Złośliwa hipertermia – Etiologia i przyczyny

Złośliwa hipertermia
Etiologia i przyczyny

Złośliwa hipertermia (MH) to rzadkie, autosomalnie dominujące zaburzenie farmakogenetyczne mięśni szkieletowych, związane głównie z mutacjami w genie RYR1 (odpowiedzialnym za 50-70% przypadków) oraz rzadziej w CACNA1S i STAC3. Patofizjologia opiera się na niekontrolowanym uwalnianiu jonów wapnia z siateczki sarkoplazmatycznej do cytoplazmy miocytów, co prowadzi do nadmiernej aktywacji skurczu mięśni, wzrostu metabolizmu komórkowego, produkcji ciepła, kwasicy metabolicznej i rabdomiolizy. Epizody MH wywołują przede wszystkim anestetyki wziewne (halotan, sewofluran, desfluran, izofluran) oraz sukcynylocholina, a w rzadkich przypadkach także intensywny wysiłek fizyczny czy ekspozycja na wysoką temperaturę. Częstość epizodów MH szacuje się na około 1:100 000 znieczuleń, a podatność genetyczna występuje u około 1:2000 osób, z penetracją mutacji RYR1 na poziomie około 40% i ryzykiem rozwoju MH po ekspozycji na czynniki wyzwalające około 25% (wzrost do 76% po wcześniejszym epizodzie).

Etiologia złośliwej hipertermii

Złośliwa hipertermia (MH) to rzadkie zaburzenie farmakogenetyczne mięśni szkieletowych, charakteryzujące się hipermetaboliczną odpowiedzią organizmu na określone bodźce. Jest to stan zagrażający życiu, wymagający natychmiastowej interwencji medycznej. Choroba ta manifestuje się przede wszystkim w odpowiedzi na podanie niektórych leków anestetycznych, choć w rzadkich przypadkach może być również wywołana przez inne czynniki.¹²

Podłoże genetyczne

Złośliwa hipertermia jest schorzeniem o podłożu genetycznym, zazwyczaj dziedziczonym w sposób autosomalny dominujący. Oznacza to, że wystarczy odziedziczenie jednego zmutowanego allelu od rodzica, aby rozwinąć podatność na złośliwą hipertermię (MHS – malignant hyperthermia susceptibility). Penetracja tej cechy jest jednak zmienna, co oznacza, że nie wszystkie osoby posiadające mutację doświadczą epizodu złośliwej hipertermii po ekspozycji na czynniki wyzwalające.¹²³

Podatność na złośliwą hipertermię najczęściej związana jest z mutacjami w następujących genach:

RYR1 (gen kodujący receptor rianodynowy typu 1) – odpowiada za około 50-70% przypadków MHS. Zidentyfikowano ponad 400 wariantów tego genu, z czego co najmniej 34 uznano za przyczynowe dla złośliwej hipertermii.¹²³
CACNA1S (gen kodujący podjednostkę alfa kanału wapniowego typu L) – odpowiada za mniej niż 1% przypadków MHS.¹²
STAC3 – rzadziej spotykana mutacja, zidentyfikowana m.in. u rdzennych Amerykanów.¹²

Warto podkreślić, że u około 50% osób z podatnością na złośliwą hipertermię nie udaje się zidentyfikować mutacji w jednym z poznanych genów, co wskazuje na istnienie innych, jeszcze niepoznanych loci genowych mających znaczenie w rozwoju tego schorzenia.¹²

Patofizjologia

Podstawowy mechanizm patofizjologiczny złośliwej hipertermii związany jest z zaburzeniami gospodarki wapniowej w komórkach mięśni szkieletowych. U osób podatnych na złośliwą hipertermię występują nieprawidłowości w funkcjonowaniu kanałów wapniowych, co prowadzi do niekontrolowanego uwalniania jonów wapnia z siateczki sarkoplazmatycznej (SR) do cytoplazmy komórek mięśniowych.¹²

W normalnych warunkach receptor rianodynowy (RyR1) kontroluje uwalnianie wapnia z siateczki sarkoplazmatycznej podczas skurczu mięśni. U osób z mutacją w genie RYR1 kanał ten otwiera się łatwiej i zamyka wolniej w odpowiedzi na określone leki, co powoduje nadmierny wypływ jonów wapnia. Prowadzi to do sekwencji zdarzeń:¹²

Podwyższone stężenie wapnia w cytosolu aktywuje procesy związane ze skurczem mięśni
Dochodzi do ciągłej aktywacji aparatu kurczliwego mięśni
Następuje gwałtowny wzrost metabolizmu komórkowego
Zwiększa się produkcja ciepła (prowadząca do hipertermii)
Pojawia się kwasica metaboliczna
Dochodzi do wyczerpania zasobów ATP i uszkodzenia komórek mięśniowych

Następstwem tych procesów jest rozwój pełnoobjawowego zespołu złośliwej hipertermii z zagrażającymi życiu powikłaniami ogólnoustrojowymi.¹²

Czynniki wyzwalające

Złośliwa hipertermia rozwija się u osób predysponowanych genetycznie po ekspozycji na określone czynniki wyzwalające. Najczęstszymi czynnikami prowokującymi wystąpienie zespołu są:¹²

Leki anestetyczne

Wziewne anestetyki halogenowe są najczęstszymi czynnikami wyzwalającymi złośliwą hipertermię. Należą do nich:¹²³

Halotan – historycznie pierwszy zidentyfikowany czynnik wyzwalający MH
Sewofluran – powszechnie stosowany obecnie anestetyk wziewny
Desfluran – nowoczesny anestetyk wziewny
Izofluran – anestetyk wziewny średniego działania
Enfluran – rzadziej stosowany obecnie anestetyk

Drugi istotny czynnik wyzwalający to sukcynylocholina (suksametonium) – depolaryzujący środek zwiotczający mięśnie, stosowany przy indukcji znieczulenia. Może wywołać złośliwą hipertermię zarówno samodzielnie, jak i w połączeniu z anestetykami wziewnymi.¹²

Warto zauważyć, że podtlenek azotu (N₂O) nie wywołuje złośliwej hipertermii i jest uważany za bezpieczny u pacjentów z MHS.¹

Czynniki pozaanestetyczne

W rzadkich przypadkach złośliwa hipertermia może być wywołana przez inne czynniki, niepowiązane z anestezją:¹²³

Intensywny wysiłek fizyczny – szczególnie w warunkach podwyższonej temperatury otoczenia
Ekspozycja na wysoką temperaturę – może wyzwolić reakcję u osób predysponowanych
Stres – silny stres emocjonalny lub fizyczny
Infekcje przebiegające z wysoką gorączką – w niektórych przypadkach

Istnieją doniesienia o spontanicznym wystąpieniu złośliwej hipertermii u dzieci z mutacją receptora rianodynowego w normalnych warunkach życiowych, bez wyraźnego czynnika wyzwalającego.¹

Choroby współwystępujące

Podatność na złośliwą hipertermię często współwystępuje z pewnymi rzadkimi chorobami mięśni. Do najważniejszych należą:¹²³

Choroba central core (central core disease, CCD) – miopatia wrodzona charakteryzująca się zmianami w centralnej części włókien mięśniowych
Zespół King-Denborough – rzadki zespół charakteryzujący się dysmorfią twarzy, niskim wzrostem i miopatią
Miopatia wielordzeniowa (multiminicore myopathy) – charakteryzująca się małymi ogniskami dezorganizacji sarkomerów
Rdzennoamerykańska miopatia (Native American Myopathy, NAM) – związana z mutacją w genie STAC3
Miopatia nemalinowa (Nemaline Rod Myopathy) – związana z mutacjami w RYR1

Ponadto, u pacjentów z dystrofią mięśniową również może występować zwiększone ryzyko złośliwej hipertermii.¹²

Czynniki ryzyka demograficzne

Oprócz podłoża genetycznego, zidentyfikowano również pewne demograficzne czynniki ryzyka złośliwej hipertermii:¹²

Płeć – częściej występuje u mężczyzn niż u kobiet
Wiek – średni wiek zgłaszanych przypadków wynosi 18,3 lat, jednak ponad 52% przypadków dotyczy pacjentów pediatrycznych poniżej 15 roku życia
Wywiad rodzinny – najsilniejszy czynnik ryzyka, znacznie zwiększający prawdopodobieństwo wystąpienia złośliwej hipertermii

Co istotne, u około 50% pacjentów, którzy doświadczyli epizodu złośliwej hipertermii, w przeszłości miała miejsce ekspozycja na czynniki wyzwalające bez wystąpienia reakcji. Oznacza to, że wcześniejsza bezproblemowa anestezja nie wyklucza ryzyka MH w przyszłości.¹²

