Malignant hyperthermia
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225236783
2008-07-12T16:53:03Z
Cyclonenim
1572590
Reverted edits by [[Special:Contributions/88.117.72.70|88.117.72.70]] to last version by DOI bot (using [[WP:HG|Huggle]])
{{Infobox_Disease |
Name = Malignant hyperthermia |
Image = PBB Protein RYR1 image.jpg |
Caption = Abnormalities in the [[RYR1|Ryanodine receptor 1]] gene are commonly detected in malignant hyperthermia |
DiseasesDB = 7776 |
ICD10 = {{ICD10|T|88|3|t|80}} |
ICD9 = {{ICD9|995.89}} |
ICDO = |
OMIM = 145600 |
OMIM_mult = {{OMIM2|154275}} {{OMIM2|154276}} {{OMIM2|600467}} {{OMIM2|601887}} {{OMIM2|601888}} |
MedlinePlus = |
eMedicineSubj = |
eMedicineTopic = |
MeshID = D008305 |
}}
'''Malignant hyperthermia''' ('''MH''' or '''MHS''' for "malignant hyperthermia syndrome", or "malignant [[hyperpyrexia]] due to anaesthesia") is a rare life-threatening condition that is triggered by exposure to certain drugs used for [[general anaesthesia]] (specifically all [[volatile anaesthetic]]s), nearly all [[gas anesthetic|gas anaesthetic]]s, and the neuromuscular blocking agent [[succinylcholine]]. In susceptible individuals, these drugs can induce a drastic and uncontrolled increase in [[skeletal muscle]] [[oxidative metabolism]] which overwhelms the body's capacity to supply [[oxygen]], remove [[carbon dioxide]], and regulate [[body temperature]], eventually leading to [[blood circulation|circulatory]] collapse and death if not treated quickly.
Susceptibility to MH is often inherited as an [[autosomal dominant]] disorder, for which there are at least 6 genetic loci of interest,<ref name="Litman_2005"/> most prominently the [[ryanodine receptor]] gene (''RYR1''). MH susceptibility is phenotypically and genetically related to [[central core disease]] (CCD), an autosomal dominant disorder characterized both by MH symptoms and [[myopathy]]. MH is usually unmasked by anesthesia, or when a family member develops the symptoms. There is no simple, straightforward test to diagnose the condition. When MH develops during a procedure, treatment with [[dantrolene|dantrolene sodium]] is usually initiated; dantrolene and the avoidance of anesthesia in susceptible people have markedly reduced the mortality from this condition.
==Signs and symptoms==
Malignant hyperthermia develops during or after receiving a [[general anaesthetic]], and symptoms are generally identified by operating department staff. Characteristic signs are [[skeletal muscle|muscular]] rigidity, followed by a hypermetabolic state with increased [[oxygen]] consumption, increased [[carbon dioxide]] production ([[hypercapnia]], usually measured by [[capnography]]), [[tachycardia]] (fast heart rate), and an increase in body temperature ([[hyperthermia]]) at a rate of up to ~2°C per hour; temperatures up to 42°C are not uncommon. [[Rhabdomyolysis]] (breakdown of muscle tissue) may develop, as evidenced by red-brown decoloration of the [[urine]] and cardiological or neurological evidence of [[electrolyte]] disturbances.{{fact|date=March 2008}}
[[Halothane]], a once popular but now rarely used volatile anaesthetic, has been linked to a large proportion of cases, however, ''all'' halogenated [[volatile anaesthetics]] are potential triggers of malignant hyperthermia. [[Succinylcholine]], a neuromuscular blocking agent, is also a trigger for MH. MH does not occur with every exposure to triggering agents, and susceptible patients may undergo multiple uneventful episodes of anesthesia before developing an episode of MH. The symptoms usually develop within one hour after exposure to trigger substances, but may even occur several hours later in rare instances.
A proportion of people susceptible to malignant hyperthermia may have particular characteristics. A 1972 report on a family with MH also described [[myopathy]] (muscle weakness due to muscle cell abnormality), [[short stature]], [[cryptorchidism]] (undescended testicles), [[pectus carinatum]] (a chest wall deformity), lumbar [[lordosis]] and thoracic [[kyphosis]] (reversed curvature of the spine), and unusual facial characteristics.<ref>{{cite journal |author=King JO, Denborough MA, Zapf PW |title=Inheritance of malignant hyperpyrexia |journal=Lancet |volume=1 |issue=7746 |pages=365–70 |year=1972 |pmid=4109748 |doi=10.1016/S0140-6736(72)92854-1}}</ref> Later reports have termed this combinations the '''King-Denborough syndrome''', after the authors of the report.
