Hostname: page-component-cd9895bd7-jn8rn Total loading time: 0 Render date: 2024-12-23T12:34:20.108Z Has data issue: false hasContentIssue false
  • English
  • Français

Multicentre evaluation of in vitro contracture testing with bolus administration of 4-chloro-m-cresol for diagnosis of malignant hyperthermia susceptibility

Published online by Cambridge University Press:  11 July 2005

F. Wappler ,
M. Anetseder ,
C. P. Baur ,
K. Censier ,
S. Doetsch ,
P. Felleiter ,
M. Fiege ,
R. Fricker ,
P. J. Halsall  and
E. Hartung
...Show all authors
F. Wappler
Affiliation:
University Hospital Hamburg-Eppendorf, Department of Anaesthesiology, Hamburg, Germany
M. Anetseder
Affiliation:
University of Würzburg, Department of Anaesthesiology, Würzburg, Germany
C. P. Baur
Affiliation:
University of Ulm, Department of Anaesthesiology, Ulm, Germany
K. Censier
Affiliation:
University of Basel, Department of Anaesthesiology, Basel, Switzerland
S. Doetsch
Affiliation:
University of Mainz, Department of Anaesthesiology, Mainz, Germany
P. Felleiter
Affiliation:
University of Vienna, Department of Anaesthesiology and General Intensive Care B, Vienna, Austria
M. Fiege
Affiliation:
University Hospital Hamburg-Eppendorf, Department of Anaesthesiology, Hamburg, Germany
R. Fricker
Affiliation:
University of Vienna, Department of Anaesthesiology and General Intensive Care B, Vienna, Austria
P. J. Halsall
Affiliation:
University of Leeds, Academic Unit of Anaesthesia, Leeds, UK
E. Hartung
Affiliation:
University of Würzburg, Department of Anaesthesiology, Würzburg, Germany Hospital of Stralsund, Department of Anaesthesiology, Stralsund, Germany
J. J. A. Heffron
Affiliation:
University College, Department of Biochemistry, Cork, Ireland
L. Heytens
Affiliation:
University of Antwerp, Department of Intensive Care, Antwerp, Belgium
P. M. Hopkins
Affiliation:
University of Leeds, Academic Unit of Anaesthesia, Leeds, UK
W. Klingler
Affiliation:
University of Ulm, Department of Applied Physiology, Ulm, Germany University of Ulm, Department of Neurology, Ulm, Germany
F. Lehmann-Horn
Affiliation:
University of Ulm, Department of Applied Physiology, Ulm, Germany
Y. Nivoche
Affiliation:
University of Paris, Department of Anaesthesiology, Paris, France
V. Tegazzin
Affiliation:
Traumatic-Orthopaedic Hospital, Department of Anaesthesiology, Padua, Italy
I. Tzanova
Affiliation:
University of Mainz, Department of Anaesthesiology, Mainz, Germany
A. Urwyler
Affiliation:
University of Basel, Department of Anaesthesiology, Basel, Switzerland
R. Weißhorn
Affiliation:
University Hospital Hamburg-Eppendorf, Department of Anaesthesiology, Hamburg, Germany
J. Schulte am Esch
Affiliation:
University Hospital Hamburg-Eppendorf, Department of Anaesthesiology, Hamburg, Germany
Get access

Extract

Summary

Background and objective: The in vitro contracture test with halothane and caffeine is the gold standard for the diagnosis of susceptibility to malignant hyperthermia (MH). However, the sensitivity of the in vitro contracture test is between 97 and 99% and its specificity is 78–94% with the consequence that false-negative as well as false-positive test results are possible. 4-Chloro-m-cresol is potentially a more specific test drug for the in vitro contracture test than halothane or caffeine. This multicentre study was designed to investigate whether an in vitro contracture test with bolus administration of 4-chloro-m-cresol can improve the accuracy of the diagnosis of susceptibility to MH.