Występowanie i rozpowszechnienie

Złośliwa hipertermia jest rzadkim zaburzeniem, choć jej rzeczywista częstość występowania jest trudna do określenia ze względu na zmienną penetrację genów i fakt, że nie każda osoba predysponowana rozwinie reakcję po ekspozycji na czynniki wyzwalające.¹

Szacuje się, że:

Epizody złośliwej hipertermii występują z częstością około 1:100 000 znieczuleń w populacji ogólnej¹
Podatność genetyczna na złośliwą hipertermię może występować u około 1:2000 osób¹
Prawdopodobieństwo rozwoju MH po ekspozycji na czynniki wyzwalające wynosi około 25% wśród wszystkich nosicieli patogennych wariantów RYR1, ale wzrasta do 76% wśród osób, które doświadczyły wcześniejszej reakcji MH¹

Penetracja dla MHS związanej z RYR1 wynosi około 40%, przy czym jest większa u mężczyzn niż u kobiet.¹

Złożone mechanizmy patofizjologiczne

Patofizjologia złośliwej hipertermii jest złożona i angażuje wiele mechanizmów na poziomie komórkowym, które w konsekwencji prowadzą do objawów klinicznych. Proces ten rozpoczyna się od zaburzeń homeostazy wapniowej w komórkach mięśni szkieletowych.¹²

Zaburzenia homeostazy wapniowej

Kluczowym elementem patofizjologii złośliwej hipertermii jest niekontrolowany wzrost stężenia wapnia wewnątrzkomórkowego w miocytach. W prawidłowych warunkach, stężenie wapnia w cytoplazmie komórek mięśniowych jest ściśle regulowane przez różne mechanizmy, w tym przez receptor rianodynowy (RyR1), który kontroluje uwalnianie wapnia z siateczki sarkoplazmatycznej.¹

U osób z predyspozycją do złośliwej hipertermii, mutacje w genach kodujących kanały wapniowe (głównie RYR1) powodują, że:¹²

Kanał RyR1 otwiera się łatwiej w odpowiedzi na czynniki wyzwalające
Kanał pozostaje otwarty dłużej niż powinien
Prowadzi to do nadmiernego wypływu wapnia z siateczki sarkoplazmatycznej do cytoplazmy
Wzrost stężenia wapnia w cytoplazmie aktywuje mechanizmy skurczu mięśni i procesy metaboliczne

Warto zauważyć, że w normalnych warunkach życiowych osoby z mutacją zazwyczaj nie doświadczają objawów, ponieważ mechanizmy kompensacyjne są wystarczające do utrzymania homeostazy wapniowej. Jednak w obecności czynników wyzwalających, takich jak anestetyki wziewne czy sukcynylocholina, dochodzi do przeciążenia tych mechanizmów.¹²

Kaskada reakcji metabolicznych

Podwyższone stężenie wapnia w cytoplazmie komórek mięśniowych inicjuje kaskadę przemian metabolicznych:¹²

Nadmierna aktywacja skurczu mięśni – prowadzi do sztywności mięśniowej i zwiększonego zapotrzebowania energetycznego
Przyspieszony metabolizm – wzrost produkcji ATP dla zaspokojenia zwiększonych potrzeb energetycznych
Zwiększone zużycie tlenu – związane z przyspieszonym metabolizmem
Aktywacja glikogenolizy – rozkład glikogenu w celu dostarczenia substratów energetycznych
Produkcja ciepła – wynikająca z intensywnych przemian metabolicznych i ciągłego skurczu mięśni
Przejście na metabolizm beztlenowy – gdy zapotrzebowanie na tlen przekracza możliwości jego dostarczenia przez układ krążenia

W konsekwencji tych przemian dochodzi do hipertermii, kwasicy metabolicznej i ostatecznie do rabdomiolizy (rozpadu mięśni prążkowanych).¹²

Powikłania ogólnoustrojowe

Nieleczona złośliwa hipertermia prowadzi do szeregu poważnych zaburzeń ogólnoustrojowych:¹²

Hiperkaliemia – wynikająca z rozpadu komórek mięśniowych i uwolnienia potasu do krążenia
Arytmie serca – związane z hiperkaliemią i kwasicą
Zaburzenia krzepnięcia – mogące prowadzić do rozsianego wykrzepiania wewnątrznaczyniowego (DIC)
Niewydolność nerek – spowodowana mioglobinurią (obecnością mioglobiny w moczu) po rabdomiolizie
Niewydolność wątroby – jako konsekwencja ogólnoustrojowych zaburzeń
Uszkodzenie mózgu – wynikające z hipertermii i niedotlenienia
Zatrzymanie krążenia – końcowy efekt nieleczonej złośliwej hipertermii

Bez szybkiej interwencji terapeutycznej śmiertelność w przebiegu złośliwej hipertermii może sięgać 80%.¹

Rola leków anestetycznych w wyzwalaniu złośliwej hipertermii

Anestetyki wziewne i sukcynylocholina działają jako czynniki wyzwalające złośliwą hipertermię poprzez interakcję z receptorem rianodynowym. Dokładny mechanizm tej interakcji nie jest w pełni poznany, ale wiadomo, że leki te zwiększają prawdopodobieństwo otwarcia się kanału rianodynowego i wypływu wapnia z siateczki sarkoplazmatycznej.¹²

W przypadku leków wziewnych, efekt ten jest prawdopodobnie związany z ich lipofilnością i zdolnością do wbudowywania się w błony komórkowe, co może wpływać na stabilność i funkcję kanałów wapniowych. Sukcynylocholina z kolei powoduje depolaryzację błony komórkowej, co może bezpośrednio aktywować receptor rianodynowy.¹

Co istotne, nie wszystkie środki anestetyczne wywołują złośliwą hipertermię. Leki dożylne, takie jak propofol, etomidat, ketamina, barbiturany, benzodiazepiny, oraz środki znieczulenia miejscowego są uważane za bezpieczne u pacjentów z predyspozycją do złośliwej hipertermii.¹

Znaczenie kliniczne i konsekwencje

Zrozumienie etiologii złośliwej hipertermii ma kluczowe znaczenie dla praktyki klinicznej, szczególnie w kontekście anestezjologii i intensywnej terapii. Wiedza na temat mechanizmów powstawania oraz czynników wyzwalających pozwala na wdrożenie odpowiednich strategii zapobiegawczych i terapeutycznych.¹

Identyfikacja pacjentów z grupy ryzyka

Rozpoznanie pacjentów z grupy ryzyka złośliwej hipertermii przed ekspozycją na czynniki wyzwalające jest kluczowe dla zapobiegania epizodom tego zagrażającego życiu stanu. Do metod identyfikacji należą:¹²³

Szczegółowy wywiad – obejmujący pytania o wcześniejsze problemy z anestezją, reakcje na leki, występowanie złośliwej hipertermii w rodzinie, choroby mięśni
Badania genetyczne – umożliwiające identyfikację mutacji w genach RYR1, CACNA1S i innych
Test kontraktury kofeina-halotan (CHCT) – złoty standard w diagnostyce podatności na złośliwą hipertermię, wykonywany na biopsji mięśnia
Identyfikacja chorób współistniejących – szczególnie miopatii predysponujących do złośliwej hipertermii

Warto podkreślić, że diagnostyka genetyczna ma pewne ograniczenia – ze względu na heterogenność genetyczną złośliwej hipertermii, negatywny wynik testu DNA nie wyklucza podatności na tę chorobę.¹

Implikacje terapeutyczne

Zrozumienie mechanizmów patofizjologicznych złośliwej hipertermii doprowadziło do opracowania skutecznych strategii leczenia tego stanu:¹²

Dantrolene – lek z wyboru w leczeniu złośliwej hipertermii, działa poprzez hamowanie uwalniania wapnia z siateczki sarkoplazmatycznej, bezpośrednio przeciwdziałając podstawowemu mechanizmowi choroby
Przerwanie podawania czynników wyzwalających – natychmiastowe odstawienie anestetyków wziewnych i sukcynylocholiny
Leczenie objawowe – obejmujące chłodzenie pacjenta, korektę zaburzeń elektrolitowych, kwasicy, wspomaganie funkcji układu krążenia i oddechowego
Zapobieganie powikłaniom – stosowanie diuretyków w celu zapobiegania uszkodzeniu nerek wskutek mioglobinurii

Skuteczne leczenie rozpoczęte natychmiast po rozpoznaniu złośliwej hipertermii znacząco zmniejsza śmiertelność związaną z tym stanem.¹