==Diagnosis==
===During an attack===
Malignant hyperthermia is diagnosed on clinical grounds, but various investigations are generally performed. This includes [[blood test]]s, which may show a raised [[creatine kinase]] level, elevated [[potassium]], increased [[phosphate]] (leading to decreased [[calcium in biology|calcium]]) and - if determined - raised [[myoglobin]]; this is the result of damage to muscle cells. [[Metabolic acidosis]] and [[respiratory acidosis]] (raised acidity of the blood) may both occur. Severe rhabdomyolysis may lead to [[acute renal failure]], so [[renal function|kidney function]] is generally measured on a frequent basis.{{fact|date=March 2008}}
===Susceptibility testing===
In patients who have suffered an episode of MH, further tests are usually not performed as even a normal test would not mean that the patient is not at further risk of further episodes on future occasions. The exception would be if it is unclear whether the initial attack was due to a different medical problem, such as [[sepsis]] (severe infection).{{fact|date=March 2008}}
The main candidates for testing are those with a close relative who has suffered an episode of MH or has been shown to be susceptible. The standard procedure is the "caffeine-halothane contracture test", CHCT. A muscle [[biopsy]] is carried out at an approved research center, under local anesthesia. The fresh biopsy is bathed in solutions containing [[caffeine]] or [[halothane]] and observed for contraction; under good conditions, the [[sensitivity (tests)|sensitivity]] is 97% and the [[Specificity (tests) | specificity]] 78%.<ref name="Allen_1998>{{cite journal | author = Allen G, Larach M, Kunselman A | title = The sensitivity and specificity of the caffeine-halothane contracture test: a report from the North American Malignant Hyperthermia Registry | journal = Anesthesiology | volume = 88 | issue = 3 | pages = 579–88 | year = 1998 | pmid= 9523799 | url = http://www.anesthesiology.org/pt/re/anes/fulltext.00000542-199803000-00006.htm | doi = 10.1097/00000542-199803000-00006}}</ref> Negative biopsies are ''not'' definitive, so any patient who is suspected of MH by their medical history or that of blood relatives is generally treated with non-triggering anesthetics even if the biopsy was negative. Some researchers advocate the use of the "[[calcium in biology|calcium]]-induced calcium release" test in addition to the CHCT to make the test more specific.{{fact|date=March 2008}}
Less invasive diagnostic techniques have been proposed. Intramuscular injection of [[halothane]] 6 vol% has been shown to result in higher than normal increases in local [[pCO2|pCO<sub>2</sub>]] among patients with known malignant hyperthermia susceptibility. The [[sensitivity (tests)|sensitivity]] was 100% and [[specificity (tests)|specificity]] was 75%. For patients at similar risk to those in this study, this leads to a [[positive predictive value]] of 80% and [[negative predictive value]] of 100%. This method may provide a suitable alternative to more invasive techniques.<ref name="pmid17697213">{{cite journal |author=Schuster F, Gardill A, Metterlein T, Kranke P, Roewer N, Anetseder M |title=A minimally invasive metabolic test with intramuscular injection of halothane 5 and 6 vol% to detect probands at risk for malignant hyperthermia |journal=Anaesthesia |volume=62 |issue=9 |pages=882–7 |year=2007 |pmid=17697213 |doi=10.1111/j.1365-2044.2007.05173.x }}</ref>
A 2002 study examined another possible metabolic test. In this test, intramuscular injection of caffeine was followed by local measurement of the pCO<sub>2</sub>; those with known MH susceptibility had a significantly higher pCO<sub>2</sub> (63 versus 44 mmHg). The authors propose larger studies to assess the test's suitability for determining MH risk.<ref>{{cite journal |author=Anetseder M, Hager M, Müller CR, Roewer N |title=Diagnosis of susceptibility to malignant hyperthermia by use of a metabolic test |journal=Lancet |volume=359 |issue=9317 |pages=1579–80 |year=2002 |pmid=12047971 |doi=10.1016/S0140-6736(02)08506-9}}</ref>
