Malignant hyperthermia: Difference between revisions

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==Overview==
==Overview==
'''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 anesthesia]] (specifically all [[volatile anesthetic]]s), nearly all [[gas anesthetic]]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.
'''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 anesthesia]] (specifically all [[volatile anesthetic]]s), nearly all [[gas anesthetic]]s, and the neuromuscular blocking agent [[succinylcholine]]. MH is an autosomal-dominant inherited disorder, [[children]] and young [[adults]] are most affected, with a significant male predilection. [[Mutations]] in the RYR1 gene on chromosome 19q13.1 have been associated with a predisposition to MH. When an MH-susceptible (MHS) individual is exposed to a volatile anesthetic (eg, [[halothane]], [[isoflurane]], [[enfluran]]<nowiki/>e, [[sevoflurane]], [[desflurane]]) or [[succinylcholine]], the triggering agent induces prolonged opening of functionally altered ryanodine receptors, causes an uncontrolled release of [[calcium]] from the sarcoplasmic reticulum and ongoing muscle rigidity. This may lead to a metabolic crisis which manifests clinically as [[tachycardia]], [[Hypercarbia|hypercarbi]]<nowiki/>a, [[hyperpyrexia]], [[kidney failure]] and eventually death may occur if left untreated. Management of malignant hyperthermia crisis includes administration of [[dantrolene|dantrolene sodium]], which is a postsynaptic [[muscle]] relaxant that reduces excitation-contraction coupling in muscle cells, and the avoidance of triggering [[anesthetic]] agents or [[succinylcholine]], external and internal cooling until body [[temperature]] reaches 38.5°C, [[hemodynamic]] monitoring in [[Intensive care unit]]. This strategy has markedly reduced the mortality from this condition.
MH susceptibility is phenotypically and genetically related to [[central core disease]] (CCD), an autosomal dominant disorder characterized both by MH symptoms and [[myopathy]]. 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==
==Signs and symptoms==
* Malignant hyperthermia develops during or after receiving a [[general anaesthetic]], and symptoms are generally identified by operating department staff.  
* Malignant hyperthermia develops during or after receiving a [[general anaesthetic]], and symptoms are generally identified by operating department staff. <ref name="pmid24868161">{{cite journal |vauthors=Schneiderbanger D, Johannsen S, Roewer N, Schuster F |title=Management of malignant hyperthermia: diagnosis and treatment |journal=Ther Clin Risk Manag |volume=10 |issue= |pages=355–62 |date=2014 |pmid=24868161 |pmc=4027921 |doi=10.2147/TCRM.S47632 |url=}}</ref><ref name="pmid31040503">{{cite journal |vauthors=Kaur H, Katyal N, Yelam A, Kumar K, Srivastava H, Govindarajan R |title=Malignant Hyperthermia |journal=Mo Med |volume=116 |issue=2 |pages=154–159 |date=2019 |pmid=31040503 |pmc=6461318 |doi= |url=}}</ref><ref name="pmid7282770">{{cite journal |vauthors=McPherson EW, Taylor CA |title=The King syndrome: malignant hyperthermia, myopathy, and multiple anomalies |journal=Am. J. Med. Genet. |volume=8 |issue=2 |pages=159–65 |date=1981 |pmid=7282770 |doi=10.1002/ajmg.1320080206 |url=}}</ref>
* 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.  
* Clinical signs and symptoms of patients with malignant hyperthermia are include [[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.  


* [[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.
* [[Halothane]], a once popular but now rarely used volatile anesthetic, has been linked to a large proportion of cases, however, ''all'' halogenated [[volatile anesthetics]] 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.
* 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. Later reports have termed this combinations the '''King-Denborough syndrome''', after the authors of the report.<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>
* 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. Later reports have termed this combinations the '''King-Denborough syndrome''', after the authors of the report.<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>


==Diagnosis==
==Diagnosis==
===Susceptibility testing===
===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).<ref name="pmid26238698">{{cite journal |vauthors=Rosenberg H, Pollock N, Schiemann A, Bulger T, Stowell K |title=Malignant hyperthermia: a review |journal=Orphanet J Rare Dis |volume=10 |issue= |pages=93 |date=August 2015 |pmid=26238698 |pmc=4524368 |doi=10.1186/s13023-015-0310-1 |url=}}</ref><ref name="pmid17697213">{{cite journal |vauthors=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 |date=September 2007 |pmid=17697213 |doi=10.1111/j.1365-2044.2007.05173.x |url=}}</ref>
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).<ref name="pmid26238698">{{cite journal |vauthors=Rosenberg H, Pollock N, Schiemann A, Bulger T, Stowell K |title=Malignant hyperthermia: a review |journal=Orphanet J Rare Dis |volume=10 |issue= |pages=93 |date=August 2015 |pmid=26238698 |pmc=4524368 |doi=10.1186/s13023-015-0310-1 |url=}}</ref><ref name="pmid17697213">{{cite journal |vauthors=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 |date=September 2007 |pmid=17697213 |doi=10.1111/j.1365-2044.2007.05173.x |url=}}</ref>
* 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.  
* 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>  
* In-vitro contracture response of biopsied muscle is the only reliable procedure for diagnosis of MH in those individuals with a positive family history or previous clinical signs. <ref name="pmid9402480">{{cite journal |vauthors=Ummenhofer W, Roesslein R, Sutter PM, Moser N, Kern C, Urwyler A |title=Muscle biopsy for malignant hyperthermia screening in children |journal=Eur J Pediatr Surg |volume=7 |issue=5 |pages=259–62 |date=October 1997 |pmid=9402480 |doi=10.1055/s-2008-1071166 |url=}}</ref><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>
* 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.
* 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.


