Brazilian Journal of Anesthesiology
Brazilian Journal of Anesthesiology
Original Investigation

Predictive factors of the contracture test for diagnosing malignant hyperthermia in a Brazilian population sample: a retrospective observational study

Jean Marcel de Mello, Pamela Vieira Andrade, Joilson Moura Santos, Acary Souza Bulle Oliveira, Mariz Vainzof, José Luiz Gomes do Amaral, Helga Cristina Almeida da Silva

Downloads: 0
Views: 169


Malignant Hyperthermia (MH) is a pharmacogenetic, hereditary and autosomal dominant syndrome triggered by halogenates/succinylcholine. The In Vitro Contracture Test (IVCT) is the gold standard diagnostic test for MH, and it evaluates abnormal skeletal muscle reactions of susceptible individuals (earlier/greater contracture) when exposed to caffeine/halothane. MH susceptibility episodes and IVCT seem to be related to individual features.

To assess variables that correlate with IVCT in Brazilian patients referred for MH investigation due to a history of personal/family MH.

We examined IVCTs of 80 patients investigated for MH between 2004‒2019. We recorded clinical data (age, sex, presence of muscle weakness or myopathy with muscle biopsy showing cores, genetic evaluation, IVCT result) and IVCT features (initial and final maximum contraction, caffeine/halothane concentration triggering contracture of 0.2g, contracture at caffeine concentration of 2 and 32 mmoL and at 2% halothane, and contraction after 100 Hz stimulation).

Mean age of the sample was 35±13.3 years, and most of the subjects were female (n=43 or 54%) and MH susceptible (60%). Of the 20 subjects undergoing genetic investigation, 65% showed variants in RYR1/CACNA1S genes. We found no difference between the positive and negative IVCT groups regarding age, sex, number of probands, presence of muscle weakness or myopathy with muscle biopsy showing cores. Regression analysis revealed that the best predictors of positive IVCT were male sex (+12%), absence of muscle weakness (+20%), and personal MH background (+17%).

Positive IVCT results have been correlated to male probands, in accordance with early publications. Furthermore, normal muscle strength has been confirmed as a significant predictor of positive IVCT while investigating suspected MH cases.


Anesthesia;  Caffeine;  Halothane;  Malignant hyperthermia;  Skeletal muscle


1 H Rosenberg, N Pollock, A Schiemann, T Bulger, K. Stowell Malignant hyperthermia: a review Orphanet J Rare Dis, 10 (2015), pp. 1-19

2 JE Brady, LS Sun, H Rosenberg, G. Li Prevalence of malignant hyperthermia due to anesthesia in New York State, 2001-2005 Anesth Analg, 109 (2009), pp. 1162-1166

3 Rosenberg H, Sambuughin N, Riazi S, Dirksen R. Malignant hyperthermia susceptibility. 2020. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from:

4 The European Malignant Hyperpyrexia Group. A protocol for the investigation of malignant hyperpyrexia (MH) susceptibility Br J Anaesth, 56 (1984), pp. 1267-1271

5 PM Hopkins, H Rüffert, MM Snoeck, T Girard, KPE Glahn, FR Ellis, et al. European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility Br J Anaesth, 115 (2015), pp. 531-539

6 MG. Larach Standardization of the caffeine halothane muscle contracture test Anesth Analg, 69 (1989), pp. 511-515

7 H Ørding, V Brancadoro, S Cozzolino, FR Ellis, V Glauber, EF Gonano, 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 Acta Anaesthesiol Scand, 41 (1997), pp. 955-966

8 D Carpenter, RL Robinson, RJ Quinnell, C Ringrose, M Hogg, F Casson, et al. Genetic variation in RYR1 and malignant hyperthermia phenotypes Br J Anaesth, 103 (2009), pp. 538-548

9 AT. Ferreira Fisiologia da Contração Muscular. Rev Neurociências., 13 (2005), pp. 60-62

10 PJ Halsall, FR. Ellis Malignant hyperthermia Curr Anaesth Crit Care, 7 (1996), pp. 158-166

11 G Islander, K Rydenfelt, E Ranklev, M. Bodelsson Male preponderance of patients testing positive for malignant hyperthermia susceptibility Acta Anaesthesiol Scand, 51 (2007), pp. 614-620

12 K Witz, DE Hinkle, W Wiersma, SG. Jurs Applied Statistics for the Behavioral Sciences J Educ Stat, 15 (1990), p. 84

13 P Mezin, JF Payen, JL Bosson, E Brambilla, P. Stieglitz Histological support for the difference between malignant hyperthermia susceptible (MHS), equivocal (MHE) and negative (MHN) muscle biopsies Br J Anaesth, 79 (1997), pp. 327-331

