Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Anesthesia
Published in: Journal of Anesthesia 4/2018

01-08-2018 | Original Article

Myotoxicity of local anesthetics is equivalent in individuals with and without predisposition to malignant hyperthermia

Authors: Sachiko Otsuki, Toshimichi Yasuda, Keiko Mukaida, Yuko Noda, Rieko Kanzaki, Hirotsugu Miyoshi, Takashi Kondo, Hiroshi Hamada, Masashi Kawamoto

Published in: Journal of Anesthesia | Issue 4/2018

Login to get access

Abstract

Purpose

Malignant hyperthermia (MH) is an inherited muscle disorder caused by abnormal elevations of intracellular calcium (Ca2+) in skeletal muscle. There are several reports of myotoxicity caused by local anesthetics, and the increased intracellular Ca2+ is considered to be an important cause. However, there is insufficient evidence regarding myotoxicity in MH-susceptible individuals when large doses of local anesthetics are administered. This study investigated the effect of MH predisposition on myotoxicity.

Methods

Human skeletal muscle samples were obtained from 22 individuals to determine susceptibility to MH, and were evaluated according to whether their Ca2+-induced Ca2+ release (CICR) rates were accelerated or not. This study was performed using surplus muscle that remained after the CICR rate test. We calculated the 50% effective concentration (EC50) values of three local anesthetics, namely lidocaine, levobupivacaine, and ropivacaine using the ratiometric dye Fura-2 AM. Significance was tested using the unpaired t test.

Results

In the accelerated and unaccelerated groups, respectively, the mean ± SD of the EC50 values were 1.52 ± 0.72 and 1.75 ± 0.37 mM for lidocaine (p = 0.42), 0.72 ± 0.36 and 0.79 ± 0.46 mM for levobupivacaine (p = 0.68), and 1.21 ± 0.35 and 1.62 ± 0.57 mM for ropivacaine (p = 0.06). These values were similar in individuals with and without MH predisposition.