* 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>  
* 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>
* Based on the studies done, there is another possible metabolic test for diagnosing MH. 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>
* Based on the studies done, there is another possible metabolic test for diagnosing MH. 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>
* 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>


==Diagnostic criteria==
==Diagnostic criteria==
Diagnosis of malignant hyperhtermia is vased on clinical manifestation or laboratory testing. In 1994, a clinical grading scale was developed by Larach and colleagues in order to predict malignant hyperthermia susceptibility. The elements of this grading scales include:<ref name="pmid8024130">{{cite journal |vauthors=Larach MG, Localio AR, Allen GC, Denborough MA, Ellis FR, Gronert GA, Kaplan RF, Muldoon SM, Nelson TE, Ording H |title=A clinical grading scale to predict malignant hyperthermia susceptibility |journal=Anesthesiology |volume=80 |issue=4 |pages=771–9 |date=April 1994 |pmid=8024130 |doi= |url=}}</ref>  
Diagnosis of malignant hyperhtermia is based on clinical manifestation or laboratory testing. In 1994, a clinical grading scale was developed by Larach and colleagues in order to predict malignant hyperthermia susceptibility. The elements of this grading scales include:<ref name="pmid8024130">{{cite journal |vauthors=Larach MG, Localio AR, Allen GC, Denborough MA, Ellis FR, Gronert GA, Kaplan RF, Muldoon SM, Nelson TE, Ording H |title=A clinical grading scale to predict malignant hyperthermia susceptibility |journal=Anesthesiology |volume=80 |issue=4 |pages=771–9 |date=April 1994 |pmid=8024130 |doi= |url=}}</ref>  
* [[Respiratory acidosis]] (end-tidal CO<sub>2</sub> above 55 mmHg or arterial pCO<sub>2</sub> above 60 mgHg)
* [[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]])
*[[Heart]] involvement (unexplained [[sinus tachycardia]], [[ventricular tachycardia]] or [[ventricular fibrillation]])
* [[Metabolic acidosis]] (base excess lower than -8, pH<7.25)
* [[Metabolic acidosis]] (base excess lower than -8, pH<7.25)
* Muscle rigidity (generalized rigidity including severe masseter muscle rigidity)
* Muscle rigidity (generalized rigidity including severe masseter muscle rigidity)
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==Pathophysiology==
==Pathophysiology==
===Disease mechanism===
===Disease mechanism===
* The potential cause of Malignant hyperthermia in large porportion (50-70%) of cases is 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>  
* The potential cause of Malignant hyperthermia in large porportion (50-70%) of cases is 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.   
* 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.   
* 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 one of these sites 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>  
* 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 one of these sites 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 excess Ca<sup>2+</sup> must be reabsorbed and this process utilize large amounts of [[adenosine triphosphate|ATP]] (adenosine triphosphate), this leads to generation of 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 excess Ca<sup>2+</sup> must be reabsorbed and this process utilize large amounts of [[adenosine triphosphate|ATP]] (adenosine triphosphate), this leads to generation of 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>  
* 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.  
* 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>
* Furthermore, cells expressing these channels have an increased basal [[cytosolic]] Calcium concentration. As these channels interact with and activate RYR1, these alterations result in a drastic increase of [[intracellular]] Calcium, 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" />
* 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 pigs, a condition in which stressed pigs developed muscle rigidity within minutes after the induction with the anesthetic drug, particularly halothane. <ref name="pmid10922003">{{cite journal |vauthors=Dietze B, Henke J, Eichinger HM, Lehmann-Horn F, Melzer W |title=Malignant hyperthermia mutation Arg615Cys in the porcine ryanodine receptor alters voltage dependence of Ca2+ release |journal=J. Physiol. (Lond.) |volume=526 Pt 3 |issue= |pages=507–14 |date=August 2000 |pmid=10922003 |pmc=2270038 |doi= |url=}}</ref> <ref name="pmid7275857">{{cite journal |vauthors=Kukoyi EA, Addis PB, McGrath CJ, Rempel WE, Martin FB |title=Porcine stress syndrome and postmortem muscle characteristics of two purebreds and three specific terminal crosses |journal=J. Anim. Sci. |volume=52 |issue=2 |pages=278–84 |date=February 1981 |pmid=7275857 |doi= |url=}}</ref>
* 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.
* Gillard ''et al'' discovered the causative mutation in humans only after similar mutations had first been described in pigs.<ref name="Gillard_1991" />
* 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==
==Genetics==
* At least 70 mutations in the ryanodine receptor have been described, which are transmitted in an [[autosomal dominant]] fashion.  
* 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).  
* 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.  
* 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 channel]]<nowiki/>s and Calcium. 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.
* This region is important for allowing Calcium passage through the protein following opening.
 
