Malignant Hyperthermia Diagnostic Center

The Malignant Hyperthermia Muscle Biopsy Center at the University of Minnesota is aligned with the Paul and Sheila Wellstone Muscular Dystrophy Center. We are located in B111 Mayo Building on the east bank of University of Minnesota campus. Our center performed its first diagnostic biopsy in February of 1992. To date (5-26-17), in vitro contracture testing has been performed on muscle biopsies from 132 patients and 36 normal control subjects.

Center Personnel

Director: Paul A. Iaizzo, PhD, FHRS
(612-624-7912) or

Collaborating Anesthesiologists:
Kumar G. Belani, MBBS, MS
John Capacchione, MD
David S. Beebe, MD
Tae Kim, MD
Thomas Kozhimannil, MD

(Contact Paul A. Iaizzo, PhD, FHRS, John Capacchione (612-624-9990), or Monica Mahre (612-624-3959) for general information on malignant hyperthermia and the in vitro contracture test)

Policy and Procedure

An in vitro contracture test for the determination of susceptibility to malignant hyperthermia (MH) will be performed on patients who are viable candidates for testing, and have either agreed to pay for the procedure or have obtained prior approval for the procedure from their insurance companies. Our laboratory is a member of the North American Malignant Hyperthermia Registry.

The procedure consists of the following:

I. Consultation/Scheduling

Patients may be referred to the Malignant Hyperthermia Muscle Biopsy Center at the University of Minnesota by their physicians or they may contact the center on their own. In either case, contact either Paul A. Iaizzo, PhD, FHRS (612-624-7912), John Capacchione (612-624-9990) or Monica Mahre (612-624-3959) to determine if you are a viable candidate for the in vitro contracture test. If testing is recommended, you will be asked to seek pre-approval for the procedure from your insurance company, or agree to be personally responsible for the costs. The appropriate CPT codes for insurance reimbursement are:

Malignant Hyperthermia Biopsy:

20205 Biopsy, Muscle; deep
88049 Unlisted Misc. Pathology tests
88313 Special stains (group 2; all other)
88314 Special stains (histochemical staining)
88305 Level 4- surgical pathology
88342 Immunohistochemistry
36415 Collection of venous blood by venipuncture
82550 Creatinine Kinase (Total)
82552 Creatinine Kinase(Isoenzymes)

Neuromuscular Biopsy:

88305 Frozen, H & E
88313 (X2) Special stains (trichome, oil red O, PAS, congo red)
88314 Histochemical stains, frozen
88348 Electro microscope, diagnostic
88323 Report on material requiring preparation of slides
88305 Gross and Micro (H & E)
88313 (X4) Light microscopy
88319 (X11) Enzyme histochemistry
88348 Electron microscopy

II. Muscle Biopsy

The muscle biopsy is performed on an outpatient basis. A muscle sample is removed from the vastus lateralis or vastus medialis (thigh) muscles using anesthesia known NOT to trigger malignant hyperthermia. The minimal sample size is about 3-5 cm long and 1-1.5 cm in diameter. A second small muscle sample is removed for histologic study. In addition, each patient is asked to provide a blood sample (10-15 ml) for future genetic analysis, as recommended by the North American Malignant Hyperthermia Registry.

III. In Vitro Contracture Test

The in vitro contracture test is performed in accordance with the guidelines provided by the North American Malignant Hyperthermia Registry, and is highly accurate for diagnosing susceptibility to malignant hyperthermia. The test is initiated as soon as the muscle sample is available from the patient (fresh tissue is required). Using a dissecting microscope, six to eight small muscle bundles are prepared and then mounted in experimental chambers (see pictures below) and made to contract via electrical stimulation.
When the anesthetic "halothane" is introduced into the chamber, a muscle that is susceptible to malignant hyperthermia contracts more frequently and develops a contracture (sustained force generation). The drug "caffeine" introduced into the chamber may also lead to an abnormal contracture, as may a variety of other anesthetics. This contracture is indicative of susceptibility to malignant hyperthermia. Halothane and caffeine contracture tests are performed in triplicate.

MH pic 1 MH pic 2
IV. Test Results and Patient Counseling

The results of the contracture test are described to the patient in terms of their muscle's sensitivity to halothane and caffeine in vitro. This test has been considered 95% accurate.
Patients that have a positive contracture test will be advised to wear a medical alert bracelet. In addition, they may wish to follow up with one of our collaborating anesthesiologists to discuss: 1) known genetic details of malignant hyperthermia and new genetic screening procedures; 2) possible testing of other family members; 3) monitoring of serum CK (creatine kinase) levels in potentially susceptible family members; and 4) clinical implications for future anesthetics in malignant hyperthermia positive individuals.

