The Influence of Age on Bupivacaine Cardiotoxicity

BACKGROUND: The susceptibility of children and newborns to cardiotoxicity from racemic bupivacaine, RS(+/-)-bupivacaine, is controversial. Some studies indicate that newborns can sustain higher bupivacaine plasma levels than adults, without severe toxicity. In this study, we compared the influence of age on cardiotoxicity from RS(+/-)-bupivacaine and S(-)-bupivacaine in rats. The effects of these local anesthetics (LAs) on the regulation of intracellular Ca2+ concentrations in cardiac fibers were also investigated. METHODS: The lethal dose was determined in ventilated male Wistar rats at 2, 4, 8, and 16 weeks of age by monitoring when cardiac electrical activity stopped after infusion of RS(+/-)bupivacaine and S(-)-bupivacaine (4 mg . kg(-1) . min(-1)). The effects on cardiac muscle contraction were investigated by in vitro measurement of papillary muscle twitches in the presence and absence of RS(+/-)-bupivacaine or S(-)-bupivacaine. Skinned ventricular fibers were used to investigate the intracellular effects on Ca2+ regulation induced by both LAs. RESULTS: The lethal dose for RS(+/-)-bupivacaine and S(-)-bupivacaine in 2-week-old animals (46.0 +/- 5.2 and 91.3 +/- 4.9 mg . kg(-1), respectively) was higher than in 16-week-old animals (22.7 +/- 1.3 and 22.0 +/- 2.7 mg . kg-1, respectively). Papillary muscle twitches were reduced in a dose-dependent manner, with significant difference between young and adult hearts. In adults, the muscle twitches were reduced to 8.6% +/- 0.8% of control by RS(+/-)-bupivacaine, and to 18.1% +/- 2.7% of control by S(-)-bupivacaine (100 +/- M). S(-)-bupivacaine had a positive inotropic effect at +/- 10 +/- M, but only in 2-week-old animals. In chemically skinned ventricular fibers, RS(+/-)-bupivacaine and S(-)-bupivacaine induced similar increases in Ca2+ release from the sarcoplasmic reticulum (SR) preactivated with caffeine (1 mM), and this effect was greater in younger rats than adults. In 16-week-old rats, caffeine-induced tension was 53.9% +/- 1.7% of the maximal fiber response with RS(+/-)-bupivacaine, and 54.1% +/- 3.2% with S(-)-bupivacaine. The caffeine response in 2-week-old rats was 81.1% +/- 3.7% of the maximal response with RS(+/-)-bupivacaine, and 78.1% +/- 4.5% with S(-)-bupivacaine. The Ca2+ sensitivity of contractile proteins was equally increased at both ages tested, with RS(+/-)-bupivacaine or S(-)-bupivacaine. Ca2+ uptake from the SR was not altered by the LA or by age. CONCLUSIONS: Differences in the mechanisms for regulating intracellular SR Ca2+ may contribute to the decreased susceptibility of young animals to cardiodepression induced by RS(+/-)-bupivacaine and S(-)-bupivacaine. (Anesth Analg 2011; 112: 574-80)