Profilaktyka

Dla pacjentów z rozpoznaną podatnością na złośliwą hipertermię lub z obciążonym wywiadem rodzinnym zaleca się:¹²

Unikanie ekspozycji na czynniki wyzwalające – stosowanie alternatywnych technik anestezji, bez użycia anestetyków wziewnych i sukcynylocholiny
Informowanie personelu medycznego – pacjenci powinni zawsze informować o swojej podatności na złośliwą hipertermię przed zabiegami chirurgicznymi
Noszenie bransoletki medycznej – zawierającej informację o podatności na złośliwą hipertermię
Badania przesiewowe członków rodziny – ze względu na autosomalny dominujący charakter dziedziczenia
Unikanie nadmiernego wysiłku w wysokiej temperaturze – u osób z potwierdzoną podatnością

Ponadto, zaleca się, aby bliscy krewni osoby, która doświadczyła epizodu złośliwej hipertermii, również byli traktowani jako potencjalnie podatni, dopóki nie zostanie to wykluczone w badaniach.¹

Znaczenie badań genetycznych

Badania genetyczne odgrywają coraz większą rolę w diagnostyce podatności na złośliwą hipertermię, choć mają pewne ograniczenia:¹²

Zalety – nieinwazyjność, możliwość badania dzieci, brak konieczności wykonywania biopsji mięśnia
Ograniczenia – nie wykrywają wszystkich mutacji związanych z MHS, ograniczona dostępność, trudności interpretacyjne w przypadku nowych wariantów

Ze względu na heterogenność genetyczną złośliwej hipertermii, negatywny wynik testu genetycznego nie wyklucza podatności na tę chorobę. Dlatego w niektórych przypadkach nadal konieczne jest wykonanie testu kontraktury kofeina-halotan (CHCT).¹

Korelacje genotyp-fenotyp

Interesującym aspektem złośliwej hipertermii jest słaba korelacja między genotypem a fenotypem. Oznacza to, że:¹²³

Ta sama mutacja może prowadzić do różnych manifestacji klinicznych u różnych osób
Ciężkość epizodu złośliwej hipertermii nie koreluje ściśle z konkretną mutacją
Odpowiedź izolowanego mięśnia na kofeinę lub halotan w testach laboratoryjnych nie jest jednoznacznie związana z genotypem
Inne czynniki modyfikujące i środowiskowe mogą wpływać na ekspresję kliniczną MH

Ta złożoność stanowi wyzwanie dla przewidywania ryzyka i ciężkości potencjalnego epizodu złośliwej hipertermii u konkretnego pacjenta.¹

Podsumowanie etiologii

Złośliwa hipertermia jest rzadkim, ale potencjalnie śmiertelnym zaburzeniem farmakogenetycznym, którego przyczyną są przede wszystkim mutacje w genach kodujących białka odpowiedzialne za homeostazę wapniową w komórkach mięśni szkieletowych. Najczęściej dotyczy to genu RYR1 kodującego receptor rianodynowy, ale zidentyfikowano również mutacje w innych genach, takich jak CACNA1S i STAC3.¹²³

Choroba dziedziczy się w sposób autosomalny dominujący, choć z różną penetracją. U osób predysponowanych genetycznie złośliwa hipertermia może zostać wywołana przez ekspozycję na anestetyki wziewne (halotan, sewofluran, desfluran, izofluran) lub depolaryzujący środek zwiotczający – sukcynylocholinę. W rzadkich przypadkach czynnikami wyzwalającymi mogą być również intensywny wysiłek fizyczny czy ekspozycja na wysoką temperaturę.¹²

Patofizjologia złośliwej hipertermii opiera się na niekontrolowanym wzroście stężenia wapnia wewnątrzkomórkowego, co prowadzi do nadmiernej aktywacji skurczu mięśni, przyspieszonego metabolizmu, produkcji ciepła, kwasicy metabolicznej i ostatecznie rabdomiolizy. Bez szybkiej interwencji terapeutycznej stan ten może prowadzić do niewydolności wielonarządowej i śmierci.¹²³

Zrozumienie etiologii złośliwej hipertermii ma kluczowe znaczenie dla identyfikacji pacjentów z grupy ryzyka, wdrażania odpowiednich strategii profilaktycznych i terapeutycznych oraz badań przesiewowych członków rodziny osoby dotkniętej tą chorobą.¹²