14 F Von Breunig, F Wappler, C Hagel, V Von Richthofen, M Fiege, R Weisshorn, et al. Histomorphologic examination of skeletal muscle preparations does not differentiate between malignant hyperthermia-susceptible and normal patients Anesthesiology, 100 (2004), pp. 789-794

15 PM Kossugue, JF Paim, MM Navarro, HC Silva, RCM Pavanello, J Gurgel-Giannetti, et al. Central core disease due to recessive mutations in RYR1 gene: Is it more common than described? Muscle and Nerve, 35 (2007), pp. 670-674

16 RL Gillies, AR Bjorksten, D Du Sart, BM Hockey Analysis of the entire ryanodine receptor type 1 and alpha 1 subunit of the dihydropyridine receptor (CACNA1S) coding regions for variants associated with malignant hyperthermia in Australian families Anaesth Intensive Care, 43 (2015), pp. 157-166

17 MG Larach, GA Gronert, GC Allen, BW Brandom, EB. Lehman Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006 Anesth Analg, 110 (2010), pp. 498-507

18 GJ Knuiman, B Küsters, L Eshuis, M Snoeck, M Lammens, L Heytens, et al. The histopathological spectrum of malignant hyperthermia and rhabdomyolysis due to RYR1 mutations J Neurol, 266 (2019), pp. 876-887

19 N Monnier, G Kozak-Ribbens, R Krivosic-Horber, Y Nivoche, D Qi, N Kraev, et al. Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility Hum Mutat, 26 (2005), pp. 413-425

20 DC Andersson, MJ Betzenhauser, S Reiken, AC Meli, A Umanskaya, W Xie, et al. Ryanodine receptor oxidation causes intracellular calcium leak and muscle weakness in aging Cell Metab, 14 (2011), pp. 196-207

21 RL Robinson, C Brooks, SL Brown, FR Ellis, PJ Halsall, RJ Quinnell, et al. RYR1 mutations causing central core disease are associated with more severe malignant hyperthermia in vitro contracture test phenotypes Hum Mutat, 20 (2002), pp. 88-97

22 B Yuen, S Boncompagni, W Feng, T Yang, JR Lopez, KI Matthaei, et al. Mice expressing T4826I-RYR1 are viable but exhibit sex- and genotype-dependent susceptibility to malignant hyperthermia and muscle damage FASEB J, 26 (2012), pp. 1311-1322

23 JR Lopez, V Kaura, CP Diggle, PM Hopkins, PD. Allen Malignant hyperthermia, environmental heat stress, and intracellular calcium dysregulation in a mouse model expressing the p.G2435R variant of RYR1 Br J Anaesth, 121 (2018), pp. 953-961

24 N Dlamini, NC Voermans, S Lillis, K Stewart, EJ Kamsteeg, G Drost, et al. Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis Neuromuscul Disord, 23 (2013), pp. 540-548

25 Silva HCA da, Hiray M, M Vainzof, B Schmidt, ASB Oliveira, Amaral JLG do Atypical reaction to anesthesia in Duchenne/Becker muscular dystrophy Braz J Anesthesiol, 68 (2017), pp. 4-7

26 G Islander, ER. Twetman Comparison between the European and North American protocols for diagnosis of malignant hyperthermia susceptibility in humans Anesth Analg, 88 (1999), pp. 1155-1160

27 JE. Fletcher Comparison of European and North American Malignant Hyperthermia diagnostic protocol outcomes for use in genetic studies Anesthesiology, 90 (1999), pp. 654-661, 10.1097/00000542-199903000-00005 Available from:

28 Takagi A, Araki M, Kojima S, Ida M, Watanabe T. Caffeine contracture of the skinned muscle fiber in malignant hyperthermia and neuromuscular diseases. In: Morio M, Kikuchi H, Yuge O (eds). Malignant Hyperthermia. Tokyo, Japan: Springer; 1996. p. 67-73. Available from: 10.1007/978-4-431-68346-9_10.

29 K Jurkat-Rott, T McCarthy Lehmann-Horn F. Genetics and pathogenesis of malignant hyperthermia Muscle and Nerve, 23 (2000), pp. 4-17

30 L Figueroa, N Kraeva, C Manno, S Toro, E Ríos, S Riazi Abnormal calcium signalling and the caffeine–halothane contracture test Br J Anaesth, 122 (2019), pp. 32-41

62e4160fa953950bf35cb552 rba Articles
Links & Downloads

Braz J Anesthesiol

Share this page
Page Sections