A 2005 paper proposes a protocol for investigating people with a family history of MH, where first-line genetic screening of ''RYR1'' mutations is one of the options.<ref name="Litman_2005">{{cite journal | author = Litman R, Rosenberg H | title = Malignant hyperthermia: update on susceptibility testing | journal = JAMA | volume = 293 | issue = 23 | pages = 2918–24 | year = 2005 | pmid = 15956637 | doi = 10.1001/jama.293.23.2918}}</ref>
==Criteria==
A 1994 consensus conference led to the formulation of a set of diagnostic criteria. The higher the score (above 6), the more likely a reaction constituted MH:<ref>{{cite journal |author=Larach MG, Localio AR, Allen GC, ''et al'' |title=A clinical grading scale to predict malignant hyperthermia susceptibility |journal=Anesthesiology |volume=80 |issue=4 |pages=771–9 |year=1994 |pmid=8024130 |doi=10.1097/00000542-199404000-00008}}</ref>
* [[Respiratory acidosis]] (end-tidal CO<sub>2</sub> above 55 mmHg or arterial pCO<sub>2</sub> above 60 mgHg)
* Heart involvement (unexplained [[sinus tachycardia]], [[ventricular tachycardia]] or [[ventricular fibrillation]])
* [[Metabolic acidosis]] (base excess lower than -8, pH<7.25)
* Muscle rigidity (generalized rigidity including severe masseter muscle rigidity)
* Muscle breakdown (CK >20,000/L units, cola colored urine or excess myoglobin in urine or serum, potassium above 6 mmol/l)
* Temperature increase (rapidly increasing temperature, T >38.8°C)
* Other (rapid reversal of MH signs with dantrolene, elevated resting serum CK levels)
* Family history ([[autosomal dominant]] pattern)
==Pathophysiology==
===Disease mechanism===
The potential for malignant hyperthermia is caused in a large proportion (50-70%) of cases by a [[mutation]] of the [[ryanodine receptor]] (type 1), located on the [[sarcoplasmic reticulum]] (SR), the [[organelle]] within [[skeletal muscle]] [[cell (biology)|cells]] that stores [[calcium in biology|calcium]].<ref name="Gillard_1991">{{cite journal | author = Gillard E, Otsu K, Fujii J, Khanna V, de Leon S, Derdemezi J, Britt B, Duff C, Worton R, MacLennan D | title = A substitution of cysteine for arginine 614 in the ryanodine receptor is potentially causative of human malignant hyperthermia | journal = Genomics | volume = 11 | issue = 3 | pages = 751–5 | year = 1991 | pmid = 1774074 | doi = 10.1016/0888-7543(91)90084-R}}</ref><ref name="Galli_2006">{{cite journal | author = Galli L, Orrico A, Lorenzini S, Censini S, Falciani M, Covacci A, Tegazzin V, Sorrentino V | title = Frequency and localization of mutations in the 106 exons of the RYR1 gene in 50 individuals with malignant hyperthermia | journal = Hum Mutat | volume = 27 | issue = 8 | pages = 830 | year = 2006 | pmid = 16835904 | doi = 10.1002/humu.9442}}</ref> RYR1 opens in response to increases in intracellular [[Calcium|Ca<sup>2+</sup>]] level mediated by L-type [[calcium channel]]s, thereby resulting in a drastic increase in intracellular calcium levels and muscle contraction. RYR1 has two sites believed to be important for reacting to changing Ca<sup>2+</sup> concentrations: the A-site and the I-site. The A-site is a high [[affinity]] Ca<sup>2+</sup> binding site that mediates RYR1 opening. The I-site is a lower affinity site that mediates the protein's closing. [[Caffeine]], [[Halothane]], and other triggering agents act by drastically increasing the affinity of the A-site for Ca<sup>2+</sup> and concomitantly decreasing the affinity of the I-site in mutant proteins. Mg<sup>2+</sup> also affect RYR1 activity, causing the protein to close by acting at either the A- or I-sites. In MH mutant proteins, the affinity for Mg<sup>2+</sup> at either or these site is greatly reduced. The end result of these alterations is greatly increased Ca<sup>2+</sup> release due to a lowered activation and heightened deactivation threshold.