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Materiały źródłowe

#1 Malignant hyperthermia
https://pmc.ncbi.nlm.nih.gov/articles/PMC1867813/
Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stresses such as vigorous exercise and heat. […] The pathophysiologic changes of MH are due to uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation. […] In most cases, the syndrome is caused by a defect in the ryanodine receptor. […] Experimental evidence from a variety of sources, in vitro, in vivo, isolated cells, transfected cells and mice who’s DNA has been altered to express one of the MH causative mutations clearly indicates that the signs and symptoms of MH are related to an uncontrolled release of intracellular calcium from skeletal muscle sarcoplasmic reticulum (SR).
#1 Malignant hyperthermia – Symptoms & causes – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/malignant-hyperthermia/symptoms-causes/syc-20353750
Malignant hyperthermia can result when you have malignant hyperthermia susceptibility (MHS), a genetic disorder that’s caused by a gene change (mutation). The affected gene increases your risk of malignant hyperthermia when you’re exposed to certain anesthesia drugs that trigger a reaction. The affected gene is most commonly inherited, usually from one parent who also has it. Less often, the affected gene is not inherited and is the result of a random gene change. […] Different genes can cause MHS. The most commonly affected gene is RYR1. More rarely affected genes include CACNA1S and STAC3.
#1 Malignant hyperthermia
https://pmc.ncbi.nlm.nih.gov/articles/PMC1867813/
In humans, however, MH results most often from exposure to potent inhalation anesthetics +/- succinylcholine. […] In almost all cases, the MH susceptible patients have a defective calcium channel located in the SR membrane. This channel is termed the ryanodine receptor (RYR). […] As many as 70% of families susceptible to MH harbor one of about 30 causal mutations for MH, with approximately 40 other mutations that are yet to be characterized. […] Although mutations in the ryanodine receptor are undoubtedly important in the pathophysiology of MH, it is also clear that not all families demonstrate linkage to this gene. […] The clinical expression of MH is also poorly understood. Genotype-phenotype correlations are weak for both the clinical expression of MH and the response of isolated muscle to caffeine or halothane.
#1 Malignant hyperthermia: MedlinePlus GeneticsLock
https://medlineplus.gov/genetics/condition/malignant-hyperthermia/
Malignant hyperthermia is a severe reaction to particular anesthetic drugs that are often used during surgery and other invasive procedures. […] Certain variations of the RYR1 and CACNA1S genes increase the risk of developing malignant hyperthermia. Mutations in the RYR1 gene account for most cases of malignant hyperthermia susceptibility, while mutations in the CACNA1S gene cause less than 1 percent of all cases of malignant hyperthermia susceptibility. […] Mutations in the RYR1 or CACNA1S gene cause the RYR1 channel to open more easily and close more slowly in response to certain drugs. As a result, abnormally large amounts of calcium ions are released from storage within muscle cells. The abnormal increase in calcium ion concentration within muscle cells activates processes that generate heat (leading to increased body temperature) and produce excess acid (leading to acidosis). […] Up to half of people with malignant hyperthermia susceptibility do not have a mutation in one of the known genes. The causes of these cases are still under study.
#1 Malignant hyperthermia: a review | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/s13023-015-0310-1
As many as 70 % of families susceptible to MH harbor one of 34 causal mutations for MH, with many other variants yet to be characterized. […] At least six genetic loci, other than RYR1 have been implicated in MH, although only one other gene, CACNA1S, encoding the main subunit of the DHPR, has been shown to be altered by an MH-linked variant. […] Recently, a variant in the STAC3 gene has been linked to MH susceptibility in a native American tribe in the USA. […] Genotype-phenotype correlations are weak for both the clinical expression of MH and the response of isolated muscle to caffeine or halothane. […] It therefore seems clear that a variety of modulators influence the manifestations of the syndrome. […] In summary, because of the heterogeneity of the disorder, as well as discordance within families, a negative DNA result cannot be used to rule out MH susceptibility.
#1 Malignant Hyperthermia and Related Conditions – Cancer Therapy Advisor
https://www.cancertherapyadvisor.com/home/decision-support-in-medicine/critical-care-medicine/malignant-hyperthermia-and-related-conditions/
The high rate of hydrolysis of ATP releases thermal energy, and, as a first approximation, induces a rise in skeletal muscle and then core temperature. […] The stressed muscle mitochondria, working at maximum capacity to produce more ATP, go from aerobic metabolism to anaerobic metabolism as glycogen stores are used up and as blood flow to muscle cannot meet the demand of muscle metabolism. […] Rhabdomyolysis begins soon after, and the secondary pathophysiology ensues: release of myoglobin into the circulation and subsequent renal failure as the myoglobin precipitates in the renal tubules; release of muscle potassium and resultant hyperkalemia; release of muscle acid and subsequent severe acidosis; stress-induced autonomic activation and resultant tachycardia and hypertension; and together, circulating adrenergic agonists, acidosis and hyperkalemia all sensitize the myocardium to the development of arrhythmias and resultant cardiovascular collapse.
#1 FloridaHealthFinder | Malignant hyperthermia | Health Encyclopedia | FloridaHealthFinder
https://quality.healthfinder.fl.gov/health-encyclopedia/HIE/1/001315
Malignant hyperthermia (MH) is a disease that causes a fast rise in body temperature and severe muscle contractions when someone receives general anesthesia with one or more of the following drugs: halothane, isoflurane, sevoflurane, desflurane or succinylcholine. MH is a genetic disorder passed down through families. […] MH is inherited. Only one parent has to carry the gene for the disease for a child to inherit the condition. […] It may occur with some other inherited muscle diseases, such as multiminicore myopathy and central core disease.
#1 Malignant Hyperthermia – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK430828/
Malignant hyperthermia (MH) is a hereditary disorder of skeletal muscle that classically presents as a hypermetabolic response to halogenated anesthetic gasses and/or the depolarizing muscle relaxant succinylcholine. […] Genetically susceptible patients can have a malignant hyperthermia reaction in response to triggering agents such as halogenated anesthetic gasses and/or succinylcholine and more rarely to stressors such as vigorous exercise and heat exposure. […] The gene for the ryanodine receptor RYR1 is the primary site for mutations linked with malignant hyperthermia. Other genetic loci have been identified, such as CACNA1S and STAC3, as causative for malignant hyperthermia.
#1 Malignant Hyperthermia (MH) – EMCrit Project
https://emcrit.org/ibcc/mh/
Malignant hyperthermia (MH) can be caused by any inhalational anesthetic, other than nitrous oxide. […] Succinylcholine rarely can cause MH. […] Patients with central core myopathy are predisposed to develop malignant hyperthermia.
#1 Malignant Hyperthermia: What It Is, Symptoms & Treatment
https://my.clevelandclinic.org/health/diseases/17945-malignant-hyperthermia
Malignant hyperthermia is a genetic disease that causes a life-threatening reaction to certain anesthesia medications. The disorder usually runs in families and is treatable. […] People who are susceptible to malignant hyperthermia have a genetic mutation that causes them to have abnormal proteins in their body’s muscle cells. […] A genetic mutation is a change in a sequence of your DNA. […] While this mutation causes no symptoms in everyday life, if you have this mutation and are exposed to certain anesthetics or, in rare cases, high heat or strenuous activity it causes an abnormal release of calcium from your muscle cells. […] Malignant hyperthermia can occur when someone who is genetically susceptible to the disease is exposed to certain inhaled or intravenous anesthesia medications.
#1 Malignant Hyperthermia: An Overview
https://www.uspharmacist.com/article/malignant-hyperthermia-an-overview
Through the years, a number of medications have been implicated as MH triggers. According to the Malignant Hyperthermia Association of the United States (MHAUS), the following agents approved for use in the U.S. are known triggers of MH: inhaled general anesthetics, halothane, desflurane, enflurane, ether, isoflurane, sevoflurane, and succinylcholine. […] MH has also been reported in MH-susceptible individuals after exposure to heat stress or vigorous exercise. Rare cases of children developing spontaneous fatal MH under normal living conditions, with postmortem tests revealing abnormal ryanodine receptor mutations, have been reported.
#1 Malignant hyperthermia Guide: Causes, Symptoms and Treatment Options
https://www.drugs.com/health-guide/malignant-hyperthermia.html
Malignant hyperthermia is a severe reaction to a dose of anesthetics. The reaction is sometimes fatal. It is caused by a rare, inherited muscle abnormality. Infrequently, extreme exercise or heat stroke can trigger malignant hyperthermia in someone with the muscle abnormality. […] The muscle abnormality that can lead to malignant hyperthermia is caused by one of several genetic mutations. The most common mutation causes about half of all cases. A person with this mutation has a one in two chance of passing the gene to any of his or her children. […] This condition sometimes occurs in people who also have muscular dystrophy. It also occurs with other muscle diseases associated with genetic mutations.
#1 Malignant Hyperthermia: Causes, Triggers, Treatments
https://www.webmd.com/a-to-z-guides/what-is-malignant-hypertherima
Malignant hyperthermia is when certain kinds of anesthetics (or sometimes intense exercise or high air temperature) cause hyperthermia. […] Genetic defects (errors in the code of your DNA) increase your risk of experiencing malignant hyperthermia. […] Scientists have found over 80 different genetic code defects that can cause malignant hyperthermia. […] Malignant hyperthermia is more common in males than females.
#1 Malignant hyperthermia: causes & treatment
https://www.acls.net/malignant-hyperthermia
