palmer JW, VadeBoncouer TR, et al. Bupivacaine inhibits acylcarnitine exchange in cardiac mitochondria. Anesthesiology 2000; 92: 523–8.
3. Dony P, Dewinde V, Vanderick B, et al. The comparative toxicity of ropivacaine and bupivacaine at equipotent doses in rats. Anesth Analg 2000; 91: 1489–92.[Abstract/Free Full Text]
4. Cohen PJ. Effect of anesthetics on mitochondrial function. Anesthesiology 1973; 39: 153–64.[Web of Science][Medline]

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