Methods: Three hundred and fifty-two patients from 11 European MH laboratories participated in the study. The patients were first classified as MH susceptible, MH normal or MH equivocal by the in vitro contracture test according to the European MH protocol. Muscle specimens surplus to diagnostic requirements were used in this study (MH susceptible = 103 viable samples; MH equivocal = 51; MH normal = 204). 4-Chloro-m-cresol was added to achieve a concentration of 75 μmol L−1 in the tissue bath. The in vitro effects on contracture development and muscle twitch were observed for 60 min.

Results: After bolus administration of 4-chloro-m-cresol, 75 μmol L−1, 99 of 103 MH-susceptible specimens developed marked muscle contractures. In contrast, only two of 204 MH-normal specimens showed an insignificant contracture development following 4-chloro-m-cresol. From these results, a sensitivity rate of 96.1% and a specificity rate of 99.0% can be calculated for the in vitro contracture test with bolus administration of 4-chloro-m-cresol 75 μmol L−1. Forty-three patients were diagnosed as MH equivocal, but only specimens from 16 patients developed contractures in response to 4-chloro-m-cresol, indicating susceptibility to MH.

Conclusions: The in vitro contracture test with halothane and caffeine is well standardized in the European and North American test protocols. However, this conventional test method is associated with the risk of false test results. Therefore, an improvement in the diagnosis of MH is needed. Regarding the results from this multicentre study, the use of 4-chloro-m-cresol could increase the reliability of in vitro contracture testing.

Keywords

ANAESTHETICS, INHALATION, halothaneMALIGNANT HYPERTHERMIAMUSCLE, muscle fibresORGANIC CHEMICALS, cresols, phenolsPURINES, caffeine, purinones, xanthines
Type
Original Article
Information
European Journal of Anaesthesiology , Volume 20 , Issue 7 , September 2003 , pp. 528 - 536
Copyright
© 2003 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