Malignant hyperthermia (MH) was first described by Denborough in 1962 when deaths were occurring during and immediately (within 24 hours) following the administration of anesthesia medications. The common denominator in these patients was sudden and critical increases in body temperature. […] Anesthesia agents trigger MH, and it is silent until it has already occurred. […] Half of the patients who have an MH crisis have had prior exposure to anesthesia agents known to trigger a crisis without any such reaction. […] The most common medications administered prior to an MH event include succinylcholine, sevoflurane, desflurane, isoflurane, and halothane. […] An uncontrolled increase in skeletal muscle metabolism is a characteristic of MH. […] If not recognized and treated, the mortality rate can be expected to be as high as 80%. […] Dantrolene, a skeletal muscle relaxant specifically developed for the treatment of MH, is the backbone of the treatment regimen.
#1 Malignant hyperthermia: Diagnosis and management of acute crisis – UpToDate
https://www.uptodate.com/contents/malignant-hyperthermia-diagnosis-and-management-of-acute-crisis
Malignant hyperthermia (MH) manifests clinically as a hypermetabolic crisis when an MH-susceptible (MHS) individual is exposed to a volatile anesthetic (eg, halothane, isoflurane, sevoflurane, desflurane) or succinylcholine. […] The incidence of MH events for a given population depends upon the prevalence of MH susceptibility and use of triggering anesthetics. […] MH episodes have been estimated to occur in the general population in 1:100,000 administered anesthetics. […] An MH event does not necessarily occur every time an MH susceptible individual is exposed to an anesthetic triggering agent.
#1 Malignant Hyperthermia May Develop in People with Heat or Exercise – MHAUS
https://www.mhaus.org/about/press-releases/malignant-hyperthermia-may-develop-in-people-with-heat-or-exercise/
There is mounting evidence that some people who are susceptible to Malignant hyperthermia (MH) will develop MH when exposed to hot environments or with exercise. […] Malignant hyperthermia is a potentially fatal, inherited disorder usually associated with the administration of certain general anesthetics. The disorder is due to an acceleration of metabolism in skeletal muscle. […] The underlying defect is abnormally increased levels of cell calcium in the skeletal muscle. […] MH is inherited genetic disorder found in an estimated 1 out of 2,000 people. MH is triggered by certain anesthesia and most often experienced in individuals undergoing routine surgery but in rare cases MH can happen without anesthesia.
#1 Malignant Hyperthermia Panel, Sequencing | Test Fact Sheet
https://arupconsult.com/ati/malignant-hyperthermia-panel-sequencing
Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle calcium regulation which is triggered by volatile anesthetics, either with or without the depolarizing muscle relaxant succinylcholine. […] Pathogenic germline gain-of-function variants in the RYR1 or CACNA1S genes. […] The overall penetrance is 40% for RYR1-associated MHS, with a greater penetrance in males than in females. […] The probability of developing MH when exposed to triggers is 25% among all carriers of RYR1 pathogenic variants but 76% among individuals who have experienced a previous MH reaction.
#1
https://journals.lww.com/ejanaesthesiology/fulltext/2001/10000/malignant_hyperthermia.2.aspx
Malignant hyperthermia is an autosomal-dominant inherited disorder of the skeletal muscle cell characterized by a hypermetabolic response to all commonly used inhalational anaesthetics and depolarizing muscle relaxants. […] In human beings and animals susceptible to malignant hyperthermia, it is generally accepted that an increase in the level of myoplasmic free calcium is the cause of the syndrome. […] Various hypotheses have been proposed to account for the increase of intracellular calcium levels, e.g. a defect in the calcium release channel of the sarcoplasmic reticulum (ryanodine receptor), an abnormality of the excitation-contraction coupling mechanisms, or alterations in second messenger systems of skeletal muscles.
#1 What Causes An MH Episode? – MHAUS
https://www.mhaus.org/faqs/what-causes-an-mh-episode/
MH-susceptible persons have a mutation that results in the presence of abnormal proteins in the muscle cells of their body. […] when these patients are exposed to certain anesthetic agents, or in rare cases when exposed to high environmental heat or strenuous exercise, it causes an abnormal release of calcium from the sarcoplasmic reticulum (a storage site for calcium) in the muscle cell, which results in a sustained muscle contraction and thus an abnormal increase in metabolism and heat production. […] Left untreated, these changes can cause cardiac arrest, kidney failure, blood coagulation problems, internal hemorrhage, brain injury, liver failure, and may be fatal.
#1 Malignant Hyperthermia – Temperature Regulation Disorders for Medicine
https://www.picmonic.com/pathways/medicine/courses/standard/multisystem-miscellanea-10630/temperature-regulation-disorders-39485/malignant-hyperthermia_50109
Malignant hyperthermia is inherited in an autosomal dominant manner; this means that one abnormal allele is enough for the individual to manifest the disease. However, it is important to note that the penetrance of this disorder is variable, hence not all individuals who inherit abnormal alleles will manifest the disease. […] Malignant hyperthermia patients have a genetic predisposition due to mutations in skeletal muscle ion channels. Ryanodine receptor 1, coded by the RYR1 gene, is a commonly affected calcium channel that controls calcium release from the sarcoplasmic reticulum. Mutations in this channel result in excessive calcium accumulation within muscle cells after exposure to anesthetics or succinylcholine. […] A common trigger for malignant hyperthermia is inhaled anesthetics given during surgery, such as halothane and isoflurane. Therefore, suspect malignant hyperthermia if a post-surgical patient develops the acute onset of autonomic symptoms and muscle rigidity. […] Succinylcholine is a depolarizing neuromuscular blocking agent often used during procedures to paralyze muscles and facilitate intubation. In myocytes with mutated calcium channels, however, succinylcholine will trigger excess calcium release and lead to malignant hyperthermia.
#1 Malignant Hyperthermia and Related Conditions – Cancer Therapy Advisor
https://www.cancertherapyadvisor.com/home/decision-support-in-medicine/critical-care-medicine/malignant-hyperthermia-and-related-conditions/
MH is a rare pharmacogenetic sensitivity of skeletal muscle to volatile anesthetics and depolarizing muscle relaxants such as succinylcholine (and only to these agents not to any of the intravenous agents or local anesthetics presently or previously in clinical use) that results in autonomic activation, hypermetabolism that results in a mixed respiratory-metabolic acidosis, truncal or total body rigidity in a significant number of patients, masseter muscle spasm (trismus = jaws of steel) in some patients in response to the depolarizing effects of succinylcholine, hyperthermia (may be a late sign) and rhabdomyolysis. […] Gene mutations that confer MH susceptibility have been identified in three genes, although there are undoubtedly two or more other genes that can confer susceptibility: RyR1, the gene for the ryanodine receptor type 1, the skeletal muscle primary calcium release channel of sarcoplasmic reticulum that normally functions in excitation contraction coupling (50-70% of MH susceptible families).
#1 Malignant hyperthermia – Diagnosis & treatment – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/malignant-hyperthermia/diagnosis-treatment/drc-20353752
Malignant hyperthermia is diagnosed based on signs and symptoms, monitoring during and immediately after anesthesia, and lab tests to identify complications. […] Testing to find out if you’re at increased risk of malignant hyperthermia (susceptibility testing) may be recommended if you have risk factors. […] The gene change (mutation) that makes you susceptible to malignant hyperthermia is identified using genetic testing. […] If you or someone in your family has malignant hyperthermia susceptibility (MHS) or you think you may be at risk of malignant hyperthermia, it’s important to tell your health care provider and anesthesiologist before you get anesthesia. […] If you’ve experienced malignant hyperthermia due to certain anesthesia drugs, exercising during excessive heat and humidity could trigger another reaction.
#1
https://www.nursingcenter.com/cearticle?an=01261775-202104000-00003&Journal_ID=646631&Issue_ID=5834787
Many known triggering agents for patients susceptible to MH exist. Volatile inhaled anesthetics including desflurane, enflurane, halothane, isoflurane, and sevoflurane can trigger a hypermetabolic response. […] The first step in treatment once MH has been identified is to discontinue the offending agent. […] Dantrolene is the drug of choice for the treatment of MH and should be administered as quickly as possible to limit the progression of symptoms. […] Dantrolene works by interfering with the release of calcium ions from the sarcoplasmic reticulum of skeletal muscle, thus decreasing the calcium ion concentration available to cause continued muscle contraction.
#1 Understanding Malignant Hyperthermia
https://kumedib.staywellsolutionsonline.com/Library/Encyclopedia/3,90785
Malignant hyperthermia (MH) is a rare reaction to certain medicines used for general anesthesia. This problem runs in families (genetic). This means it’s passed down from parents to children. MH happens in people who have a gene that causes abnormal proteins in the muscles. Certain anesthesia medicines react with these proteins. This leads to sudden and severe symptoms. The problem can lead to the breakdown of muscle tissues if it’s not treated quickly. Your family members may also have the gene for MH. Even if they had surgery without problems in the past, they should not assume they couldn’t get MH in the future. […] All your close family members should tell their providers that they might be likely to get MH and consider getting tested.
#1 Understanding Malignant Hyperthermia | UMass Memorial Health
https://www.ummhealth.org/health-library/understanding-malignant-hyperthermia
Malignant hyperthermia (MH) is a rare reaction to certain medicines used for general anesthesia. This problem runs in families (genetic). This means it’s passed down from parents to children. […] MH happens in people who have a gene that causes abnormal proteins in the muscles. Certain anesthesia medicines react with these proteins. […] Your family members may also have the gene for MH. Even if they had surgery without problems in the past, they should not assume they couldn’t get MH in the future. All your close family members should tell their providers that they might be likely to get MH and consider getting tested.
