Letters To The Editor: Letters & Announcements
To the Editor:
Cho et al (1). reported a salutary effect of insulin-glucose or insulin-glucose-potassium infusion on bupivacaine-induced myocardial depression in dogs. The authors hypothesize that the improved cardiac output is attributable to insulin stimulation of either the transient outward potassium current or the calcium dependent adenosine triphosphatase. We would like to offer another possible explanation of this effect.
Bupivacaine is a potent mitochondrial poison that is able to disrupt every component of oxidative phosphorylation (2–4). Thus, bupivacaine infusion should depress cardiac performance, as do other factors that inhibit mitochondrial respiration, such as cyanide or tissue ischemia. Obversely, treatment that restores intracellular adenosine triphosphate (ATP) levels should repair cardiac function. Eledjam et al (5) demonstrated that myocardial strips exposed to bupivacaine recover normal contractile force when incubated in a solution containing ATP.
We have previously shown that bupivacaine strongly inhibits the mitochondrial transport of fatty acids (6), the heart’s preferred fuel in normal aerobic metabolism, at concentrations that do not inhibit respiration supported by pyruvate, the end product of glycolysis. This substrate specificity, along with the heart’s predilection for burning lipid substrate and the brain’s preference for using carbohydrate-to-fuel respiration, may explain the disproportionate cardiotoxicity of bupivacaine relative to its neurotoxicity.
Thus we propose that the benefit of insulin-glucose infusion in treating bupivacaine cardiotoxicity is derived by supplying the heart with an alternative fuel to oxidize in support of ATP synthesis. Lacking lipid to burn, cardiac mitochondria exposed to bupivacaine will oxidize pyruvate to generate a proton motive force and synthesize ATP. Infusing insulin-glucose should increase cytoplasmic glucose concentrations and pyruvate availability to mitochondria, thereby improving myocardial energetics and performance.
Guy Weinberg, MD
Timothy VadeBoncouer, MD
1. Cho HS, Lee JJ, Chung IS, Shin BS, Kim JA, Lee KH. Insulin reverses bupivacaine-induced cardiac depression in dogs. Anesth Analg 2000; 91: 1096–102.
2. Dabadie P, Bendriss P, Erny P, Mazat JP. Uncoupling effects of local anesthetics on rat liver mitochondria. FEBS Lett 1987; 226: 77–82.
3. Dabbeni-Sala F, Schiavo G, Palatini P. Mechanism of local anesthetic effect on mitochondrial ATP synthase as deduced from photolabelling and inhibition studies with phenothiazine derivatives. Biochim Biophys Acta 1990; 1026: 117–25.
4. Sztark F, Malgat M, Dabadie P, Mazat J-P. Comparison of the effects of bupivacaine and ropivacaine on heart cell mitochondrial bioenergetics. Anesthesiology 1998; 88: 1340–9.
5. Eledjam JJ, de La Coussaye JE, Brugada J, et al. In vitro
study on mechanisms of bupivacaine-induced depression of myocardial contractility. Anesth Analg 1989; 69: 732–5.
6. Weinberg GL, Palmer JW, VadeBoncouer TR, et al. Bupivacaine inhibits acylcarnitine exchange in cardiac mitochondria. Anesthesiology 2000; 92: 523–8.