<ref name="Balog_2001">{{cite journal | author = Balog E, Fruen B, Shomer N, Louis C | title = Divergent effects of the malignant hyperthermia-susceptible Arg(615)->Cys mutation on the Ca(2+) and Mg(2+) dependence of the RyR1 | journal = Biophys J | volume = 81 | issue = 4 | pages = 2050–8 | year = 2001 | pmid=11566777 | url=http://www.biophysj.org/cgi/content/full/81/4/2050}} {{PMC|1301678}}</ref><ref name="Yang_2003">{{cite journal | author = Yang T, Ta T, Pessah I, Allen P | title = Functional defects in six ryanodine receptor isoform-1 (RyR1) mutations associated with malignant hyperthermia and their impact on skeletal excitation-contraction coupling | journal = J Biol Chem | volume = 278 | issue = 28 | pages = 25722–30 | year = 2003 | pmid= 12732639 | url=http://www.jbc.org/cgi/content/full/278/28/25722 | doi = 10.1074/jbc.M302165200}}</ref> The process of reabsorbing this excess Ca<sup>2+</sup> consumes large amounts of [[adenosine triphosphate|ATP]] (adenosine triphosphate), the main cellular energy carrier, and generates the excessive heat (hyperthermia) that is the hallmark of the disease. The muscle cell is damaged by the depletion of ATP and possibly the high temperatures, and cellular constituents "leak" into the circulation, including [[potassium]], [[myoglobin]], [[creatine]], [[phosphate]] and [[creatine kinase]].
The other known causative gene for MH is ''CACNA1S'', which encodes and [[L-type calcium channel|L-type]] [[voltage-gated calcium channel]] α-subunit. There are two known mutations in this protein, both affecting the same residue, R1086.<ref name="Monnier_1997">{{cite journal | author = Monnier N, Procaccio V, Stieglitz P, Lunardi J | title = Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle | journal = Am J Hum Genet | volume = 60 | issue = 6 | pages = 1316–25 | year = 1997 | pmid=9199552 | doi = 10.1086/515454}} {{PMC|1716149}}</ref><ref name="unknown">The R1086C mutant has never been published, but has nevertheless been referenced multiple times in the literature, e.g. {{cite journal | author = Jurkat-Rott K, McCarthy T, Lehmann-Horn F | title = Genetics and pathogenesis of malignant hyperthermia | journal = Muscle Nerve | volume = 23 | issue = 1 | pages = 4–17 | year = 2000 | pmid = 10590402 | doi = 10.1002/(SICI)1097-4598(200001)23:1<4::AID-MUS3>3.0.CO;2-D}}</ref> This residue is located in the large intracellular loop connecting domains 3 and 4, a domain possibly involved in negatively regulating RYR1 activity. When these mutant channels are expressed in [[HEK cell|HEK 293]] (human embryonic kidney) cells, the resulting channels are five times more sensitive to activation by caffeine (and presumably halothane) and activate at 5-10mV more hyperpolarized. Furthermore, cells expressing these channels have an increased basal cytosolic Ca<sup>2+</sup> concentration. As these channels interact with and activate RYR1, these alterations result in a drastic increase of intracellular Ca<sup>2+</sup>, and, thereby, muscle excitability.<ref name="Weiss_2004">{{cite journal | author = Weiss R, O'Connell K, Flucher B, Allen P, Grabner M, Dirksen R | title = Functional analysis of the R1086H malignant hyperthermia mutation in the DHPR reveals an unexpected influence of the III-IV loop on skeletal muscle EC coupling | journal = Am J Physiol Cell Physiol | volume = 287 | issue = 4 | pages = C1094–102 | year = 2004 | pmid=15201141 |url=http://ajpcell.physiology.org/cgi/content/full/287/4/C1094 | doi = 10.1152/ajpcell.00173.2004}}</ref>
Other mutations causing MH have been identified, although in most cases the relevant gene remains to be identified.<ref name="Litman_2005"/>
===Animal model===
Research into malignant hyperthermia was limited until the discovery of "porcine stress syndrome" in [[Landrace]] [[pig]]s, a condition in which stressed pigs develop "pale, soft, exudative" flesh (a manifestation of the effects of malignant hyperthermia) rendering their meat unmarketable at slaughter. This "awake triggering" was not observed in humans, and initially cast doubts on the value of the animal model, but subsequently susceptible humans were discovered to "awake trigger" (develop malignant hyperthermia) in stressful situations. This supported the use of the pig model for research. Pig farmers use halothane cones in swine yards to expose piglets to halothane. Those that die were MH-susceptible, thus saving the farmer the expense of raising a pig whose meat he would not be able to market.{{fact|date=March 2008}}