#1 Malignant hyperthermia | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-2-21
As many as 70% of families susceptible to MH harbor one of about 30 causal mutations for MH, with approximately 40 other mutations that are yet to be characterized. […] Although mutations in the ryanodine receptor are undoubtedly important in the pathophysiology of MH, it is also clear that not all families demonstrate linkage to this gene. At least six other genetic loci have been implicated in MH, including one that elaborates the sodium channel. […] The clinical expression of MH is also poorly understood. Genotype-phenotype correlations are weak for both the clinical expression of MH and the response of isolated muscle to caffeine or halothane. […] The identification of causative mutations suggests the widespread use of DNA testing for MH, however, this is confounded by the metabolic complexity and genetic heterogeneity of the disorder.
#2 Malignant hyperthermia: a review | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/s13023-015-0310-1
Malignant hyperthermia (MH) is a pharmacogenetic disorder that manifests as a hypermetabolic response to potent inhalation agents (such as halothane, isoflurane, sevoflurane, desflurane), the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stressors such as vigorous exercise and heat. […] The two genes that have been definitively associated with MH causative mutations are RYR1 and CACNA1S, which will be discussed later. […] Experimental evidence clearly indicates that the signs and symptoms of MH are related to an uncontrolled release of intracellular Ca2+ from skeletal muscle sarcoplasmic reticulum (SR). […] In humans, however, clinical MH results most often from exposure to potent inhalation anesthetics +/ succinylcholine. […] A defective or disordered Ca2+ channel located in the SR membrane underlies MH susceptibility. This channel is termed the ryanodine receptor (RyR1).
#2 Malignant Hyperthermia: Background, Pathophysiology, Etiology
https://emedicine.medscape.com/article/2231150-overview
MH is inherited as an autosomal dominant trait with reduced penetrance. It is associated with mutations in two genes: RYR1, which encodes the skeletal muscle isoform of the calcium-release channel of the sarcoplasmic reticulum (ryanodine receptor type 1 [RYR-1]), and CACNA1S, which encodes the alpha subunit of the L-type calcium channel isoform of the sarcolemma (dihydropyridine receptor). An aberrant termination of RYR-1 activity is found in MH-susceptible persons. […] Mutations in this gene occur in at least 50% of persons with MH and all families of central core disease. More than 30 mutations and one deletion are associated with a positive CHCT, a clinical MH episode, or both. CHCT is the criterion standard for establishing the diagnosis of MH.
#2 Orphanet: Malignant hyperthermia of anesthesia
https://www.orpha.net/en/disease/detail/423
Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane and the depolarizing muscle relaxant succinylcholine, and rarely, to stresses such as vigorous exercise and heat. […] In most cases, MH is caused by a defect in the ryanodine receptor. Over 400 variants have been identified in the ryanodine receptor gene (RYR1), located on chromosome 19q13.1, and at least 34 are causal for MH. The pathophysiologic changes of MH are due to an uncontrolled rise in myoplasmic calcium, which activates biochemical processes related to muscle activation. […] MH events are mainly triggered by volatile anesthetics and succinylcholine. Extremely rarely stresses such as exercise, emotion and heat may trigger a reaction.
#2 Malignant hyperthermia – Wikipedia
https://en.wikipedia.org/wiki/Malignant_hyperthermia
In rare cases, the biological stresses of physical exercise or heat may be the trigger. […] In a large proportion (50-70%) of cases, the propensity for malignant hyperthermia is due to a mutation of the ryanodine receptor (type 1), located on the sarcoplasmic reticulum (SR), the organelle within skeletal muscle cells that stores calcium. […] The other known causative gene for MH is CACNA1S, which encodes an L-type voltage-gated calcium channel -subunit. […] Other mutations causing MH have been identified, although in most cases the relevant gene remains to be identified.
#2 Malignant Hyperthermia and Related Conditions – Cancer Therapy Advisor
https://www.cancertherapyadvisor.com/home/decision-support-in-medicine/critical-care-medicine/malignant-hyperthermia-and-related-conditions/
CACN1S, the gene for the skeletal muscle L-type, voltage dependent calcium channel in transverse tubules that is the voltage sensor in excitation-contraction coupling (~1% of families). […] STAC3, a gene responsible for skeletal muscle myotube fusion in development, that was identified as the causative gene in Native American Myopathy and resultant MH susceptibility (see below, very restricted populations). […] MH is transmitted in an autosomal dominant fashion within families, but has both incomplete penetrance and variable expressivity. […] Furthermore, MH may present due to a sporadic mutation, i.e., when there is no family history of MH, or of unexplained perioperative deaths accompanied by hyperthermia. […] Approximately 50% of patients who present with perioperative MH have had previous, uneventful general anesthetics.
#2 Malignant Hyperthermia – Injuries and Poisoning – Merck Manual Consumer Version
https://www.merckmanuals.com/home/injuries-and-poisoning/heat-disorders/malignant-hyperthermia
Genetic testing can also be done. However, because many gene abnormalities may be involved, genetic testing does not detect all (or even most) susceptible people and is not always available. […] Doctors try to prevent malignant hyperthermia in people who are high risk, which includes those with previous episodes of malignant hyperthermia, positive genetic markers, and family members who have had problems with anesthesia.
#2 Malignant hyperthermia | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-2-21
Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stresses such as vigorous exercise and heat. […] The pathophysiologic changes of MH are due to uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation. […] In most cases, the syndrome is caused by a defect in the ryanodine receptor. […] In almost all cases, the MH susceptible patients have a defective calcium channel located in the SR membrane. This channel is termed the ryanodine receptor (RYR). […] However, mutations associated with MH susceptibility are found mainly in the gene for the ryanodine receptor.
#2 Malignant Hyperthermia: An Overview
https://www.uspharmacist.com/article/malignant-hyperthermia-an-overview
Malignant hyperthermia is a rare, life-threatening clinical syndrome of hypermetabolism involving the skeletal muscle. In susceptible individuals, this reaction is triggered primarily by exposure to volatile inhalational anesthetic agents and succinylcholine (a muscle relaxant). In patients who are susceptible to malignant hyperthermia, the ryanodine receptor in skeletal muscle is abnormal and causes a buildup of calcium in skeletal muscle, resulting in a massive metabolic reaction upon exposure to the triggering agents. […] MH susceptibility is an inherited autosomal-dominant trait. Individuals who are susceptible to MH have abnormal skeletal-muscle ryanodine receptors; this abnormality interferes with calcium regulation in the muscle. When an abnormal ryanodine receptor that controls calcium release is present, a buildup of calcium can occur, leading to a substantial metabolic reaction upon exposure to a triggering agent.
#2 What Causes An MH Episode? – MHAUS
https://www.mhaus.org/faqs/what-causes-an-mh-episode/
MH-susceptible persons have a mutation that results in the presence of abnormal proteins in the muscle cells of their body. […] when these patients are exposed to certain anesthetic agents, or in rare cases when exposed to high environmental heat or strenuous exercise, it causes an abnormal release of calcium from the sarcoplasmic reticulum (a storage site for calcium) in the muscle cell, which results in a sustained muscle contraction and thus an abnormal increase in metabolism and heat production. […] Left untreated, these changes can cause cardiac arrest, kidney failure, blood coagulation problems, internal hemorrhage, brain injury, liver failure, and may be fatal.
#2 Malignant hyperthermia – Wikipedia
https://en.wikipedia.org/wiki/Malignant_hyperthermia
Abnormalities in the ryanodine receptor 1 gene are commonly detected in people who have experienced an episode of malignant hyperthermia. […] Causes volatile anesthetic agents or succinylcholine in those who are susceptible. […] Exposure to triggering agents (certain volatile anesthetic agents or succinylcholine) can lead to the development of MH in those who are susceptible. […] Susceptibility can occur due to at least six genetic mutations, with the most common one being of the RYR1 gene. […] Malignant hyperthermia is a disorder that can be considered a gene-environment interaction. […] The most common triggering agents are volatile anesthetic gases, such as halothane, sevoflurane, desflurane, isoflurane, enflurane or the depolarizing muscle relaxants suxamethonium and decamethonium used primarily in general anesthesia.
#2 Malignant Hyperthermia: An Overview
https://www.uspharmacist.com/article/malignant-hyperthermia-an-overview
Through the years, a number of medications have been implicated as MH triggers. According to the Malignant Hyperthermia Association of the United States (MHAUS), the following agents approved for use in the U.S. are known triggers of MH: inhaled general anesthetics, halothane, desflurane, enflurane, ether, isoflurane, sevoflurane, and succinylcholine. […] MH has also been reported in MH-susceptible individuals after exposure to heat stress or vigorous exercise. Rare cases of children developing spontaneous fatal MH under normal living conditions, with postmortem tests revealing abnormal ryanodine receptor mutations, have been reported.
#2 Malignant Hyperthermia – Injuries; Poisoning – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/injuries-poisoning/heat-illness/malignant-hyperthermia
