title: Cardiac and CNS toxicity of levobupivacaine: strengths of evidence for advantage over bupivacaine.
abstract: Bupivacaine is currently the most widely used long-acting local anaesthetic. Its uses include surgery and obstetrics; however, it has been associated with potentially fatal cardiotoxicity, particularly when given intravascularly by accident. Levobupivacaine, a single enantiomer of bupivacaine, has recently been introduced as a new long-acting local anaesthetic with a potentially reduced toxicity compared with bupivacaine. Numerous preclinical and clinical studies have compared levobupivacaine with bupivacaine and in most but not all studies there is evidence that levobupivacaine is less toxic. Advantages for levobupivacaine are seen on cardiac sodium and potassium channels, on isolated animal hearts and in whole animals, anaesthetised or awake. In particular the intravascular dose of levobupivacaine required to cause lethality in animals is consistently higher compared with bupivacaine. In awake sheep, for example, almost 78% more levobupivacaine was required to cause death. In contrast, in anaesthetised dogs no differences were seen in the incidence of spontaneous or electrical stimulation- induced ventricular tachycardia and fibrillations among animals exposed to levobupivacaine or bupivacaine. The reversibility of levobupivacaine-induced cardiotoxicity has also been assessed. Some data point to an advantage of levobupivacaine over bupivacaine but this potential advantage was not confirmed in a recent study in anaesthetised dogs. Three clinical studies have been conducted using surrogate markers of both cardiac and CNS toxicity. In these studies levobupivacaine or bupivacaine were given by intravascular injection to healthy volunteers. Levobupivacaine was found to cause smaller changes in indices of cardiac contractility and the QTc interval of the electrocardiogram and also to have less depressant effect on the electroencephalogram. Assuming that levobupivacaine has the same local anaesthetic potency as bupivacaine, then, all things being equal, it is difficult to argue that levobupivacaine should not displace bupivacaine as the long-acting local anaesthetic of choice. It would appear, however, that levobupivacaine has not yet significantly displaced bupivacaine from the markets in which it is sold. This may be due to a lack of perceived safety benefit and/or consideration of the additional costs that are associated with switching to levobupivacaine, which is approximately 57% more expensive than bupivacaine. If the price of levobupivacaine were closer to bupivacaine then the argument to switch to levobupivacaine would undoubtedly be much stronger. With the continued clinical use of levobupivacaine the database available to make comparisons will increase and this may allow cost-benefit arguments to be made more forcefully for levobupivacaine in the future.
authors.affiliation: Arachnova Limited, St John's Innovation Centre, Cambridge, United Kingdom. robert.gristwood@arachnova.com
authors.forename: Robert W
authors.initials: RW
authors.lastname: Gristwood
mesh_terms: D000779:Anesthetics, Local / Q000008:administration & dosage / Q000009:adverse effects* / Q000191:economics / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D002045:Bupivacaine / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D015221:Potassium Channels / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D000779:Anesthetics, Local; D015220:Calcium Channels; D015221:Potassium Channels; D015222:Sodium Channels; D002045:Bupivacaine