==[[Differential diagnosis of malignant hyperthermia]]==
==[[Differential diagnosis of malignant hyperthermia]]==
A number of conditions may present with clinical manifestation similar to those of acute malignant hyperthermia. Although treatment for malignant hyperthermia should be initiated during an acute attack, it is important to consider other causes as an alternative diagnosis. <ref name="pmid17456235">{{cite journal |vauthors=Rosenberg H, Davis M, James D, Pollock N, Stowell K |title=Malignant hyperthermia |journal=Orphanet J Rare Dis |volume=2 |issue= |pages=21 |date=April 2007 |pmid=17456235 |pmc=1867813 |doi=10.1186/1750-1172-2-21 |url=}}</ref>
A number of conditions may present with clinical manifestation similar to those of acute malignant hyperthermia. Although treatment for malignant hyperthermia should be initiated during an acute attack, it is important to consider other causes as an alternative diagnosis. <ref name="pmid17456235">{{cite journal |vauthors=Rosenberg H, Davis M, James D, Pollock N, Stowell K |title=Malignant hyperthermia |journal=Orphanet J Rare Dis |volume=2 |issue= |pages=21 |date=April 2007 |pmid=17456235 |pmc=1867813 |doi=10.1186/1750-1172-2-21 |url=}}</ref>
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! colspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Lab Findings
! colspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Lab Findings
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Other differentating  
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Other differentating findings
|-
|-
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |ECG
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |ECG
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* [[Myoglobinuria]]
* [[Myoglobinuria]]
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* The initial acid-base disturbance is respiratory acidosis.
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| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Sepsis]] induced [[hyperpyrexia]]<ref name="pmid262386982">{{cite journal |vauthors=Rosenberg H, Pollock N, Schiemann A, Bulger T, Stowell K |title=Malignant hyperthermia: a review |journal=Orphanet J Rare Dis |volume=10 |issue= |pages=93 |date=August 2015 |pmid=26238698 |pmc=4524368 |doi=10.1186/s13023-015-0310-1 |url=}}</ref>
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Sepsis]] induced [[hyperpyrexia]]<ref name="pmid262386982">{{cite journal |vauthors=Rosenberg H, Pollock N, Schiemann A, Bulger T, Stowell K |title=Malignant hyperthermia: a review |journal=Orphanet J Rare Dis |volume=10 |issue= |pages=93 |date=August 2015 |pmid=26238698 |pmc=4524368 |doi=10.1186/s13023-015-0310-1 |url=}}</ref>
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| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Neuroleptic malignant syndrome]]<ref name="pmid28144147">{{cite journal |vauthors=Oruch R, Pryme IF, Engelsen BA, Lund A |title=Neuroleptic malignant syndrome: an easily overlooked neurologic emergency |journal=Neuropsychiatr Dis Treat |volume=13 |issue= |pages=161–175 |date=2017 |pmid=28144147 |pmc=5248946 |doi=10.2147/NDT.S118438 |url=}}</ref>
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Neuroleptic malignant syndrome]]<ref name="pmid28144147">{{cite journal |vauthors=Oruch R, Pryme IF, Engelsen BA, Lund A |title=Neuroleptic malignant syndrome: an easily overlooked neurologic emergency |journal=Neuropsychiatr Dis Treat |volume=13 |issue= |pages=161–175 |date=2017 |pmid=28144147 |pmc=5248946 |doi=10.2147/NDT.S118438 |url=}}</ref><ref name="pmid24991155">{{cite journal |vauthors=Feng Y, Yang X, Huang Y |title=Two cases of neuroleptic malignant syndrome in elderly patients taking atypical antipsychotics |journal=Shanghai Arch Psychiatry |volume=25 |issue=3 |pages=178–82 |date=June 2013 |pmid=24991155 |pmc=4054545 |doi=10.3969/j.issn.1002-0829.2013.03.009 |url=}}</ref>
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* NMS symptoms usually presents after hours or days of the drug intake whereas in MH symptoms occur within minutes after drug intake
* NMS symptoms usually presents after hours or days of the drug intake whereas in MH symptoms occur within minutes after drug intake
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* Parkinsonian-like muscle rigidity
* Parkinsonian-like muscle rigidity
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* Small Q-waves
* T-waves changes
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* Leukocytosis
* Leukocytosis
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* Anti-dopaminergic side effect  of metoclopramide
* Anti-dopaminergic side effect  of metoclopramide
|-
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Pheochromocytoma]]<ref name="pmid28665830">{{cite journal |vauthors=Ramani NS, Stoppacher R, Morani AC, Catanese C |title=Undiagnosed Pheochromocytoma Simulating Malignant Hyperthermia |journal=Am J Forensic Med Pathol |volume=38 |issue=3 |pages=262–265 |date=September 2017 |pmid=28665830 |doi=10.1097/PAF.0000000000000326 |url=}}</ref>
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Pheochromocytoma]]<ref name="pmid28665830">{{cite journal |vauthors=Ramani NS, Stoppacher R, Morani AC, Catanese C |title=Undiagnosed Pheochromocytoma Simulating Malignant Hyperthermia |journal=Am J Forensic Med Pathol |volume=38 |issue=3 |pages=262–265 |date=September 2017 |pmid=28665830 |doi=10.1097/PAF.0000000000000326 |url=}}</ref><ref name="pmid10999582">{{cite journal |vauthors=Liao WB, Liu CF, Chiang CW, Kung CT, Lee CW |title=Cardiovascular manifestations of pheochromocytoma |journal=Am J Emerg Med |volume=18 |issue=5 |pages=622–5 |date=September 2000 |pmid=10999582 |doi=10.1053/ajem.2000.7341 |url=}}</ref>
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* [[Heavy sweating]].
* [[Heavy sweating]].
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* [[Dyspnea]]
* [[Dyspnea]]
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* ST-T segment changes
* ECG mimics ischemic changes
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* Plasma or urinary [[catecholamines]] are elevated
* Plasma or urinary [[catecholamines]] are elevated
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|[[Thyrotoxicosis]]<ref name="pmid30627307">{{cite journal |vauthors=Baladi IH, Rai AA, Ahmed SM |title=ECG changes in patients with primary hyperthyroidism |journal=Pan Afr Med J |volume=30 |issue= |pages=246 |date=2018 |pmid=30627307 |pmc=6307920 |doi=10.11604/pamj.2018.30.246.12244 |url=}}</ref>
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Thyrotoxicosis]]<ref name="pmid30627307">{{cite journal |vauthors=Baladi IH, Rai AA, Ahmed SM |title=ECG changes in patients with primary hyperthyroidism |journal=Pan Afr Med J |volume=30 |issue= |pages=246 |date=2018 |pmid=30627307 |pmc=6307920 |doi=10.11604/pamj.2018.30.246.12244 |url=}}</ref>
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* [[Goiter]]
* [[Goiter]]
* Skin [[flushing]]
* Skin [[flushing]]
* [[Weight loss]]
* [[Weight loss]]
* Heat intolerance
* Heat intolerance
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* Increased [[bowel]] disturbances
* Increased [[bowel]] disturbances
* Normal muscle tone
* Normal muscle tone
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* [[Sinus tachycardia]]  
* [[Sinus tachycardia]]  
* Higher voltage of P and T waves  
* Higher voltage of P and T waves  
* Elevated amplitude of [[QRS]] complex
* Elevated amplitude of [[QRS]] complex
* Prolonged P-Q and shortened Q-T  
* Prolonged P-Q and shortened Q-T  
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|Meperidine/MAOI/cocaine abuse
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==History==
==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>  
* 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>  
* 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>