Conclusion

The myotoxicity of local anesthetics was equivalent in individuals with and without predisposition to MH.
Literature
1.
Halsall PJ, Ellis FR. Malignant hyperthermia. Anaesth Intensive Care. 2005;14:192–4.CrossRef
2.
Schneiderbanger D, Johannsen S, Roewer N, Schuster F. Management of malignant hyperthermia: diagnosis and treatment. Ther Clin Risk Manag. 2014;10:355–62.PubMedPubMedCentral
3.
Zink W, Bohl JRE, Hacke N, Sinner B, Martin E, Graf BM. The long term myotoxic effects of bupivacaine and ropivacaine after continuous peripheral nerve blocks. Anesth Analg. 2005;101:548–54.CrossRefPubMed
4.
Neal JM, Salinas FV, Choi DS. Local anesthetic-induced myotoxicity after continuous adductor canal block. Reg Anesth Pain Med. 2016;41:723–7.CrossRefPubMed
5.
Benoit PW, Yagiela A, Fort NF. Pharmacologic correlation between local anesthetic-induced myotoxicity and disturbances of intracellular calcium distribution. Toxicol Appl Pharmacol. 1980;52:187–98.CrossRefPubMed
6.
Plank C, Hofmann P, Gruber M, Bollwein G, Graf BM, Zink W, et al. Modification of bupivacaine-induced myotoxicity with dantrolene and caffeine in vitro. Anesth Analg. 2016;122:418–23.CrossRefPubMed
7.
Harrison GG, Morrell DF. Response of mhs swine to i.v. infusion of lignocaine and bupivacaine. Br J Anaesth. 1980;52:385–7.CrossRefPubMed
8.
Wingard DW, Bobko S. Failure of lidocaine to trigger porcine malignant hyperthermia. Anesth Analg. 1979;58:99–103.CrossRefPubMed
9.
Ibarra MCA, Ichihara Y, Hikita M, Yoshida K, Junji S, Maehara Y, et al. Effect of bupivacaine enantiomers on Ca2+ release from sarcoplasmic reticulum in skeletal muscle. Eur J Pharmacol. 2005;512:77–83.CrossRef
10.
Maemura Y. Effect of ropivacaine on Ca function of skinned skeletal muscle. Masui. 2002;51:19–24.PubMed
11.
Endo M, Iino M. Measurement of Ca2 + release in skinned fibers from skeletal muscle. Methods Enzymol. 1988;157:12–26.CrossRefPubMed
12.
Ohta T, Endo M, Nakano T, Morohoshi Y, Wanikawa K, Ohga A. Ca-induced Ca release in malignant hyperthermia-susceptible pig skeletal muscle. Am J Physiol. 1989;256:C358–67.CrossRefPubMed
13.
Oku S, Mukaida K, Nosaka S, Sai Y, Maehara Y, Yuge O. Comparison of the in vitro caffeine-halothane contracture test with the Ca-induced Ca release rate test in patients suspected of having malignant hyperthermia susceptibility. J Anesth. 2000;14:6–13.CrossRefPubMed
14.
Kobayashi M, Mukaida K, Migita T, Hamada H, Kawamoto M, Yuge O. Analysis of human cultured myotubes responses mediated by ryanodine receptor 1. Anaesth Intensive Care. 2011;39:252–61.PubMed
15.
Hofmann P, Metterlein T, Bollwein G, Gruber M, Plank C, Graf BM, et al. The myotoxic effect of bupivacaine and ropivacaine on myotubes in primary mouse cell culture and an immortalized cell line. Anesth Analg. 2013;117:634–40.CrossRefPubMed
16.
Zink W, Seif C, Bohl JRE, Hacke N, Braun PM, Sinner B, et al. The acute myotoxic effects of bupivacaine and ropivacaine after continuous peripheral nerve blockades. Anesth Analg. 2003;97:1173–9 (table of contents).CrossRefPubMed
17.
Zhang C, Phamonvaechavan P, Rajan A, Poon DY, Topcu-Yilmaz P, Guyton DL. Concentration-dependent bupivacaine myotoxicity in rabbit extraocular muscle. J AAPOS. 2010;14:323–7.CrossRefPubMed
18.
Benoit PW, Belt WD. Destruction and regeneration of skeletal muscle after treatment with a local anaesthetic, bupivacaine (Marcaine). J Anat. 1970;107:547–56.PubMedPubMedCentral
19.
McLoon LK, Nguyen LT, Wirtschafter J. Time course of the regenerative response in bupivacaine injured orbicularis oculi muscle. Cell Tissue Res. 1998;294:439–47.CrossRefPubMed
20.
Zink W, Graf BM. Local anesthetic myotoxicity. Reg Anesth Pain Med.;29:333–40.
21.
Melzer W, Herrmann-Frank A, Lüttgau HC. The role of Ca2+ ions in excitation-contraction coupling of skeletal muscle fibres. Biochim Biophys Acta. 1995;1241:59–116.CrossRefPubMed
22.
Schiemann AH, Stowell KM. Comparison of pathogenicity prediction tools on missense variants in RYR1 and CACNA1S associated with malignant hyperthermia. Br J Anaesth. 2016;117:124–8.CrossRefPubMedPubMedCentral
23.
Shoshan-Barmatz V, Zchut S. The interaction of local anesthetics with the ryanodine receptor of the sarcoplasmic reticulum. J Membr Biol. 1993;133:171–81.CrossRefPubMed
24.
Hyvelin JM, Martin C, Roux E, Marthan R, Savineau JP. Human isolated bronchial smooth muscle contains functional ryanodine/caffeine-sensitive Ca-release channels. Am J Respir Crit Care Med. 2000;162:687–94.CrossRefPubMed
25.
Gordienko DV, Harhun MI, Kustov MV, Pucovský V, Bolton TB. Sub-plasmalemmal [Ca2+]i upstroke in myocytes of the guinea-pig small intestine evoked by muscarinic stimulation: IP3R-mediated Ca2+ release induced by voltage-gated Ca2+ entry. Cell Calcium. 2008;43:122–41.CrossRefPubMedPubMedCentral
26.
27.
Franco-Obregón A, Lansman JB. Changes in mechanosensitive channel gating following mechanical stimulation in skeletal muscle myotubes from the mdx mouse. J Physiol. 2002;539:391–407.CrossRefPubMedPubMedCentral
28.
Riazi S, Kraeva N, Muldoon SM, Dowling J, Ho C, Petre M-A, et al. Malignant hyperthermia and the clinical significance of type-1 ryanodine receptor gene (RYR1) variants: proceedings of the 2013 MHAUS Scientific Conference. Can J Anesth. 2014;61:1040–9.CrossRefPubMed
29.
Hopkins PM, Rüffert H, Snoeck MM, Girard T, Glahn KPE, Ellis FR, et al. European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility. Br J Anaesth. 2015;115:531–9.CrossRefPubMed
30.
Wehner M, Rueffert H, Koenig F, Meinecke CD, Olthoff D. The Ile2453Thr mutation in the ryanodine receptor gene 1 is associated with facilitated calcium release from sarcoplasmic reticulum by 4-chloro-m-cresol in human myotubes. Cell Calcium. 2003;34:163–8.CrossRefPubMed
Metadata
Title
Myotoxicity of local anesthetics is equivalent in individuals with and without predisposition to malignant hyperthermia
Authors
Sachiko Otsuki
Toshimichi Yasuda
Keiko Mukaida
Yuko Noda
Rieko Kanzaki
Hirotsugu Miyoshi
Takashi Kondo
Hiroshi Hamada
Masashi Kawamoto
Publication date
01-08-2018
Publisher
Springer Japan
Published in
Journal of Anesthesia / Issue 4/2018
Print ISSN: 0913-8668
Electronic ISSN: 1438-8359
DOI
https://doi.org/10.1007/s00540-018-2526-4

Other articles of this Issue 4/2018

Journal of Anesthesia 4/2018 Go to the issue

Original Article

The impact of low body mass index on postoperative outcomes in pancreatectomy patients: a retrospective analysis of Japanese administrative data

Original Article

Interaction between anesthetic conditioning and ischemic preconditioning on metabolic function after hepatic ischemia–reperfusion in rabbits

Original Article

Comparison of a new simplified acid–base tool to the original Stewart–Figge approach: a study on cardiac surgical patients

Letter to the Editor

Thoraco-esophageal fistula during percutaneous tracheostomy

Original Article

Inhibiting EZH2 rescued bupivacaine-induced neuronal apoptosis in spinal cord dorsal root ganglia in mice

Original Article

Relationship between fresh frozen plasma to packed red blood cell transfusion ratio and mortality in cardiovascular surgery