Bupivacaine-Induced Myonecrosis

Fig. 47.1

Concentration-dependent bupivacaine myotoxicity. Rabbit extraocular muscles at 5 days after injection of bupivacaine or saline. (a) Saline injection: normal-appearing muscle fiber cells displayed regular arrangement with the nuclei in the periphery of the fiber cells. (b) Bupivacaine 0.75% injection: large areas of degenerated muscle tissue with regenerating muscle fibers and inflammatory cell infiltrate and fibrous tissue formation between these cells (between arrows). (c) Bupivacaine 0.38% injection: scattered degenerated areas showed regenerating muscle fibers (arrows). (d) Bupivacaine 0.19% injection: normal-appearing muscle fibers were seen. Reproduced with permission from Elsvier [16]

When the histological changes 5 days after injection of either saline or bupivacaine were compared, normal appearing muscle fibers were seen with saline and 0.19% bupivacaine. Injection of 0.38% bupivacaine showed degenerative changes at 5 days. The most pronounced effects were at bupivacaine concentrations of 0.75% with large areas of degenerated muscle tissue, inflammation, and fibrous tissue.

The severity of myotoxicity from bupivacaine and ropivacaine was demonstrated in a study in pigs. In the study, 0.5% bupivacaine or 0.75% ropivacaine was injected through a catheter inserted next to the femoral nerve. Then an infusion of 0.25% bupivacaine or 0.375% ropivacaine was administered at 8 mL/h for 6 h. At 7 and 28 days, the biopsied muscle samples showed varying stages of necrosis and regeneration with calcium deposits and necrotic clusters of myocytes and signs of fiber regeneration with proliferation of myoblasts with myotubes. The greatest damage was along the surface of the muscle fascicles, presumably along the path of local anesthetic spread. Scars were formed and in each case, the degree of damage was greater with bupivacaine [10]. In another study in humans findings were similar. Muscle damage was confirmed in lesions obtained after radical neck dissection where 1.8 mL of 2% lidocaine with 1:100,000 epinephrine was injected before surgery [3].

The mechanism of myotoxicity, thought to be related to the concentration of local anesthetic, is time dependent, enhanced by preexisting altered metabolism, and is often associated with young age [14]. Thus, it is expected that effects are more pronounced with peripheral nerve catheters with prolonged duration at high concentrations. It has been proposed that continued release or “depo” preparations increase myonecrosis. More evidence is needed before the effects of time and concentration in humans are known. Consistent with its use in trigger point injections, the effects of local anesthetics combined with glucocorticoids are known to increase muscle breakdown. The co-administration of epinephrine is believed to increase the incidence of myotoxicity.

For several decades, the theoretical risk of needle and catheter-induced mechanical trauma in patients with preexisting neural compromise made regional techniques a rarity in various surgical procedures. There may be a component of a double-insult phenomenon with local anesthetic myotoxicity as well. Certainly, patients with rare mitochondrial disorders may suffer more from local anesthetics than other patients. Patients who have a defect in the basal lamina, connective tissue, muscle-related neuronal structure, myotubules, and similar structures of regeneration may experience a greater degree and possibly permanent effects from administration of local anesthetics.

47.2.2.4 Prevention

To decrease the risk and magnitude of myotoxicity, the “As Low As Reasonably Achievable” or ALARA principle should be adopted from our experience with radiation exposure. Given the strong correlation between concentration and time of exposure, the lowest effective concentration should be used, and the duration of administration should be limited to the shortest time possible. The widespread problems of chronic opioid use should not be unfamiliar to anyone in the practice of medicine today. Respiratory depression and the risk of dependence will likely outweigh the risk of local anesthetic-induced myotoxicity. For certain patients, the scales may tip in the other direction. Knowing even the rarest of side effects helps to set one apart as a true consultant and practitioner of the art of medicine.

There are several possible strategies that may reduce or even prevent local anesthetic-induced myotoxicity. When co-administered, dexmedetomidine has been shown to decrease the degree of bupivacaine-induced neurotoxicity and extend the duration of the block. Given the degree of involvement of Ca²⁺ discussed above, it should be no surprise that Ca²⁺ channel antagonists are preventative in in vitro studies. Antioxidants decrease the presence of reactive oxygen species, and recombinant human erythropoietin is thought to mitigate mitochondrial damage. In preclinical studies, both those agents had a protective effect when co-administered with bupivacaine [14].

Ropivacaine and levobupivacaine have fewer cardiotoxic effects and are less myotoxic than bupivacaine. Both agents have an onset and duration of action similar to that of bupivacaine. Bupivacaine is off-patent unlike the others, which decreases cost. It is difficult to demonstrate an overall cost savings using expensive medications when the incidence of myotoxicity is low or under-acknowledged and underreported.

Care should be taken to evaluate the potential effects of long-term or repeated administration of local anesthetics, especially at higher concentrations. Further studies are needed, but ultrasound may allow a decrease in the volume of local anesthetic to achieve effective neural blockade. Patients with certain mitochondrial disorders, although rare indeed, may suffer a large “first hit” and there may be many other phenotypes which predispose patients to local anesthetic-induced myonecrosis. The preventative measures that can be taken to reduce the risk of myonecrosis are summarized in Table 47.1.

Table 47.1

Factors that decrease risk of myotoxicity

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