Hostname: page-component-586b7cd67f-tf8b9 Total loading time: 0 Render date: 2024-11-24T06:35:34.997Z Has data issue: false hasContentIssue false
  • English
  • Français

Similar susceptibility to halothane, caffeine and ryanodine in vitro reflects pharmacogenetic variability of malignant hyperthermia

Published online by Cambridge University Press:  23 December 2004

H. F. Ginz ,
T. Girard ,
K. Censier  and
A. Urwyler
H. F. Ginz
Affiliation:
University of Basel, Department of Anaesthesia, Basel, Switzerland
T. Girard
Affiliation:
University of Basel, Department of Anaesthesia, Basel, Switzerland
K. Censier
Affiliation:
University of Basel, Department of Anaesthesia, Basel, Switzerland
A. Urwyler
Affiliation:
University of Basel, Department of Anaesthesia, Basel, Switzerland
Get access

Abstract

Summary

Background and objective: To analyse the use of standardized application of ryanodine for in vitro muscle contracture testing to define cut-off values separating malignant hyperthermia susceptible from malignant hyperthermia negative subjects. Furthermore, we compared the results of in vitro muscle-contracture tests following the halothane, caffeine and ryanodine challenges.

Methods: In 113 subjects, halothane, caffeine and ryanodine muscle-contracture tests were performed according to the protocol of the European Malignant Hyperthermia Group.

Results: Malignant hyperthermia susceptible subjects (n = 77) had significantly shorter onset times in the ryanodine in vitro muscle-contracture test (1 μmol ryanodine) compared with malignant hyperthermia negative subjects (n = 36), median 4.8 vs. 20.1 min, respectively, without any influence of age or gender. The best cut-off value was 10 min (sensitivity 0.78 and specificity 0.94, respectively). Shorter cut-off values had greater specificity, but lower sensitivity. Groups could not be separated without an overlap. In susceptible subjects, we found a correlation between onset time and threshold concentrations for halothane and caffeine (ρ = 0.47 and 0.52, respectively). In addition, muscle bundles with high susceptibility to halothane and caffeine also showed high susceptibility to ryanodine.

Conclusions: The ryanodine in vitro muscle-contracture test confirmed the malignant hyperthermia status that was determined using the halothane and caffeine in vitro muscle-contracture tests. Due to an overlap between the two groups, discrimination ability was not always perfect and short cut-off values with higher specificity had reduced sensitivity and vice versa. The correlation of contractures following the halothane, caffeine and ryanodine challenges points towards a similar individual pharmacogenetic effect rather than a specific, different pharmacological action between the three agents.

Keywords

ALKALOIDS, ryanodineMUSCLE CONTRACTIONPATHOLOGICAL PROCESSES, malignant hyperthermia
Type
Original Article
Information
European Journal of Anaesthesiology , Volume 21 , Issue 2 , February 2004 , pp. 151 - 157
Copyright
2004 European Society of Anaesthesiology