Malignant hyperthermia is a life-threatening elevation in body temperature usually resulting from a hypermetabolic response to concurrent use of a depolarizing muscle relaxant and a potent, volatile inhalational general anesthetic. […] The muscle relaxant involved is usually succinylcholine; the inhalational anesthetic is most often halothane, but other anesthetics (eg, isoflurane, sevoflurane, desflurane) may also be involved. […] Malignant hyperthermia affects about 1/20,000 people. Susceptibility is inherited, with autosomal dominant inheritance and variable penetrance. Most often, the causative mutation affects the ryanodine receptor of skeletal muscle; however, 22 other causative mutations have been identified. […] The mechanism may involve anesthetic-induced potentiation of calcium (Ca) exit from the sarcoplasmic reticulum of skeletal muscle in susceptible patients. […] Malignant hyperthermia develops in genetically susceptible patients who have been exposed (usually more than once) simultaneously to a depolarizing muscle relaxant and a potent, volatile inhalational general anesthetic.
#2 Malignant Hyperthermia and Related Conditions – Cancer Therapy Advisor
https://www.cancertherapyadvisor.com/home/decision-support-in-medicine/critical-care-medicine/malignant-hyperthermia-and-related-conditions/
There are now three known rare skeletal myopathies, however, with proven high concordance with MH susceptibility: central core disease (CCD), King-Denborough syndrome, and Native American Myopathy (NAM). […] Two other myopathies, Nemaline Rod Myopathy and Congenital Neuromuscular Disease with Uniform Type 1 Fiber (CNMDU1), both associated with RyR1 mutations, have been reported to be concordant with MH susceptibility. […] The hallmark of a full blown episode of MH is runaway metabolism and a rate of production of CO2 that is difficult if not impossible to control with increasing minute ventilation. […] While not pathognomonic, the sine qua non of a full blown MH episode, however, is the mixed respiratory-metabolic acidosis in the setting of general anesthesia with volatile anesthetics, whether succinylcholine is used or not, and in the presence a rising end-tidal CO2 that cannot be controlled with increasing minute ventilation.
#2 Nursing Guide to Malignant Hyperthermia – Straight A Nursing
https://straightanursingstudent.com/malignant-hyperthermia/
Malignant hyperthermia is a hypermetabolic crisis that is fatal if left untreated. It occurs in individuals with a specific genetic condition when they are exposed to certain anesthetic gasses or the medication succinylcholine. […] Individuals with the genetic mutation that allows too much calcium to flow into skeletal muscle cells experience malignant hyperthermia when exposed to a triggering agent. This is an autosomal dominant disorder, meaning it can be passed on to children if only one parent has the genetic mutation. Each child of a parent with MH susceptibility has a 50% chance of inheriting the disorder. […] Other individuals at risk of experiencing malignant hyperthermia include those with a history of unexplained rhabdomyolysis, muscular dystrophy, myotonia (impaired muscle relaxation) and rare muscular diseases including Central Core disease and King Denborough Syndrome.
#2
https://www.nursingcenter.com/cearticle?an=01261775-202104000-00003&Journal_ID=646631&Issue_ID=5834787
Malignant hyperthermia (MH) is caused by a genetic disorder of the skeletal muscle that induces a hypermetabolic response when patients are exposed to a triggering agent such as volatile inhaled anesthetics or depolarizing neuromuscular blockers. […] Malignant hyperthermia is more common in males and the mean age of reported cases is 18.3 years; however, pediatric patients younger than 15 years make up 52.1% of reported cases. […] Because the genetic mutation for MH is an autosomal dominant disorder, a family history of MH is a well-known risk factor for susceptibility. […] Malignant hyperthermia is caused by a genetic abnormality of calcium channels within skeletal muscle. […] The complications associated with MH are caused by a cascade of events that begins with exposure to a triggering agent, leading to the uncontrolled release of calcium from skeletal muscle.
#2 Malignant Hyperthermia Panel, Sequencing | Test Fact Sheet
https://arupconsult.com/ati/malignant-hyperthermia-panel-sequencing
Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle calcium regulation which is triggered by volatile anesthetics, either with or without the depolarizing muscle relaxant succinylcholine. […] Pathogenic germline gain-of-function variants in the RYR1 or CACNA1S genes. […] The overall penetrance is 40% for RYR1-associated MHS, with a greater penetrance in males than in females. […] The probability of developing MH when exposed to triggers is 25% among all carriers of RYR1 pathogenic variants but 76% among individuals who have experienced a previous MH reaction.
#2 Malignant hyperthermia – Knowledge @ AMBOSS
https://www.amboss.com/us/knowledge/malignant-hyperthermia/
Malignant hyperthermia (MH) is a subclinical myopathy in which general anesthesia triggers an uncontrollable contraction of skeletal muscle that leads to a life-threatening hypercatabolic state and an increase in body temperature. The disease is primarily autosomal dominant; mutations in receptors (especially ryanodine receptor type 1) predispose to volatile anesthetic agents or succinylcholine causing an accumulation of intracellular calcium in skeletal muscle that leads to its overactivation and hypermetabolism. […] Most cases are associated with a mutation in the ryanodine receptor type 1 (RYR-1); or mutations in the dihydropyridine receptors (DHPR). […] Some cases are due to a spontaneous mutation. […] Volatile anesthetics (e.g., isoflurane, sevoflurane, desflurane, halothane; except nitrous oxide) and succinylcholine are triggering agents.
#2 Malignant hyperthermia
https://pmc.ncbi.nlm.nih.gov/articles/PMC1867813/
In humans, however, MH results most often from exposure to potent inhalation anesthetics +/- succinylcholine. […] In almost all cases, the MH susceptible patients have a defective calcium channel located in the SR membrane. This channel is termed the ryanodine receptor (RYR). […] As many as 70% of families susceptible to MH harbor one of about 30 causal mutations for MH, with approximately 40 other mutations that are yet to be characterized. […] Although mutations in the ryanodine receptor are undoubtedly important in the pathophysiology of MH, it is also clear that not all families demonstrate linkage to this gene. […] The clinical expression of MH is also poorly understood. Genotype-phenotype correlations are weak for both the clinical expression of MH and the response of isolated muscle to caffeine or halothane.
#2 Malignant hyperthermiaÂ (MH)Â | EBSCO Research Starters
https://www.ebsco.com/research-starters/health-and-medicine/malignant-hyperthermia-mh
Scientists have identified the ryanodine receptor (RYR1) gene as the primary location of inherited malignant hyperthermia. This gene mediates calcium release in the muscle tissues. […] Anesthetic gases such as halothane, desflurane, isoflurane, sevoflurane, and enfluranemost commonly trigger malignant hyperthermia. The condition can also be caused by muscle relaxant medications administered during anesthesia, such as suxamethonium and decamethonium. […] The biological mechanisms behind malignant hyperthermia begin with the muscles. The anesthetic drugs react with muscle cells to release a large amount of calcium, which builds up in the muscle tissue and causes contractions. […] Most patients do not know they carry the gene for malignant hyperthermia until they receive anesthesia. […] Individuals with a known family history of malignant hyperthermia can be given specific exams and tests to determine if they have the gene. […] When malignant hyperthermia occurs following anesthesia, health professionals must immediately stop administering the anesthetic that triggered the reaction. A drug called dantrolene is given intravenously to inhibit further calcium release into skeletal muscle.
#2 Treating Malignant Hyperthermia: What You Should Know
https://www.healthline.com/health/malignant-hyperthermia-treatment
Malignant hyperthermia is a condition thats often triggered by certain anesthesia drugs and can be life threatening. […] Malignant hyperthermia is typically triggered by drugs used as part of the anesthesia process during a surgical procedure. […] Dantrolene is a skeletal muscle relaxant that acts by directly interfering with the release of calcium. During a malignant hyperthermia reaction, its believed that triggering agents impact the skeletal muscle cells elevating myoplasmic calcium. Dantrolene is thought to prevent or reduce this calcium release. […] Malignant hyperthermia is a life threatening condition that needs to be treated immediately. If left untreated, it can lead to: cardiac arrest, brain damage, internal bleeding, failure of other body systems, including the kidneys and liver, muscle damage, seizures, coma. […] Regardless of age, once signs of malignant hyperthermia are identified, its important for the surgical team to stop use of the triggering drugs, administer dantrolene, and treat any complications or symptoms that malignant hyperthermia has brought on.
#2 Malignant hyperthermia – Diagnosis & treatment – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/malignant-hyperthermia/diagnosis-treatment/drc-20353752
Also, check with your health care provider to see if you should have genetic testing to determine if you have a genetic disorder that puts you at risk of malignant hyperthermia. […] If you have the genetic disorder MHS that puts you at risk of malignant hyperthermia, wear a medical alert bracelet or necklace.
#2 Malignant hyperthermia – Diagnosis & treatment – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/malignant-hyperthermia/diagnosis-treatment/drc-20353752
Malignant hyperthermia is diagnosed based on signs and symptoms, monitoring during and immediately after anesthesia, and lab tests to identify complications. […] Testing to find out if you’re at increased risk of malignant hyperthermia (susceptibility testing) may be recommended if you have risk factors. […] The gene change (mutation) that makes you susceptible to malignant hyperthermia is identified using genetic testing. […] If you or someone in your family has malignant hyperthermia susceptibility (MHS) or you think you may be at risk of malignant hyperthermia, it’s important to tell your health care provider and anesthesiologist before you get anesthesia. […] If you’ve experienced malignant hyperthermia due to certain anesthesia drugs, exercising during excessive heat and humidity could trigger another reaction.
#2 Malignant hyperthermia: a review | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/s13023-015-0310-1