V. Molecular Genetic Testing for Malignant Hyperthermia

When a person is known to be susceptible to malignant hyperthermia (as determined by in vitro contracture testing or a confirmed clinical episode) and subsequent DNA screening has identified an associative DNA mutation, then his/her relatives may be tested through a blood test. In other words, a MH diagnosis can be made with DNA analyses and family members do not need to have the muscle biopsy for confirmation. The DNA molecular testing requires only a blood sample that can be drawn by the patient’s physician, and then sent to a molecular genetic testing laboratory (see below):

PreventionGenetics, LLC
3700 Downwind Drive
Marshfield, WI 55449
Tel: 715-387-0484

Center for Medical Genetics
University of Pittsburgh Medical Center
3550 Terrace St., S701 Scaife Hall
Pittsburgh, PA 15213
Tel: 800-454-8155

Malignant Hyperthermia Research

Anesthetic complications in muscle disorders: using animal models for muscle disease to identify sensitivity and specificity of the malignant hyperthermia in vitro contracture test.

Mechanism of action of succinylcholine-induced hypotension and/or malignant hyperthermia in susceptible swine.

Relative potency of sevoflurane vs. halothane to trigger malignant hyperthermia (in situ and in vitro studies).
Publications Related to Malignant Hyperthermia

Larach MG, Brandom BW, Allen GC, Gronert GA, Lehman EB: Cardiac arrests and deaths associated with malignant hyperthermia in North America from 1987 to 2006: A report from the North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States. Anesthesiology 108:603-11, 2008

Iaizzo PA: Malignant hyperthermia: blood and blood flow. In: Malignant Hyperthermia, Schulte am Esch J, Scholz J, Wappler F (eds.), Pabst Science Publishers, pages 148-153, 2000

Sigg DC, Iaizzo PA: Malignant hyperthermia phenotype: hypotension induced by succinylcholine in susceptible swine. Anesthesiology 92: 1777-1788, 2000

Brinkmeier H, Krämer J, Krämer R, Iaizzo PA, Baur C, Lehmann-Horn F, Rudel R: Malignant hyperthermia causing Gly2435Arg mutation of the ryanodine receptor facilitates ryanodine-induced calcium release in myotubes. British Journal of Anaesthesiology 83:855-861, 1999

Kumar MVS, Komanduri V, Beebe DS, Iaizzo PA, Belani KG: Hemodynamic and metabolic manifestations of acute endotoxin infusion in pigs with and without the malignant hyperthermia mutation. Anethesiology 99:833-838, 1999

Iaizzo PA, Johnson BA, Nagao K, Gallagher WJ: 4-Chloro-m-cresol at hemolytic doses triggers malignant hyperthermia in susceptible swine. Anesthesiology 90:1723-1732, 1999. Kumar MVS, Carr RJ, Komanduri V, Reardon RF, Beebe DS, Iaizzo PA, Belani KG: Differential diagnosis of thyroid crisis and malignant hyperthermia in an anesthetized porcine model. Endocrine Research 25:87-103, 1999

Otten W, Iaizzo PA, Eichinger HM : Effects of a high omega-3 fatty acid diet on membrane lipid composition of heart and skeletal muscle in normal swine and those with the genetic mutation for malignant hyperthermia. Journal of Lipid Research 38:2023-2034, 1997

Hartmann S, Otten W, Kratzmair M, Seewald MJ, Iaizzo PA, Eichinger HM: Effects of breed, susceptibility to malignant hyperthermia and gender on lipid composition of skeletal muscle and adipose tissue in swine. American Journal of Veterinary Research 58:738-743, 1997

Iaizzo PA: Methods for Monitoring Modulations in Intracellular [Ca2+]. In: ANESTHESIA: BIOLOGICAL FOUNDATIONS, Yaksh TL, Lynch C III, Zapol WM, Maze M, Biebuyck JF, Saidman LJ, (eds.), Raven Press, New York, Chapter 24, pages 399-415, 1997

Iaizzo PA, Belani KG, Rosenberg H: VIIIth International workshop on malignant hyperthermia. The American Journal of Anesthesiology 24:40, 1997

Iaizzo PA, Day JW: The potential for anesthetic complications in patients with muscle disorders. In: Progress in Anesthesiology. 1996

Iaizzo PA, Kehler CH, Carr RJ, Sessler DI, Belani KG: Prior hypothermia attenuates malignant hyperthermia in susceptible swine. Anesthesia and Analgesia, 1996

Iaizzo PA, Kehler CH, Zink RS, Belani KG, Sessler DI: Thermal response in acute porcine malignant hyperthermia. Anesthesia and Analgesia, 1996

Iaizzo PA, Lehmann-Horn F: Anesthetic Complications in muscle disorders. Anesthesiology 82:1093-1096, 1995

Wedel DJ, Quinlan JG, Iaizzo PA: Clinical Effects of Intravenously Administered Dantrolene Mayo Clin Proc. 1995;70:241-246.