* The efficacy of dantrolene as a treatment was discovered by South African anesthesiologist Gaisford Harrison and reported in a 1975 article published in the ''[[British Journal of Anaesthesia]]''.<ref name="Harrison">{{cite journal |author=Harrison GG |title=Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium |journal=British Journal of Anaesthesia |volume=47 |issue=1 |pages=62–5 |year=1975|month=January |pmid=1148076}} A reprint of the article, which became a "Citation Classic", is available in ''Br J Anaesth'''''81''' (4): 626–9. PMID 9924249 (free full text).</ref>
* The efficacy of dantrolene as a treatment was discovered by South African anesthesiologist Gaisford Harrison and reported in a 1975 article published in the ''[[British Journal of Anaesthesia]]''.<ref name="Harrison">{{cite journal |author=Harrison GG |title=Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium |journal=British Journal of Anaesthesia |volume=47 |issue=1 |pages=62–5 |year=1975|month=January |pmid=1148076}} A reprint of the article, which became a "Citation Classic", is available in ''Br J Anaesth'''''81''' (4): 626–9. PMID 9924249 (free full text).</ref>
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==Treatment==
==Treatment==
* The current treatment of choice is the intravenous administration of [[dantrolene]].
 
* Treatment must be initiated emergently as soon as malignant hyperthermia diagnosed based on clinical suspicion of the onset of symptoms.
'''Management of malignant hyperthermia crisis include the following steps:'''<ref name="pmid26238698">{{cite journal |vauthors=Rosenberg H, Pollock N, Schiemann A, Bulger T, Stowell K |title=Malignant hyperthermia: a review |journal=Orphanet J Rare Dis |volume=10 |issue= |pages=93 |date=August 2015 |pmid=26238698 |pmc=4524368 |doi=10.1186/s13023-015-0310-1 |url=}}</ref><ref name="pmid24868161">{{cite journal |vauthors=Schneiderbanger D, Johannsen S, Roewer N, Schuster F |title=Management of malignant hyperthermia: diagnosis and treatment |journal=Ther Clin Risk Manag |volume=10 |issue= |pages=355–62 |date=2014 |pmid=24868161 |pmc=4027921 |doi=10.2147/TCRM.S47632 |url=}}</ref>
 
* Discontinue the potent Inhaled anesthetic agents,  remove the vaporizer and hyperventilate with 100% oxygen to increase elimination of triggering agent and CO2 and to maximize oxygen delivery.
* If succinylcholine has been given, do not readminister it
* Call for help
* Stop surgery as soon as possible or switch to total IV anesthesia to complete the surgical procedure if it cannot be stopped
* Increase the minute ventilation to decrease end-tidal carbon dioxide (EtCO<sub>2</sub>)
* Increase fresh gas flow with 100% oxygen to 10 L/min
* Administer IV dantrolene, The starting dose of dantrolene is 2.5 mg/kg, then 2.5 mg/kg every 5-10 minutes until acidosis, tachycardia, pyrexia, and muscular rigidity are resolving. Adult patients will require multiple vials for the starting dose (e.g. 10 vials for a patient of 80 kg). One person should be assisting in preparing the drug.
* Cool patient with IV sodium chloride 0.9% at 4ºC, ice packs, and gastric lavage; stop cooling at 38.5ºC to prevent rebound hypothermia
* Obtain values for arterial blood gases (ABG), electrolytes, creatine kinase, and blood and urine myoglobin
* Treat arrhythmias and hyperkalemia - Do not use calcium-channel blockers
* Observe the patient in the intensive care unit (ICU) for 24 hours
* Ensure urine output of 2 mL/kg/hr with mannitol, furosemide, or fluids as needed
* Continue dantrolene 2.5 mg/kg if signs or symptoms recur
* Refer the patient and family for MH testing
 