Wappler F. Malignant hyperthermia. Eur J Anaesthesiol 2001; 18: 632–652.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
Fill M, Coronado R, Mickelson JR, et al. Abnormal ryanodine receptor channels in malignant hyperthermia. Biophys J 1990; 57: 471–475.Google Scholar
Pessah IN, Lynch C, Gronert GA. Complex pharmacology of malignant hyperthermia. Anesthesiology 1996; 84: 1275–1279.Google Scholar
Coronado R, Morrissette J, Sukhareva M, Vaughan DM. Structure and function of ryanodine receptors. Am J Physiol 1994; 266: C1485–C1504.Google Scholar
Kalow W, Britt BA, Terreau ME, Haist C. Metabolic error of muscle metabolism after recovery from malignant hyperthermia. Lancet 1970; ii: 895–898.Google Scholar
Ellis FR, Harriman DGF, Keaney NP, et al. Halothane-induced muscle contracture as a cause of hyperpyrexia. Br J Anaesth 1971; 43: 721–722.Google Scholar
European Malignant Hyperpyrexia Group. A protocol for the investigation of malignant hyperpyrexia (MH) susceptibility. Br J Anaesth 1984; 56: 1267–1269.
Larach MG, North American Malignant Hyperthermia Group. Standardization of the caffeine halothane muscle contracture test. Anesth Analg 1989; 69: 511–515.Google Scholar
Ørding 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 malignant hyperthermia registry. Anesthesiology 1998; 88: 579–588.Google Scholar
Isaacs H, Badenhorst M. False-negative results with the muscle caffeine halothane contracture testing for malignant hyperthermia. Anesthesiology 1993; 79: 5–9.Google Scholar
Wedel DJ, Nelson TE. Malignant hyperthermia – diagnostic dilemma: false-negative contracture responses with halothane and caffeine alone. Anesth Analg 1994; 78: 787–792.Google Scholar
Madson L, Raab CR, Kahl SD. Identification and characterization of the high affinity [3H]ryanodine receptor of the junctional sarcoplasmic reticulum Ca2+ release channel. J Biol Chem 1987; 343: 559–561.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
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
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
Hopkins PM, Hartung E, Wappler F, European MH Group. Multicentre evaluation of ryanodine contracture testing in malignant hyperthermia. Br J Anaesth 1998; 80: 389–394.Google Scholar
Zorzato F, Scutari E, Tegazzin V, Clementi E, Treves S. Chlorocresol: an activator of ryanodine receptor-mediated Ca2+ release. Mol Pharmacol 1993; 44: 1192–1201.Google Scholar
Herrmann-Frank A, Richter M, Sarközi S, Mohr U, Lehmann-Horn F. 4-Chloro-m-cresol, a potent and specific activator of the skeletal muscle ryanodine receptor. Biophys Biochim Acta 1996; 1289: 31–40.Google Scholar
Herrmann-Frank A, Richter M, Lehmann-Horn F. 4-Chloro-m-cresol: a specific tool to distinguish between malignant hyperthermia-susceptible and normal muscle. Biochem Pharmacol 1996; 52: 149–155.Google Scholar
Galloway GJ, Denborough MA. Suxamethonium chloride and malignant hyperpyrexia. Br J Anaesth 1986; 58: 447–450.Google Scholar
Tegazzin V, Scutari E, Treves S, Zorzato F. Chlorocresol, an additive to commercial succinylcholine, induces contracture of human malignant hyperthermia-susceptible muscles via activation of the ryanodine receptor Ca2+ channel. Anesthesiology 1996; 84: 1380–1385.Google Scholar
Wappler F, Scholz J, von Richthofen V, Fiege M, Steinfath M, Schulte am Esch J. 4-Chloro-m-cresol induziert Kontrakturen an Skelettmuskelpräparaten von Patienten mit Disposition zu maligner Hyperthermie. Anästhesiol Intensivmed Notfallmed Schmerzther 1997; 32: 541–548.Google Scholar
Anetseder M, Ritter L, Horbaschek H, Hartung E, Roewer N. The impact of 4-chloro-m-cresol in heparin formulas on malignant hyperthermia: in vitro and in vivo. Acta Anaesthesiol Scand 2000; 44: 338–342.Google Scholar
Baur CP, Bellon L, Felleiter P, et al. A multicenter study of 4-chloro-m-cresol for diagnosing malignant hyperthermia susceptibility. Anesth Analg 2000; 90: 200–205.Google Scholar
Ørding H, Glahn K, Gardi T, Fagerlund T, Bendixen D. 4-Chloro-m-cresol test – a supplementary test for diagnosis of malignant hyperthermia susceptibility. Acta Anaesthesiol Scand 1997; 41: 967–972.Google Scholar
Wappler F, Scholz J, Fiege M, et al. 4-Chloro-m-cresol is a trigger of malignant hyperthermia in susceptible swine. Anesthesiology 1999; 90: 1733–1740.Google Scholar
Iaizzo PA, Johnson BA, Nagao K, Gallagher WJ. 4-Chloro-m-cresol triggers malignant hyperthermia in susceptible swine at doses greatly exceeding those found in drug preparations. Anesthesiology 1999; 90: 1723–1732.Google Scholar
Loke J, MacLennan DH. Malignant hyperthermia and central core disease: disorders of Ca2+ release channels. Am J Med 1998; 104: 470–486.Google Scholar
Jurkatt-Rott K, McCarthy TV, Lehmann-Horn F. Genetics and pathogenesis of malignant hyperthermia. Muscle and Nerve 2000; 23: 4–17.Google Scholar
Urwyler A, Censier K, Kaufmann M, Drewe J. Genetic effects on the variability of the halothane and caffeine muscle contracture tests. Anesthesiology 1994; 80: 1287–1295.Google Scholar
Fiege M, Wappler F, Weißhorn R, et al. The results of contracture tests with halothane, caffeine and ryanodine depend on different malignant hyperthermia associated ryanodine receptor gene mutations. Anesthesiology 2002; 97: 345–350.Google Scholar