Iaizzo PA: The physiology and biochemistry of skeletal muscle and its correlates to malignant hyperthermia. In: Anaesthesia and Pharmacogenetic Diseases: Malignant Hyperthermia. Minerva Anaesthesiologica 60: 131-136, 1994

Iaizzo PA, Palahniuk RJ, Cameron CB, Belani KG: Malignant hyperthermia. Journal of Anaesthesiology - Clinical Pharmacology 9:95-104, 1993

Iaizzo PA, Seewald M, Olsen R, Wedel DJ, Chapman DE, Berggren M, Eichinger HM, Powis G: Enhanced mobilization of intracellular Ca2+ induced by halothane in hepatocytes isolated from swine susceptible to malignant hyperthermia. Anesthesiology 74: 531-538, 1991

Seewald M, Eichinger HM, Iaizzo PA: An altered phospholipid and fatty acid composition of muscle membranes obtained from pigs susceptible to malignant hyperthermia. Acta Anaesthesiologica Scandinavica 35:380-386, 1991

Seewald M, Eichinger HM, Lehmann-Horn F, Iaizzo PA: Characterization of homozygous and heterozygous pigs susceptible to malignant hyperthermia by in vivo, in vitro and post-mortem techniques. Acta Anaesthesiologica Scandinavica 35:345-349, 1991

Wedel DJ, Iaizzo PA, Milde JH: Desflurane is a trigger of malignant hyperthermia in susceptible swine. Anesthesiology 74: 508-512, 1991

Lehmann-Horn F, Iaizzo PA: Are myotonias and periodic paralyses associated with susceptibility to malignant hyperthermia? British Journal of Anaesthesia 65:692-697, 1990

Quinlan JG, Wedel DJ, Iaizzo PA: Multiple-pulse stimulation and dantrolene in malignant hyperthermia. Muscle and Nerve 13:904-908, 1990

Eichinger HM, Seewald MJ, Iaizzo PA: Porcine malignant hyperthermia: new insights into the pathophysiology as it may relate to meat quality. In: Proceedings Vol. III ICOMST. Copenhagen, Denmark, pp. 1119-1123, 1989

Iaizzo PA, Klein W, Lehmann-Horn F: Myoplasmic calcium and contractures in MH susceptible skeletal muscle. In: Malignant Hyperthermia, An Update. Proceedings of the VI Myology Colloquium. Hofmann JG, Schmidt A (eds.). Volk and Gesundheit, Berlin, pp. 247-252, 1989

Iaizzo PA: The pathophysiology of malignant hyperthermia. Acta Anaesthesiiologica Scandinavica 33:45-47, 1989

Iaizzo PA, Lehmann-Horn F: The in vitro determination of susceptibility to malignant hyperthermia. Muscle and Nerve 12:184-190, 1989

Iaizzo PA, Lehmann-Horn F, Taylor SR, Gallant EM: Malignant hyperthermia: Effects of halothane on the surface membrane. Muscle and Nerve 12:178-183, 1989

Iaizzo PA, Seewald M, Oakes SG, Lehmann-Horn F: The use of fura-2 to estimate myoplasmic [Ca2+] in human skeletal muscle. Cell Calcium 10:151-158, 1989

Lehmann-Horn F, Iaizzo PA: Neuromuscular diseases and their relationship to malignant hyperthermia. In: Advances in Neuromuscular Diseases. Serratrice G, Pellissier JF, Desnuelle C, Pouget J (eds.). Expansion Scientifique Francaise, pp. 260-266, 1989

Lehmann-Horn F, Iaizzo PA: Physiologie der menschlichen skelettmuskulatur: Ergebnisse an routinemäßig entnommenen muskelproben. In: Malignant Hyperthermia. Mauritz W, Bergmann H, Steinbereithner K (eds.). Beiträe zur Anaesthesiiologie unt Intensivmedizin 27:19-23, 1989

Lehmann-Horn F, Iaizzo PA: Use of fiber segments to investigate the pathophysiology of human skeletal muscle. In: Advances in Neuromuscular diseases. Serratrice G, Pellissier JF, Desnuelle C, Pouget J (eds.). Expansion Scientifique Francaise, pp. 44-50, 1989

Lehmann-Horn F, Klein W, Hohne E, Iaizzo PA: In vitro diagnosis of susceptibility to malignant hyperthermia. In: Malignant Hyperthermia, An Update. Proceedings of the VI Myology Colloquium. Hofmann JG, Schmidt A (eds.). Volk and Gesundheit, Berlin, pp. 97-100, 1989

Quinlan JG, Iaizzo PA, Gronert GA, Lambert EH: Ankle dorsiflexor twitch properties in malignant hyperthermia. Muscle and Nerve 12:119-125, 1989

Eichinger H, Seewald M, Iaizzo PA: Membrane phospholipid concentrations in cardiac and skeletal muscles from normal and malignant hyperthermia susceptible pigs. In: Control and Regulation of Animal Growth. Quirke JF and Schmid H (eds.), EAAP Pub. No. 36, Pudoc, Wageningen, Netherlands, pp. 191-200,1988

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. Pflügers Archive, European Journal of Physiology 411:648-653, 1988

Quinlan JG, Iaizzo PA, Gronert GA, Taylor SR: Use of dantrolene plus multiple pulses to detect stress-susceptible porcine muscle. Journal of Applied Physiology 60:1313-1320, 1986

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