* Recrudescence of the hypermetabolic reaction can occur for up to 14 h after initial resolution.
* Treatment must be started as early as malignant hyperthermia diagnosed based on clinical suspicion of the onset of symptoms.
* Dantrolene is a post-synaptic muscle relaxant which inhibits Ca2+ ions release from sarcoplasmic reticulum stores by antagonizing ryanodine receptors directly on the ryanodine receptor to prevent the release of calcium that leads to lesser excitation-contraction of muscle cells.  
* Dantrolene is a post-synaptic muscle relaxant which inhibits Ca2+ ions release from sarcoplasmic reticulum stores by antagonizing ryanodine receptors directly on the ryanodine receptor to prevent the release of calcium that leads to lesser excitation-contraction of muscle cells.  
* After the widespread introduction of treatment with [[dantrolene]] the mortality of malignant hyperthermia fell from 80% in the 1960s to less than 10%.<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>
* After the widespread introduction of treatment with [[dantrolene]] the mortality of malignant hyperthermia fell from 80% in the 1960s to less than 10%.<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>

Latest revision as of 21:58, 3 July 2019

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Malignant hyperthermia
Abnormalities in the Ryanodine receptor 1 gene are commonly detected in malignant hyperthermia
ICD-10 T88.3
ICD-9 995.89
OMIM 145600 154275 154276 600467 601887 601888
DiseasesDB 7776
MeSH D008305

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Nima Nasiri, M.D.[2]

Overview

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 anesthesia (specifically all volatile anesthetics), nearly all gas anesthetics, and the neuromuscular blocking agent succinylcholine. MH is an autosomal-dominant inherited disorder, children and young adults are most affected, with a significant male predilection. Mutations in the RYR1 gene on chromosome 19q13.1 have been associated with a predisposition to MH. When an MH-susceptible (MHS) individual is exposed to a volatile anesthetic (eg, halothane, isoflurane, enflurane, sevoflurane, desflurane) or succinylcholine, the triggering agent induces prolonged opening of functionally altered ryanodine receptors, causes an uncontrolled release of calcium from the sarcoplasmic reticulum and ongoing muscle rigidity. This may lead to a metabolic crisis which manifests clinically as tachycardia, hypercarbia, hyperpyrexia, kidney failure and eventually death may occur if left untreated. Management of malignant hyperthermia crisis includes administration of dantrolene sodium, which is a postsynaptic muscle relaxant that reduces excitation-contraction coupling in muscle cells, and the avoidance of triggering anesthetic agents or succinylcholine, external and internal cooling until body temperature reaches 38.5°C, hemodynamic monitoring in Intensive care unit. This strategy has 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. [1][2][3]
  • Clinical signs and symptoms of patients with malignant hyperthermia are include 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.
  • Halothane, a once popular but now rarely used volatile anesthetic, has been linked to a large proportion of cases, however, all halogenated volatile anesthetics 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. Later reports have termed this combinations the King-Denborough syndrome, after the authors of the report.[4]

Diagnosis

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).[5][6]

  • 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.
  • In-vitro contracture response of biopsied muscle is the only reliable procedure for diagnosis of MH in those individuals with a positive family history or previous clinical signs. [7][8]
  • 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-induced calcium release" test in addition to the CHCT to make the test more specific.
  • 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 among patients with known malignant hyperthermia susceptibility. The sensitivity was 100% and 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.[6]
  • Based on the studies done, there is another possible metabolic test for diagnosing MH. In this test, intramuscular injection of caffeine was followed by local measurement of the pCO2; those with known MH susceptibility had a significantly higher pCO2 (63 versus 44 mmHg). The authors propose larger studies to assess the test's suitability for determining MH risk.[9]
  • 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.[10]

Diagnostic criteria

Diagnosis of malignant hyperhtermia is based on clinical manifestation or laboratory testing. In 1994, a clinical grading scale was developed by Larach and colleagues in order to predict malignant hyperthermia susceptibility. The elements of this grading scales include:[11]

  • Respiratory acidosis (end-tidal CO2 above 55 mmHg or arterial pCO2 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 cause of Malignant hyperthermia in large porportion (50-70%) of cases is a mutation of the ryanodine receptor (type 1), located on the sarcoplasmic reticulum (SR), the organelle within skeletal muscle cells that stores calcium.[12][13]
  • RYR1 opens in response to increases in intracellular Ca2+ level mediated by L-type calcium channels, 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 Ca2+ concentrations: the A-site and the I-site.
  • Mg2+ 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 Mg2+ at either one of these sites is greatly reduced. The end result of these alterations is greatly increased Ca2+ release due to a lowered activation and heightened deactivation threshold.[14][15]
  • The excess Ca2+ must be reabsorbed and this process utilize large amounts of ATP (adenosine triphosphate), this leads to generation of 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 voltage-gated calcium channel α-subunit. There are two known mutations in this protein, both affecting the same residue, R1086.[16][17]
  • 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 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 Calcium concentration. As these channels interact with and activate RYR1, these alterations result in a drastic increase of intracellular Calcium, and, thereby, muscle excitability.[18]
  • Other mutations causing MH have been identified, although in most cases the relevant gene remains to be identified.[10]

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 Calcium. MH3 is located in the transmembrane forming C-terminus.
  • This region is important for allowing Calcium passage through the protein following opening.

