Assessment of possible central nervous system or cardiac toxicity associated with use of bupivacaine or levobupivacaine
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Bupivacaine (1-butyl-N-[2,6-dimethylphenyl] piperidine-2-carboxamide) is used as a local anesthetic for many surgical procedures, and is injected directly into surgical sites to reduce pain for up to 20 hours postsurgery. As an injectable local anesthetic, the drug is used to effect peripheral, sympathetic, caudal, epidural, or retrobulbar nerve membrane permeability to sodium ions, which results in inhibition of depolarization with resultant conduction blockade.(1)
The onset and duration of anesthesia is route- and dose-dependent, ranging from 1 to 17 minutes and lasting for 2 to 9 hours.(1) The drug is highly protein bound (approximately 95%), and has a volume of distribution (Vd) of 0.4 L/kg to 1.0 L/kg. Bupivacaine under goes significant metabolism; <1% of a dose is excreted unchanged.(2) The half-life elimination is age-dependent: approximately 8 hours in neonates and 1.5 to 5.5 hours in adults.(1)
Serum levels of bupivacaine correlate poorly with anesthesia effect because the drug's distribution out of the injection site is variable. However, serum levels may have value in indicating potential toxicity remote from the injection site. In general, central nervous system (CNS) and cardiovascular events are the primary toxicities and include tremor, tinnitus, dizziness, blurred vision, hypotension, and bradycardia. CNS symptoms of toxicity appear at lower serum levels than do cardiovascular symptoms.(3) Intralipid has been proposed as a treatment for the cardiotoxicity, but neither the optimum dose nor guidelines for intervention have been defined, so its use remains controversial and limited to those cases of cardiotoxicity when cardiopulmonary bypass is the only other option.
The drug is now available as the principally active optical isomer, levobupivacaine (this assay measures levobupivacaine and the racemic mixture [levobupivacaine and bupivacaine] equally). The occurrence of CNS toxicity with use of levobupivacaine is 1.5 to 2.5 times lower than with bupivacaine, from studies in healthy volunteers, with CNS toxicity onset coming at approximately 25% higher doses.(4) Since both drugs are often administered for local anesthesia at levels near the top of the tolerated range, it has proven difficult to objectively assess potency, and there is no clear conclusion as to which drug is more potent.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
No established reference values
In trials with healthy volunteers, the threshold for central nervous system (CNS) toxicity has been reported at 2.1 (+/- 1.2) mg/L following intravenous infusion,(3) and in another trial, 13 of 14 healthy volunteers reported signs of CNS toxicity at 2.25 mg/L of racemic bupivacaine.(5) Cardiovascular symptoms were reported in many fewer subjects, indicating slightly higher threshold for cardiovascular toxicity.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
This assay is to be used only for serum drawn from a vein. Arterial levels are approximately twice venous levels and no clear relationship between arterial levels and toxicity has been established.(3)
This assay measures only total bupivacaine; levels of the free (unbound) portion may correlate more closely with symptoms.
Clinical Reference Provides recommendations for further in-depth reading of a clinical nature
1. Physician's Desk Reference (PDR). 61st edition. Montvale, NJ. Thomson PDR, 2007
2. Baselt RC: Disposition of Toxic Drugs and Chemicals in Man. 7th edition. Foster City, CA, Biomedical Publications, 2004, p 1254
3. Knudsen K, Beckman SM, Blomberg S, et al: Central nervous and cardiovascular effects of i.v. infusions of ropivacaine, bupivacaine and placebo in volunteers. Br J Anaesth 1997;78:507-514
4. Zink W, Graf BM: The toxicity of local anesthetics: the place of ropivacaine and levobupivacaine. Curr Opin Anaesthesiol 2008;21:645-650
5. Bardsley H, Gristwood R, Baker H, et al: A comparison of the cardiovascular effects of levobupivacaine and rac-bupivacaine following intravenous administration to healthy volunteers. Br J Clin Pharmacol 1998;46:245-429