Gillard ''et al'' discovered the causative mutation in humans only after similar mutations had first been described in pigs.<ref name="Gillard_1991"/>
Horses also suffer from malignant hyperthermia. It is the Thoroughbred breed that was found to have susceptibility. It can be caused by overwork, anesthesia, or stress. An inheritable genetic mutation is found in susceptible animals. <ref name="pmid10659313">{{cite journal |author=Valberg SJ, Mickelson JR, Gallant EM, MacLeay JM, Lentz L, de la Corte F |title=Exertional rhabdomyolysis in quarter horses and thoroughbreds: one syndrome, multiple aetiologies |journal=Equine Vet J Suppl |volume=30 |issue= |pages=533–8 |year=1999 |pmid=10659313}}</ref>
An MH mouse has been constructed, bearing the R163C mutation prevalent in humans. These mice display symptoms similar to human MH patients, including sensitivity to halothane (increased respiration, body temperature, and death). Blockade of RYR1 by [[dantrolene]] prevents adverse reaction to [[halothane]] in these mice, as with humans. Muscle from these mice also shows increased K<sup>+</sup>-induced depolarization and an increased caffeine sensitivity.<ref name="Yang_2006">{{cite journal |author=Yang T, Riehl J, Esteve E, ''et al'' |title=Pharmacologic and functional characterization of malignant hyperthermia in the R163C RyR1 knock-in mouse |journal=Anesthesiology |volume=105 |issue=6 |pages=1164–75 |year=2006 |pmid=17122579 |url=http://www.anesthesiology.org/pt/re/anes/fulltext.00000542-200612000-00016.htm |doi=10.1097/00000542-200612000-00016}}</ref>
==Genetics==
At least 70 mutations in the ryanodine receptor have been described, which are transmitted in an [[autosomal dominant]] fashion. The [[gene]] is located on the long arm of the nineteenth [[chromosome]] (19q13.1). These mutations tend to cluster in one of three domains within the protein, designated MH1-3. MH1 and MH2 are located in the N-terminus of the protein, which interacts with L-type calcium channels and Ca<sup>2+</sup>. MH3 is located in the transmembrane forming C-terminus. This region is important for allowing Ca<sup>2+</sup> passage through the protein following opening.{{Fact|date=November 2007}}
==Treatment==
[[Image:Dantrolene.svg|right|thumb|Dantrolene sodium, the only known medical treatment for malignant hyperthermia.]]
The current treatment of choice is the intravenous administration of [[dantrolene]], the only known antidote, discontinuation of triggering agents, and supportive therapy directed at correcting hyperthermia, acidosis, and organ dysfunction. Treatment must be instituted rapidly on clinical suspicion of the onset of malignant hyperthermia.{{fact|date=March 2008}}
Dantrolene is a muscle relaxant that appears to work directly on the ryanodine receptor to prevent the release of calcium.
After the widespread introduction of treatment with [[dantrolene]] the mortality of malignant hyperthermia fell from 80% in the 1960s to less than 10%. Dantrolene remains as the only drug known to be effective in the treatment of MH.<ref name=Krause>{{cite journal |author=Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F |title=Dantrolene--a review of its pharmacology, therapeutic use and new developments |journal=Anaesthesia |volume=59 |issue=4 |pages=364–73 |year=2004 |pmid=15023108 |doi=10.1111/j.1365-2044.2004.03658.x | url=http://www.blackwell-synergy.com/doi/full/10.1111/j.1365-2044.2004.03658.x}}</ref>
Its clinical use has been limited by its low [[water solubility]], leading to requirements of large fluid volumes which may complicate clinical management. [[Azumolene]] is a 30-fold more water-soluble [[Analog (chemistry)|analogue]] of dantrolene that also works to decrease the release of intracellular calcium by its action on the ryanodine receptor. In MH susceptible swine, azumolene was as potent as dantrolene.<ref>{{cite journal |author=Dershwitz M, Sréter FA |title=Azumolene reverses episodes of malignant hyperthermia in susceptible swine |journal=Anesth. Analg. |volume=70 |issue=3 |pages=253–5 |year=1990 |pmid=2305975|doi=10.1213/00000539-199003000-00004}}</ref> It has yet to be studied in vivo in humans, but may present a suitable alternative to dantrolene in the treatment of MH.