Differential diagnosis of malignant hyperthermia

A number of conditions may present with clinical manifestation similar to those of acute malignant hyperthermia. Although treatment for malignant hyperthermia should be initiated during an acute attack, it is important to consider other causes as an alternative diagnosis. [19]

Diseases Clinical manifestations Para-clinical findings
Differentiating Signs/Symptoms
Lab Findings Other differentating findings
ECG Other labs
Malignant hyperthermia[1][20]
  • Muscular rigidity/dystonia, no hyperreflexia unlike serotonin syndrome.
  • non-specific ST-T changes
  • Q waves or increased voltage
  • Rise in end tidal CO2 (earliest sign)
  • The initial acid-base disturbance is respiratory acidosis.
Sepsis induced hyperpyrexia[21]
Neuroleptic malignant syndrome[22][23]
  • NMS symptoms usually presents after hours or days of the drug intake whereas in MH symptoms occur within minutes after drug intake
  • Arise as a result of administration of potent psychotropic agents.
  • Autonomic nervous system imbalance,
  • Mental disturbances (manifested mostly as delirium),
  • Parkinsonian-like muscle rigidity
  • Small Q-waves
  • T-waves changes
  • Leukocytosis
  • Increased in creatinin kinase
  • The potent nonselective dopamine receptor (D) antagonist neuroleptics, such as haloperidol (a butyrophenone), promethazine, and chlorpromazine (phenothiazines) are well-known causative factors.
  • Abrupt discontinution of Levodopa in Parkinson's patients.
  • Anti-dopaminergic side effect of metoclopramide
Pheochromocytoma[24][25]
  • ST-T segment changes
  • ECG mimics ischemic changes
Serotonin syndrome[26]
  • Triggered by serotonergic drugs rather than inhalation anesthetics.
  • Monoaminoxidase (MAO) inhibition
  • Other drugs via unspecified mechanism such as: Lithium, Buspirone,
  • Ergotamine LSD
Thyrotoxicosis[27]
  • Sinus tachycardia
  • Higher voltage of P and T waves
  • Elevated amplitude of QRS complex
  • Prolonged P-Q and shortened Q-T

Epidemiology

  • The 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.

History

  • The syndrome was first recognized in Australia in an affected family by Denborough et al in 1962.[28]
  • Similar reactions were found in pigs.[29]
  • The efficacy of dantrolene as a treatment was discovered by South African anesthesiologist Gaisford Harrison and reported in a 1975 article published in the British Journal of Anaesthesia.[30]
  • After further animal studies corroborated the possible benefit from dantrolene, a 1982 study confirmed its usefulness in humans.[31]

Treatment

Management of malignant hyperthermia crisis include the following steps:[5][1]

  • Discontinue the potent Inhaled anesthetic agents, remove the vaporizer and hyperventilate with 100% oxygen to increase elimination of triggering agent and CO2 and to maximize oxygen delivery.
  • If succinylcholine has been given, do not readminister it
  • Call for help
  • Stop surgery as soon as possible or switch to total IV anesthesia to complete the surgical procedure if it cannot be stopped
  • Increase the minute ventilation to decrease end-tidal carbon dioxide (EtCO2)
  • Increase fresh gas flow with 100% oxygen to 10 L/min
  • Administer IV dantrolene, The starting dose of dantrolene is 2.5 mg/kg, then 2.5 mg/kg every 5-10 minutes until acidosis, tachycardia, pyrexia, and muscular rigidity are resolving. Adult patients will require multiple vials for the starting dose (e.g. 10 vials for a patient of 80 kg). One person should be assisting in preparing the drug.
  • Cool patient with IV sodium chloride 0.9% at 4ºC, ice packs, and gastric lavage; stop cooling at 38.5ºC to prevent rebound hypothermia
  • Obtain values for arterial blood gases (ABG), electrolytes, creatine kinase, and blood and urine myoglobin
  • Treat arrhythmias and hyperkalemia - Do not use calcium-channel blockers
  • Observe the patient in the intensive care unit (ICU) for 24 hours
  • Ensure urine output of 2 mL/kg/hr with mannitol, furosemide, or fluids as needed
  • Continue dantrolene 2.5 mg/kg if signs or symptoms recur
  • Refer the patient and family for MH testing
  • Recrudescence of the hypermetabolic reaction can occur for up to 14 h after initial resolution.
  • Treatment must be started as early as malignant hyperthermia diagnosed based on clinical suspicion of the onset of symptoms.
  • Dantrolene is a post-synaptic muscle relaxant which inhibits Ca2+ ions release from sarcoplasmic reticulum stores by antagonizing ryanodine receptors directly on the ryanodine receptor to prevent the release of calcium that leads to lesser excitation-contraction of muscle cells.
  • After the widespread introduction of treatment with dantrolene the mortality of malignant hyperthermia fell from 80% in the 1960s to less than 10%.[32]
  • Its clinical use has been limited by its low water solubility, leading to requirements of large fluid volumes which may complicate clinical management.
  • In MH susceptible swine, azumolene was as potent as dantrolene. It has yet to be studied in vivo in humans, but may present a suitable alternative to dantrolene in the treatment of MH.[33]

Prevention

  • In the past, the prophylactic use of dantrolene was recommended for MH susceptible patients undergoing general anesthesia. However, multiple retrospective studies, have demonstrated the safety of trigger-free general anesthesia in these patients in the absence of prophylactic dantrolene administration. [32]
  • 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.[34]
  • The only sure way to prevent MH is to avoid the use of triggering agents in patients known or suspected of being susceptible to MH.