As many as 70 % of families susceptible to MH harbor one of 34 causal mutations for MH, with many other variants yet to be characterized. […] At least six genetic loci, other than RYR1 have been implicated in MH, although only one other gene, CACNA1S, encoding the main subunit of the DHPR, has been shown to be altered by an MH-linked variant. […] Recently, a variant in the STAC3 gene has been linked to MH susceptibility in a native American tribe in the USA. […] Genotype-phenotype correlations are weak for both the clinical expression of MH and the response of isolated muscle to caffeine or halothane. […] It therefore seems clear that a variety of modulators influence the manifestations of the syndrome. […] In summary, because of the heterogeneity of the disorder, as well as discordance within families, a negative DNA result cannot be used to rule out MH susceptibility.
#2 Understanding Malignant Hyperthermia
https://kumedib.staywellsolutionsonline.com/Library/Encyclopedia/3,90785
Malignant hyperthermia (MH) is a rare reaction to certain medicines used for general anesthesia. This problem runs in families (genetic). This means it’s passed down from parents to children. MH happens in people who have a gene that causes abnormal proteins in the muscles. Certain anesthesia medicines react with these proteins. This leads to sudden and severe symptoms. The problem can lead to the breakdown of muscle tissues if it’s not treated quickly. Your family members may also have the gene for MH. Even if they had surgery without problems in the past, they should not assume they couldn’t get MH in the future. […] All your close family members should tell their providers that they might be likely to get MH and consider getting tested.
#3 Malignant Hyperthermia – Temperature Regulation Disorders for Medicine
https://www.picmonic.com/pathways/medicine/courses/standard/multisystem-miscellanea-10630/temperature-regulation-disorders-39485/malignant-hyperthermia_50109
Malignant hyperthermia is inherited in an autosomal dominant manner; this means that one abnormal allele is enough for the individual to manifest the disease. However, it is important to note that the penetrance of this disorder is variable, hence not all individuals who inherit abnormal alleles will manifest the disease. […] Malignant hyperthermia patients have a genetic predisposition due to mutations in skeletal muscle ion channels. Ryanodine receptor 1, coded by the RYR1 gene, is a commonly affected calcium channel that controls calcium release from the sarcoplasmic reticulum. Mutations in this channel result in excessive calcium accumulation within muscle cells after exposure to anesthetics or succinylcholine. […] A common trigger for malignant hyperthermia is inhaled anesthetics given during surgery, such as halothane and isoflurane. Therefore, suspect malignant hyperthermia if a post-surgical patient develops the acute onset of autonomic symptoms and muscle rigidity. […] Succinylcholine is a depolarizing neuromuscular blocking agent often used during procedures to paralyze muscles and facilitate intubation. In myocytes with mutated calcium channels, however, succinylcholine will trigger excess calcium release and lead to malignant hyperthermia.
#3 Malignant hyperthermia: a review | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/s13023-015-0310-1
As many as 70 % of families susceptible to MH harbor one of 34 causal mutations for MH, with many other variants yet to be characterized. […] At least six genetic loci, other than RYR1 have been implicated in MH, although only one other gene, CACNA1S, encoding the main subunit of the DHPR, has been shown to be altered by an MH-linked variant. […] Recently, a variant in the STAC3 gene has been linked to MH susceptibility in a native American tribe in the USA. […] Genotype-phenotype correlations are weak for both the clinical expression of MH and the response of isolated muscle to caffeine or halothane. […] It therefore seems clear that a variety of modulators influence the manifestations of the syndrome. […] In summary, because of the heterogeneity of the disorder, as well as discordance within families, a negative DNA result cannot be used to rule out MH susceptibility.
#3 Malignant hyperthermia: causes & treatment
https://www.acls.net/malignant-hyperthermia
Malignant hyperthermia (MH) was first described by Denborough in 1962 when deaths were occurring during and immediately (within 24 hours) following the administration of anesthesia medications. The common denominator in these patients was sudden and critical increases in body temperature. […] Anesthesia agents trigger MH, and it is silent until it has already occurred. […] Half of the patients who have an MH crisis have had prior exposure to anesthesia agents known to trigger a crisis without any such reaction. […] The most common medications administered prior to an MH event include succinylcholine, sevoflurane, desflurane, isoflurane, and halothane. […] An uncontrolled increase in skeletal muscle metabolism is a characteristic of MH. […] If not recognized and treated, the mortality rate can be expected to be as high as 80%. […] Dantrolene, a skeletal muscle relaxant specifically developed for the treatment of MH, is the backbone of the treatment regimen.
#3 Malignant Hyperthermia May Develop in People with Heat or Exercise – MHAUS
https://www.mhaus.org/about/press-releases/malignant-hyperthermia-may-develop-in-people-with-heat-or-exercise/
There is mounting evidence that some people who are susceptible to Malignant hyperthermia (MH) will develop MH when exposed to hot environments or with exercise. […] Malignant hyperthermia is a potentially fatal, inherited disorder usually associated with the administration of certain general anesthetics. The disorder is due to an acceleration of metabolism in skeletal muscle. […] The underlying defect is abnormally increased levels of cell calcium in the skeletal muscle. […] MH is inherited genetic disorder found in an estimated 1 out of 2,000 people. MH is triggered by certain anesthesia and most often experienced in individuals undergoing routine surgery but in rare cases MH can happen without anesthesia.
#3 AnesthesiologyQR: A Quick Reference for medical students learning anesthesiology at University of Toronto
http://pie.med.utoronto.ca/anesthesiaqr/AnesthesiaQR_content/AnesthesiaQR_Pharmacology_Complications.html
Malignant hyperthermia (MH) is a hypermetabolic muscle disease that is usually triggered by exposure to volatile anaesthetic agents or succinylcholine. […] MH is caused by abnormal release of calcium from the sarcoplasmic reticulum in skeletal myocytes. […] MH involves a complex inheritance pattern involving numerous genes. One gene that likely plays a large role is the gene for the ryanodine receptor, which encodes the ion channels responsible for calcium release from the sarcoplasmic reticulum. […] Susceptibility to MH is also increased in some myopathies such as central core disease and King-Denborough syndrome.
#3 Malignant Hyperthermia – Injuries and Poisoning – Merck Manual Consumer Version
https://www.merckmanuals.com/home/injuries-and-poisoning/heat-disorders/malignant-hyperthermia
Genetic testing can also be done. However, because many gene abnormalities may be involved, genetic testing does not detect all (or even most) susceptible people and is not always available. […] Doctors try to prevent malignant hyperthermia in people who are high risk, which includes those with previous episodes of malignant hyperthermia, positive genetic markers, and family members who have had problems with anesthesia.
#3 Malignant hyperthermia | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-2-21
As many as 70% of families susceptible to MH harbor one of about 30 causal mutations for MH, with approximately 40 other mutations that are yet to be characterized. […] Although mutations in the ryanodine receptor are undoubtedly important in the pathophysiology of MH, it is also clear that not all families demonstrate linkage to this gene. At least six other genetic loci have been implicated in MH, including one that elaborates the sodium channel. […] The clinical expression of MH is also poorly understood. Genotype-phenotype correlations are weak for both the clinical expression of MH and the response of isolated muscle to caffeine or halothane. […] The identification of causative mutations suggests the widespread use of DNA testing for MH, however, this is confounded by the metabolic complexity and genetic heterogeneity of the disorder.
#3 Malignant hyperthermia: MedlinePlus GeneticsLock
https://medlineplus.gov/genetics/condition/malignant-hyperthermia/
Malignant hyperthermia is a severe reaction to particular anesthetic drugs that are often used during surgery and other invasive procedures. […] Certain variations of the RYR1 and CACNA1S genes increase the risk of developing malignant hyperthermia. Mutations in the RYR1 gene account for most cases of malignant hyperthermia susceptibility, while mutations in the CACNA1S gene cause less than 1 percent of all cases of malignant hyperthermia susceptibility. […] Mutations in the RYR1 or CACNA1S gene cause the RYR1 channel to open more easily and close more slowly in response to certain drugs. As a result, abnormally large amounts of calcium ions are released from storage within muscle cells. The abnormal increase in calcium ion concentration within muscle cells activates processes that generate heat (leading to increased body temperature) and produce excess acid (leading to acidosis). […] Up to half of people with malignant hyperthermia susceptibility do not have a mutation in one of the known genes. The causes of these cases are still under study.
#3 Treating Malignant Hyperthermia: What You Should Know
https://www.healthline.com/health/malignant-hyperthermia-treatment
Malignant hyperthermia is a condition thats often triggered by certain anesthesia drugs and can be life threatening. […] Malignant hyperthermia is typically triggered by drugs used as part of the anesthesia process during a surgical procedure. […] Dantrolene is a skeletal muscle relaxant that acts by directly interfering with the release of calcium. During a malignant hyperthermia reaction, its believed that triggering agents impact the skeletal muscle cells elevating myoplasmic calcium. Dantrolene is thought to prevent or reduce this calcium release. […] Malignant hyperthermia is a life threatening condition that needs to be treated immediately. If left untreated, it can lead to: cardiac arrest, brain damage, internal bleeding, failure of other body systems, including the kidneys and liver, muscle damage, seizures, coma. […] Regardless of age, once signs of malignant hyperthermia are identified, its important for the surgical team to stop use of the triggering drugs, administer dantrolene, and treat any complications or symptoms that malignant hyperthermia has brought on.