Malignant Hyperthermia
Diagnostic Center
For detailed information about malignant hyperthermia
and its diagnosis, please visit the Malignant
Hyperthermia Association of the United States web site.
Quick jump to Center Information, Center
Personnel, Policy & Procedure, Malignant
Hyperthermia Research, or Publications Related
to Malignant Hyperthermia
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 (8-22-2008), in vitro contracture testing has been
performed on muscle biopsies from 77 patients and 36 normal control
subjects.
Director: Paul A. Iaizzo, Ph.D. (612-624-7912) or text page
(Contact Paul
A. Iaizzo, Ph.D. for general information on malignant hyperthermia
and the in vitro contracture test)
Clinical Coordinator: John W. Day, M.D., Ph.D.
John W. Day, M.D., Ph.D.
Clinical Assistant: Dorathy Faiella (612-626-3916)
(Contact Dorathy
Faiella to schedule a clinical consultation or to schedule a
biopsy date following insurance pre-authorization)
If you have any difficulty contacting
our director, clinical coordinator, or clinical assistant, please
contact Monica Mahre
(612-624-3959)
Collaborating Anesthesiologists:
Kumar G. Belani, M.B.B.S., M.S.
David S. Beebe, M.D.
Richard Prielipp, M.D.
Policy
and Procedure
An in vitro contracture test for the determination
of susceptibility to malignant hyperthermia (MH) will be performed
on patients who have had a preliminary consultation, 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, hence test results will be
added to its database.
The procedure consists of the following:
I. Consultation
Each patient referred to the Malignant Hyperthermia
Muscle Biopsy Center at the University of Minnesota (or individuals
who contact the center on their own) must have a consultation with
a medical doctor who will determine whether or not the procedure
is appropriate. Please contact Dorathy
Faiella (612-626-3916)
to schedule a consultation. If a muscle biopsy is recommended, the
patient is then requested to seek pre-approval for the procedure
from his/her insurance company, or agree to be personally responsible
for the costs. The appropriate CPT codes for insurance reimbursement
are:
20205 Biopsy, Muscle; deep
88399 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)
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.
This usually involves block of the lateral femoral cutaneous nerve
along with mild sedation; children typically receive anesthesia
with a non-triggering agent. 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.
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.
Test results are also sent to the North American Malignant Hyperthermia
Registry. Prior to the muscle biopsy, we will request that the patient
sign a consent form giving us permission to share the patient's
information related to malignant hyperthermia with the Registry.
Patients that have a positive contracture test
will be advised to wear a medical alert bracelet. In addition, the
Clinical Coordinator or Staff Anesthesiologist will discuss the
following issues with patients that have positive test results:
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 via 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
Email: clinicaltesting@preventiongenetics.com
Center for Medical Genetics
University of Pittsburgh Medical Center
3550 Terrace St., S701 Scaife Hall
Pittsburgh, PA 15213
Tel: 800-454-8155
- 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).
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, Palahniuk RJ: Malignant hyperthermia:
diagnosis, treatment, genetics and pathophysiology. Investigative
Radiology 26:1013-1018, 1991
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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