References

  1. ↑ 1.0 1.1 1.2 Schneiderbanger D, Johannsen S, Roewer N, Schuster F (2014). "Management of malignant hyperthermia: diagnosis and treatment". Ther Clin Risk Manag. 10: 355–62. doi:10.2147/TCRM.S47632. PMC 4027921. PMID 24868161.
  2. ↑ Kaur H, Katyal N, Yelam A, Kumar K, Srivastava H, Govindarajan R (2019). "Malignant Hyperthermia". Mo Med. 116 (2): 154–159. PMC 6461318. PMID 31040503.
  3. ↑ McPherson EW, Taylor CA (1981). "The King syndrome: malignant hyperthermia, myopathy, and multiple anomalies". Am. J. Med. Genet. 8 (2): 159–65. doi:10.1002/ajmg.1320080206. PMID 7282770.
  4. ↑ King JO, Denborough MA, Zapf PW (1972). "Inheritance of malignant hyperpyrexia". Lancet. 1 (7746): 365–70. doi:10.1016/S0140-6736(72)92854-1. PMID 4109748.
  5. ↑ 5.0 5.1 Rosenberg H, Pollock N, Schiemann A, Bulger T, Stowell K (August 2015). "Malignant hyperthermia: a review". Orphanet J Rare Dis. 10: 93. doi:10.1186/s13023-015-0310-1. PMC 4524368. PMID 26238698.
  6. ↑ 6.0 6.1 Schuster F, Gardill A, Metterlein T, Kranke P, Roewer N, Anetseder M (September 2007). "A minimally invasive metabolic test with intramuscular injection of halothane 5 and 6 vol% to detect probands at risk for malignant hyperthermia". Anaesthesia. 62 (9): 882–7. doi:10.1111/j.1365-2044.2007.05173.x. PMID 17697213.
  7. ↑ Ummenhofer W, Roesslein R, Sutter PM, Moser N, Kern C, Urwyler A (October 1997). "Muscle biopsy for malignant hyperthermia screening in children". Eur J Pediatr Surg. 7 (5): 259–62. doi:10.1055/s-2008-1071166. PMID 9402480.
  8. ↑ Allen G, Larach M, Kunselman A (1998). "The sensitivity and specificity of the caffeine-halothane contracture test: a report from the North American Malignant Hyperthermia Registry". Anesthesiology. 88 (3): 579–88. doi:10.1097/00000542-199803000-00006. PMID 9523799.
  9. ↑ Anetseder M, Hager M, Müller CR, Roewer N (2002). "Diagnosis of susceptibility to malignant hyperthermia by use of a metabolic test". Lancet. 359 (9317): 1579–80. doi:10.1016/S0140-6736(02)08506-9. PMID 12047971.
  10. ↑ 10.0 10.1 Litman R, Rosenberg H (2005). "Malignant hyperthermia: update on susceptibility testing". JAMA. 293 (23): 2918–24. doi:10.1001/jama.293.23.2918. PMID 15956637.
  11. ↑ Larach MG, Localio AR, Allen GC, Denborough MA, Ellis FR, Gronert GA, Kaplan RF, Muldoon SM, Nelson TE, Ording H (April 1994). "A clinical grading scale to predict malignant hyperthermia susceptibility". Anesthesiology. 80 (4): 771–9. PMID 8024130.
  12. ↑ Gillard E, Otsu K, Fujii J, Khanna V, de Leon S, Derdemezi J, Britt B, Duff C, Worton R, MacLennan D (1991). "A substitution of cysteine for arginine 614 in the ryanodine receptor is potentially causative of human malignant hyperthermia". Genomics. 11 (3): 751–5. doi:10.1016/0888-7543(91)90084-R. PMID 1774074.
  13. ↑ Galli L, Orrico A, Lorenzini S, Censini S, Falciani M, Covacci A, Tegazzin V, Sorrentino V (2006). "Frequency and localization of mutations in the 106 exons of the RYR1 gene in 50 individuals with malignant hyperthermia". Hum Mutat. 27 (8): 830. doi:10.1002/humu.9442. PMID 16835904.
  14. ↑ Balog E, Fruen B, Shomer N, Louis C (2001). "Divergent effects of the malignant hyperthermia-susceptible Arg(615)->Cys mutation on the Ca(2+) and Mg(2+) dependence of the RyR1". Biophys J. 81 (4): 2050–8. PMID 11566777. PMC 1301678
  15. ↑ Yang T, Ta T, Pessah I, Allen P (2003). "Functional defects in six ryanodine receptor isoform-1 (RyR1) mutations associated with malignant hyperthermia and their impact on skeletal excitation-contraction coupling". J Biol Chem. 278 (28): 25722–30. doi:10.1074/jbc.M302165200. PMID 12732639.
  16. ↑ Monnier N, Procaccio V, Stieglitz P, Lunardi J (1997). "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". Am J Hum Genet. 60 (6): 1316–25. doi:10.1086/515454. PMID 9199552. PMC 1716149
  17. ↑ The R1086C mutant has never been published, but has nevertheless been referenced multiple times in the literature, e.g. Jurkat-Rott K, McCarthy T, Lehmann-Horn F (2000). "Genetics and pathogenesis of malignant hyperthermia". Muscle Nerve. 23 (1): 4–17. doi:10.1002/(SICI)1097-4598(200001)23:1<4::AID-MUS3>3.0.CO;2-D. PMID 10590402.