==Prevention==
In the past, the [[prophylactic]] use of [[dantrolene]] was recommended for MH susceptible patients undergoing general anesthesia.<ref name=Krause/> However, multiple retrospective studies, have demonstrated the safety of trigger-free [[general anesthesia]] in these patients in the absence of prophylactic dantrolene administration. The largest of these studies looked at the charts of 2214 patients who underwent general or [[regional anesthesia]] for an elective muscle biopsy. 1082 of the patients were muscle biopsy positive for MH. Only five of these patients exhibited symptoms consistent with MH, four of which were treated successfully with [[parenteral]] dantrolene, and the remaining one recovered with only symptomatic therapy.<ref>{{cite journal |author=Carr AS, Lerman J, Cunliffe M, McLeod ME, Britt BA |title=Incidence of malignant hyperthermia reactions in 2,214 patients undergoing muscle biopsy |journal=Can J Anaesth |volume=42 |issue=4 |pages=281–6 |year=1995 |pmid=7788824}}</ref> After weighing its questionable benefits against its possible adverse effects, experts no longer recommend the use of prophylactic dantrolene prior to trigger-free general anesthesia in MH susceptible patients.<ref name=Krause/>
The only sure way to prevent MH is avoid the use of triggering agents in patients known or suspected of being susceptible to MH.{{fact|date=March 2008}}
==Epidemiology==
The [[incidence (epidemiology)|incidence]] has been reported to be between 1:4,500 to 1:60,000 procedures involving [[general anaesthesia]]. This disorder occurs worldwide and affects all racial groups. Most cases however occur in children and young adults, which might be related to the fact that many older people will have already had surgeries and thus would know about and be able to avoid this condition.{{Fact|date=November 2007}}
==History==
The syndrome was first recognized in Australia in an affected family by Denborough ''et al'' in 1962.<ref name="Denborough_1962">{{cite journal |author=Denborough MA, Forster JF, Lovell RR, Maplestone PA, Villiers JD |title=Anaesthetic deaths in a family |journal=British journal of anaesthesia |volume=34 |issue= |pages=395–6 |year=1962 |pmid=13885389 |doi=10.1093/bja/34.6.395}} Historical account in {{cite journal |author=Denborough MA |title=Malignant hyperthermia. 1962 |journal=Anesthesiology |volume=108 |issue=1 |pages=156–7 |year=2008 |pmid=18156894 |doi=10.1097/01.anes.0000296107.23210.dd | url=http://www.anesthesiology.org/pt/re/anes/fulltext.00000542-200801000-00023.htm |doi_brokendate=2008-06-21}}</ref> Similar reactions were found in pigs.<ref>{{cite journal |author=Hall LW, Woolf N, Bradley JW, Jolly DW |title=Unusual reaction to suxamethonium chloride |journal=Br Med J |volume=2 |issue=5525 |pages=1305 |year=1966 |pmid=5924819}} {{PMC|1944316}}</ref> After animal studies indicated possible benefit from dantrolene, a 1982 study confirmed its usefulness in humans.<ref>{{cite journal |author=Kolb ME, Horne ML, Martz R |title=Dantrolene in human malignant hyperthermia |journal=Anesthesiology |volume=56 |issue=4 |pages=254–62 |year=1982 |pmid=7039419 |doi=10.1097/00000542-198204000-00005}}</ref>
==References==
{{Reflist|2}}
==External links==
<!-- BEFORE inserting new links here you should first post it to the talk page, otherwise your edit is likely to be reverted; this section is reserved for official or authoritative resources-->
*[http://www.mhaus.org/ Malignant Hyperthermia Association of the United States]
*[http://opa.faseb.org/pages/PublicEducators/mh/ Making Anesthesia Safer - Unraveling the Malignant Hyperthermia Puzzle] by Marilyn Green Larach, [[Federation of American Societies for Experimental Biology|FASEB]] "Breakthroughs in Bioscience"
{{Consequences of external causes}}
[[Category:Anesthesia]]
[[Category:Channelopathy]]
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[[ja:悪性高熱症]]
[[pt:Hipertermia maligna]]
[[pl:Hipertermia złośliwa]]