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Iaizzo PA, Klein W, Lehmann-Horn F. Fura-2 detected myoplasmic calcium and its correlation with contracture force in skeletal muscle from normal and malignant hyperthermia susceptible pigs. Pflugers Arch 1988; 411: 648–653.Google Scholar
Larach MG, Localio AR, Allen GC, et al. A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology 1994; 80: 771–779.Google Scholar
Ball SP, Johnson KJ. The genetics of malignant hyperthermia. J Med Genet 1993; 30: 89–93.Google Scholar
Jurkat-Rott K, McCarthy T, Lehmann-Horn F. Genetics and pathogenesis of malignant hyperthermia. Muscle Nerve 2000; 23: 4–17.Google Scholar
Manning BM, Quane KA, Ording H, et al. Identification of novel mutations in the ryanodine-receptor gene (RYR1) in malignant hyperthermia: genotype–phenotype correlation. Am J Hum Genet 1998; 62: 599–609.Google Scholar
Mickelson JR, Gallant EM, Litterer LA, Johnson KM, Rempel WE, Louis CF. Abnormal sarcoplasmic reticulum ryanodine receptor in malignant hyperthermia. J Biol Chem 1988; 263: 9310–9315.Google Scholar
MacLennan DH, Duff C, Zorzato F, et al. Ryanodine receptor gene is a candidate for predisposition to malignant hyperthermia. Nature 1990; 343: 559–561.Google Scholar
McCarthy TV, Healy JM, Heffron JM, et al. Localization of the malignant hyperthermia susceptibility locus to human chromosome 19q12–13.2. Nature 1990; 343: 562–564.Google Scholar
Fujii J, Otsu K, Zorzato F, et al. Identification of a mutation in porcine ryanodine receptor associated with malignant hyperthermia. Science 1991; 253: 448–451.Google Scholar
Robinson RL, Monnier N, Wolz W, et al. A genome wide search for susceptibility loci in three European malignant hyperthermia pedigrees. Hum Mol Genet 1997; 6: 953–961.Google Scholar
European Malignant Hyperpyrexia Group. A protocol for the investigation of malignant hyperpyrexia susceptibility. Br J Anaesth 1984; 56: 1267–1269.
Jenden DJ, Fairhurst AS. The pharmacology of ryanodine. Pharmacol Rev 1969; 21: 1–25.Google Scholar
Mickelson JR, Gallant EM, Litterer LA, Johnson KM, Rempel WE, Louis CF. Abnormal sarcoplasmic reticulum ryanodine receptor in malignant hyperthermia. J Biol Chem 1988; 263: 9310–9315.Google Scholar
Lai FA, Misra M, Xu L, Smith HA, Meissner G. The ryanodine receptor-Ca2+ release channel complex of skeletal muscle sarcoplasmic reticulum. Evidence for a cooperatively coupled, negatively charged homotetramer. J Biol Chem 1989; 264: 16776–16785.Google Scholar
Hopkins PM, Ellis FR, Halsall PJ. Ryanodine contracture: a potentially specific in vitro diagnostic test for malignant hyperthermia. Br J Anaesth 1991; 66: 611–613.Google Scholar
Hopkins PM, Ellis FR, Halsall PJ. Comparison of in vitro contracture testing with ryanodine, halothane and caffeine in malignant hyperthermia and other neuromuscular disorders. Br J Anaesth 1993; 70: 397–401.Google Scholar
Hopkins PM, Hartung E, Wappler F and the European Malignant Hyperthermia Group. Multicentre evaluation of ryanodine contracture testing in malignant hyperthermia. Br J Anaesth 1998; 80: 389–394.Google Scholar
Hartung E, Koob M, Anetseder M, et al. Malignant hyperthermia (MH) diagnostics: a comparison between the halothane-, caffeine- and the ryanodine-contracture-test results in MH susceptible, normal and control muscle. Acta Anaesthesiol Scand 1996; 40: 437–444.Google Scholar
Wappler F, Roewer N, Köchling A, Scholz J, Steinfath M, Schulte am Esch J. In vitro diagnosis of malignant hyperthermia susceptibility with ryanodine-induced contractures in human skeletal muscles. Anesth Analg 1996; 82: 1230–1236.Google Scholar
Lenzen C, Roewer N, Wappler F, et al. Accelerated contractures after administration of ryanodine to skeletal muscle of malignant hyperthermia susceptible patients. Br J Anaesth 1993; 71: 242–246.Google Scholar
Ording H, Brancadoro V, Cozzolino S, et al. In vitro contracture test for diagnosis of malignant hyperthermia following the protocol of the European MH Group: results of testing patients surviving fulminant MH and unrelated low-risk subjects. The European Malignant Hyperthermia Group. Acta Anaesthesiol Scand 1997; 41: 955–966.Google Scholar
Allen GC, Larach MG, Kunselman AR. The sensitivity and specificity of the caffeine–halothane contracture test. A report from the North American Hyperthermia Registry. Anesthesiology 1998; 88: 579–588.Google Scholar
Swets JA. Measuring the accuracy of diagnostic systems. Science 1988; 240: 1285–1293.Google Scholar
Glantz SA. Primer of Biostatistics, 5th edn. New York, NY, USA: McGraw-Hill, 2001.
Sudo RT, Nelson TE. Changes in ryanodine-induced contractures by stimulus frequency in malignant hyperthermia susceptible and malignant hyperthermia nonsusceptible dog skeletal muscle. J Pharmacol Exp Ther 1997; 282: 1331–1336.Google Scholar
Phillips MS, Fujii J, Khanna VK, et al. The structural organization of the human skeletal muscle ryanodine receptor (RYR1) gene. Genomics 1996; 34: 24–41.Google Scholar
Girard T, Urwyler A, Censier K, Mueller CR, Zorzato F, Treves S. Genotype–phenotype comparison of the Swiss malignant hyperthermia population. Hum Mutat 2001; 18: 357–358.Google Scholar
Robinson RL, Brooks C, Brown S, et al. RYR1 mutations causing central core disease are associated with more severe malignant hyperthermia in vitro contracture test phenotypes. Hum Mutat 2002; 20: 88–97.Google Scholar
Ording H, Islander G, Bendixen D, Ranklev-Twetman E. Between-center variability of results of the in vitro contracture test for malignant hyperthermia susceptibility. Anesth Analg 2000; 91: 452–457.Google Scholar
Loke JCP, MacLennan DH. Bayesian modeling of muscle biopsy contracture testing for malignant hyperthermia susceptibility. Anesthesiology 1998; 88: 589–600Google Scholar