  18. ↑ Weiss R, O'Connell K, Flucher B, Allen P, Grabner M, Dirksen R (2004). "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". Am J Physiol Cell Physiol. 287 (4): C1094–102. doi:10.1152/ajpcell.00173.2004. PMID 15201141.
  19. ↑ Rosenberg H, Davis M, James D, Pollock N, Stowell K (April 2007). "Malignant hyperthermia". Orphanet J Rare Dis. 2: 21. doi:10.1186/1750-1172-2-21. PMC 1867813. PMID 17456235.
  20. ↑ Huckell VF, Staniloff HM, Britt BA, Morch JE (April 1982). "Electrocardiographic abnormalities associated with malignant hyperthermia susceptibility". J Electrocardiol. 15 (2): 137–41. PMID 7069330.
  21. ↑ Rosenberg H, Pollock N, Schiemann A, Bulger T, Stowell K (August 2015). "Malignant hyperthermia: a review". Orphanet J Rare Dis. 10: 93. doi:10.1186/s13023-015-0310-1. PMC 4524368. PMID 26238698.
  22. ↑ Oruch R, Pryme IF, Engelsen BA, Lund A (2017). "Neuroleptic malignant syndrome: an easily overlooked neurologic emergency". Neuropsychiatr Dis Treat. 13: 161–175. doi:10.2147/NDT.S118438. PMC 5248946. PMID 28144147.
  23. ↑ Feng Y, Yang X, Huang Y (June 2013). "Two cases of neuroleptic malignant syndrome in elderly patients taking atypical antipsychotics". Shanghai Arch Psychiatry. 25 (3): 178–82. doi:10.3969/j.issn.1002-0829.2013.03.009. PMC 4054545. PMID 24991155.
  24. ↑ Ramani NS, Stoppacher R, Morani AC, Catanese C (September 2017). "Undiagnosed Pheochromocytoma Simulating Malignant Hyperthermia". Am J Forensic Med Pathol. 38 (3): 262–265. doi:10.1097/PAF.0000000000000326. PMID 28665830.
  25. ↑ Liao WB, Liu CF, Chiang CW, Kung CT, Lee CW (September 2000). "Cardiovascular manifestations of pheochromocytoma". Am J Emerg Med. 18 (5): 622–5. doi:10.1053/ajem.2000.7341. PMID 10999582.
  26. ↑ Frank C (July 2008). "Recognition and treatment of serotonin syndrome". Can Fam Physician. 54 (7): 988–92. PMC 2464814. PMID 18625822.
  27. ↑ Baladi IH, Rai AA, Ahmed SM (2018). "ECG changes in patients with primary hyperthyroidism". Pan Afr Med J. 30: 246. doi:10.11604/pamj.2018.30.246.12244. PMC 6307920. PMID 30627307.
  28. ↑ Denborough MA, Forster JF, Lovell RR, Maplestone PA, Villiers JD (1962). "Anaesthetic deaths in a family". British Journal of Anaesthesia. 34: 395–6. doi:10.1093/bja/34.6.395. PMID 13885389. Historical account in Denborough MA (2008). "Malignant hyperthermia. 1962". Anesthesiology. 108 (1): 156–7. doi:10.1097/01.anes.0000296107.23210.dd. PMID 18156894. Unknown parameter |doi_brokendate= ignored (help)
  29. ↑ Hall LW, Woolf N, Bradley JW, Jolly DW (1966). "Unusual reaction to suxamethonium chloride". Br Med J. 2 (5525): 1305. PMID 5924819. PMC 1944316
  30. ↑ Harrison GG (1975). "Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium". British Journal of Anaesthesia. 47 (1): 62–5. PMID 1148076. Unknown parameter |month= ignored (help) A reprint of the article, which became a "Citation Classic", is available in Br J Anaesth81 (4): 626–9. PMID 9924249 (free full text).
  31. ↑ Kolb ME, Horne ML, Martz R (1982). "Dantrolene in human malignant hyperthermia". Anesthesiology. 56 (4): 254–62. doi:10.1097/00000542-198204000-00005. PMID 7039419.
  32. ↑ 32.0 32.1 Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F (2004). "Dantrolene--a review of its pharmacology, therapeutic use and new developments". Anaesthesia. 59 (4): 364–73. doi:10.1111/j.1365-2044.2004.03658.x. PMID 15023108.
  33. ↑ Dershwitz M, Sréter FA (1990). "Azumolene reverses episodes of malignant hyperthermia in susceptible swine". Anesth. Analg. 70 (3): 253–5. doi:10.1213/00000539-199003000-00004. PMID 2305975.
  34. ↑ Carr AS, Lerman J, Cunliffe M, McLeod ME, Britt BA (1995). "Incidence of malignant hyperthermia reactions in 2,214 patients undergoing muscle biopsy". Can J Anaesth. 42 (4): 281–6. PMID 7788824.

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