Double-blind randomized study of lidocaine, bupivacaine, levobupivacaine, and ropivacaine myotoxicity in rats

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Background. Myotoxicity of local anesthetics in a clinical practice was revealed at various types of regional anesthesia. The degree of functional recovery of damaged muscles and the length of time before the recovery differ significantly in different studies. Despite the generally accepted opinion about the anti-inflammatory effect of local anesthetics, a number of experimental studies have shown that an inflammatory reaction developed at the place of injection into a muscle tissue.

Material and methods. A double-blind randomized study was conducted on 800 rats. A control group was formed whose members were introduced with 0.9% sodium chloride solution. Lidocaine concentrations under the study were 0.5%, 1%, 1.5%, 2%; bupivacaine, ropivacaine – 0.25%, 0.5%, 0.75%, 1%; ropivacaine – 0.25%, 0.5%, 0.75%. A 0.2-mL drug was injected into the biceps muscle under the ultrasound control. The sampling of drugs was as follows: stage 1 was in 1 h after the injection, stage 2 was in 2 days, stage 3 was in 7 days, stage 4 was in 14 days, stage 5 was in 21 days. Signs of an inflammation and damage of a muscle tissue were examined.

Results. An injection of a saline solution to laboratory animals of the control group caused the expansion of intercellular spaces and connective tissue partitions. There were no signs of cell necrosis or apoptosis. The injection of local anesthetics within an hour caused an inflammatory infiltration and a damage to a muscle tissue. The data of pairwise comparisons showed that at the stages of 1 h and day 2 in all the studied groups, the severity of a damage and an inflammation was greater than in the control group with the introduction of 0.9% sodium chloride solution. Then, there was a decrease in signs of a damage and an inflammation. At the stage of day 21, there were no statistical differences in comparison with group 1 in any of the study groups. The dependence of the appearances of damage or inflammation in a muscle tissue on the concentration of a local anesthetic was determined by an ordinal regression model. The regression model indicators were significant. They allowed us to describe 87% for damage and 95% for inflammatory changes.

Сonclusion. The toxicity of local anesthetics appeared as a damaging effect and development of an inflammatory infiltration. Local anesthetics were toxic in all studied groups with all concentrations. The higher the concentration of the anesthetic, the more expressed was the damaging effect and the development of signs of the inflammation. The maximum development of the damaging effect was at the stages of hour 1 and day 2 of the study, then there was a decrease in signs of myotoxicity, and by 21 days, the signs of damage and inflammation completely disappeared. The comparative analysis did not reveal any statistical differences that allow us to expressly form a rating from the most to the least myotoxic drug.

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About the authors

Roman E. Lakhin

S. M. Kirov Military medical Academy of the Ministry of defense of the Russian Federation

Author for correspondence.
ORCID iD: 0000-0001-6431-439X

doctor of medical sciences, professor of the department of military anesthesiology and reanimatology

Russian Federation, 194044, Saint Petersburg

I. A. Gemua

S. M. Kirov Military medical Academy of the Ministry of defense of the Russian Federation

ORCID iD: 0000-0002-8643-252X
Russian Federation, 194044, Saint Petersburg

D. A. Averyanov

S. M. Kirov Military medical Academy of the Ministry of defense of the Russian Federation

ORCID iD: 0000-0003-4353-4953
Russian Federation, 194044, Saint Petersburg


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Supplementary files

Supplementary Files
1. Fig. 1. Scheme of introduction to the experiment and elimination of animals from the experiment

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2. Fig. 2. Signs of damage to muscle fibers after administration of bupivacaine (hematoxylin and eosin staining, increased × 400): A – perimuscular edema, groups of muscle fibers with dystrophic changes, phenomena of polychromasia and apoptosis of cells; B – perimuscular edema, muscle fibers with the formation of contractile contractures, with the phenomena of polychromasia, a decrease in transverse striation

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3. Fig. 3. Infiltration of tissue with inflammatory cells (hematoxylin and eosin, magnification × 400) And the tissue without signs of inflammatory infiltration; B - single cells within the interstitium around vessels around individual nerve, muscle; predominate neutrophils are macrophages, lymphocytes isolated; In inflammatory cells in moderate quantity in the interstices around the vessels, in muscles, in the nerves; mainly cells of the macrophage type, there are a small number of neutrophils and lymphocytes; G-inflammatory cells fill the entire interstitial space, permeate muscle tissue, surround blood vessels and nerves; the predominant cell type: neutrophils, macrophages, there are single lymphocytes

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